This paper was originally written by Dr. Hamilton, as a Defence Research Establishment Suffield (DRES) Special Publication. He has rewritten his excellent and timely publication to provide the ASA professional family both an alert and a tutorial to the world of toxins and what they are and what they are not.

Toxins: The Emerging Threat

by Murray G. Hamilton

(Prologue: Try to imagine your thoughts if you were to look at your morning paper and you read the following...)

Montreal, Canada (Canadian Press) - Officials today are at a loss to explain the attack yesterday that left eight dead and hundreds hospitalized after an apparent exposure to a biological warfare agent in the crowded Place de Congres in downtown Montreal.

"Nobody has come forward to claim responsibility," said a government spokesman. "The toxin was apparently disseminated through the ventilation system(cont. p. 20 - Toxins) (Toxins - from page 1) of the Place de Congres, a vast underground concourse in the heart of downtown Montreal. The casualties are suffering from what appears to be massive cardiovascular problems, but physicians are at a loss for an explanation because the causative organism has not yet been identified."

Cardiovascular problems include high blood pressure, heart attacks, strokes, aneurysms and other types of unexplained bleeding. Lack of treatment leads to death from a variety of causes related to disruption of the heart and vascular system. Treatment is symptomatic, consisting of reducing blood pressure and eliminating bleeding and cardiac arrhythmias, if present. However, until the bacteria or virus responsible is identified, no specific vaccine or antibiotic can be given.

Witnesses said the victims were situated near a ventilation shaft in this large underground concourse. The attack occurred at approximately 12:30 pm EST during the busy lunch hour period. The Place de Congres was particularly congested because many of the some 20,000 delegates attending the United Nations World Congress on Population Planning at the nearby Palais de Congres conference centre were having lunch in the concourse. Some victims said they noticed a faint smoke or fog about 15 to 30 minutes before they began to feel sick, but others do not remember anything noteworthy.

"We are expecting more deaths," said a hospital source. "We were lucky initially that the dose used was so low because it gave us time to get so many people to proper care. We do not have the facilities to provide round-the-clock intensive care for 600 to 1000 people at the same time, especially when a large number of them require specialized intensive care. It's tragic, but without a specific vaccine, all we can do is stabilize them and hope they come out of it themselves."

 

Toxins and Mid-Spectrum Agents

1 Introduction

The fictional news story printed above underscores the confusion in the contextual use of the word toxin. Although on the surface the story may appear to be internally consistent, the underlined words and phrases point out gaps in the understanding of the differences between biological warfare agents (BWAs) and chemical warfare agents (CWAs). If the same story, for example, had reported on the use of sarin, virtually everybody in the world would have understood that a CWA had been used. Furthermore, considerable expertise, both civilian and military, could be consulted and used to identify the agent, predict the spread and persistence of the agent, optimize medical treatment, and estimate the sophistication of the perpetrators (in terms of making the agent, storing and disseminating it, quantities used, etc.). Similarly, an attack using an organism such as plague (Yersinia pestis) or rabbit fever (Francisella tularensis) would also be recognized for what it was: the use of a BWA. Again, civilian and military physicians and researchers could bring a large armamentarium of knowledge and experience in handling diseases to bear on the problem.

Toxins, on the other hand, occupy a less well-defined area and are not recognized by most people. Saying chemical warfare to someone probably results in images of dead Kurds lying in the street and in their homes or the huge blisters on Iranian soldiers caused by sulphur mustard contact. Biological warfare probably conjures up images of dying from "the black plague" or acute respiratory anthrax. Toxin warfare or toxin warfare agent, however, probably generates a question: What? Most people do not have any images or examples that immediately come to mind. Perhaps some would remember that an umbrella was used to deliver a steel pellet laden with ricin into the thigh of a Bulgarian dissident. Others may associate toxins with environmental pollutants such as dioxins, PCBs, or Agent Orange. For most, however, the phrase "toxin attack" would draw a blank.

Why is there this anonymity to "toxin warfare agent" when toxins, such as botulinum toxin and the toxin described above, constitute some of the most exquisitely lethal poisons known? First, unlike both CWAs and BWAs, toxins have not been weaponized by very many countries. [There are reports that Iraq had weaponized botulinum toxin prior to the Gulf War (Taylor, 1996) and the United States had some toxin stockpiles that were manufactured essentially as "proof of concept" only.] Secondly, toxins have sometimes been referred to as mid-spectrum agents. This designation was intended to imply that toxins bridge the gap between BWAs and CWAs, in terms of toxicity (although toxicity estimates for biological agents are not an appropriate measurement), applicability and cost per casualty. Unfortunately, mid-spectrum occasionally has been used erroneously to suggest that toxins are "less toxic" biological agents. Thirdly, research and development (R&D) in the defence community was directed at the real and accepted threat of known chemical and biological capabilities of the Eastern bloc, and therefore there was little active research with toxins. In fact, after the early 1970s when President Nixon unilaterally canceled military research with toxins in the USA, almost no toxin defence R&D was conducted among the western countries. Similarly, academic research with toxins was not very robust primarily because of a lack of available toxin supply. Until recently, toxins had to be laboriously extracted from fermentation tanks or homogenates of organisms, venom or plants. Consequently, even if one could obtain sufficient quantitites of toxins to do research, it was very expensive.

Both defense oriented and academic toxin research was relatively dormant during the 1970s and early 1980s. But this does not explain the confusion that exists when the terms toxin or toxin weapons are used. Some think of toxins as being biological agents, some as being chemical agents and some as being a mixture of the two. By the end of this report, we hope the reader has a clear understanding of differences between CWAs and BWAs and where toxins or mid-spectrum agents fit in these classifications.

2. Threat Definition

Let us begin with a definition of toxin, and, then it will be easier to discuss the nature of the threat, toxins’ effects on militarily significant performance and defense and/or civilian R&D preparations to provide a rational response and readiness in the event of toxin use.

Definition: Toxins are nonreplicating agents of biological origin.

This definition places toxins in a category of their own, distinct from both the classical CWAs and BWAs, and, also perhaps, highlights the confusion in the use of the word. Toxins are chemicals (since they are "non-replicating"), but they are often confused with biological agents ("of biological origin"). They therefore share properties of both groups of warfare agents. However, in contrast to the biological agents, toxins are neither infectious nor contagious. And, they are not treatable with antibiotics or chemotherapeutic drugs. Also, at least to the present, there are few vaccines to protect against toxin exposures. Unlike chemical agents, they are generally not the products of a chemist's imagination or synthetic skills (although that distinction may be changing) nor are they byproducts of some other process (e.g., dioxins and some organofluorines). The general differences among these three categories of warfare agents can be summarized in Table 1. From this table, it is clear that toxins occupy a discrete classification, although with some properties of both CWAs and BWAs. Similar with CWAs, toxins do not reproduce and therefore the duration and area of contamination are more predictable than for BWAs. As with biological agents, most toxins are effective only after inhalation of appropriately sized particles and have a variable delay in onset of action that is substantially longer than the seconds to minutes effected by CWAs such as nerve agents or cyanide. Because toxins are large molecules, they are not as volatile as CWAs and may take longer to reach their target systems.

Are there characteristics of (potential) toxin weapons that make them more desirable than either CWAs or BWAs? Toxins are relatively expensive to produce, and, the reactants or manufacturing expertises are generally very sophisticated for most toxins. However, some of the toxins (e.g., botulinum toxin, sarafotoxin) are among the most toxic substances known (in some cases up to 100,000 times more toxic than nerve agents; see Table 2). Because of their high toxicities, although expensive initially and requiring at least a moderate technology base, the "cost per casualty" can be actually quite moderate. Further, unlike CWAs, for which sensitive and specific detectors are available, detectors for toxins have not yet been developed. The time to onset of symptoms for toxin poisoning is much more predictable than for BWAs, where time to onset can only be estimated. Other onset variables, such as safety to users (which is similar to that of binary nerve agents), stability in the atmosphere (which is better than BWAs), treatment, which is usually supportive, not specific, and therefore resource intensive, underscore the potential for a significant place for a toxin type chemical weapon in the arsenal of an aggressor. Further, the extreme toxicity, predictable time to onset of action, lack of specific detectors and treatment, safety for users and defined duration of hazard certainly recommend their use for covert military operation or by terrorist groups, in addition to the potential for full scale military use.

3. Toxin Categorization

There are hundreds of known toxins with associated toxicity data. The discipline of toxinology is one of the most active research areas in both academic and applied pharmacology. Toxins have evolved in animals, plants and microorganisms over many thousands of years to have specific and unique effects. Often toxins target specific receptors or enzymes; the same receptors and enzymes that are disrupted, out of control or nonfunctional in some disease states. Toxins, therefore, can be used as probes for diseased systems, as models for the synthesis of new drugs or, in their native form, as drugs or remedies themselves. Some examples of toxins that are in current use by the medical community include botulinum toxin [blepharospasm], endothelin derivatives [hypertension], curare [surgical muscle relaxant], cisplatin derivatives [cancer chemotherapy] and carido glycosides [congestive heart failure].

Which toxins are most likely to be encountered or "militarized?" Scores or hundreds of new toxins are being discovered each year and a table such as Table 2 is inadequate to describe all the toxins in the medical/research/agricultural domain. The rows in this table offer examples of this diversity in structure and origin for a limited sample of toxins. The much vaster array of (potential) toxin weapons is one cause for anxiety. However, this table also provides some useful ways to categorize toxins, which may be helpful in evaluating their potential as a mass casualty/covert or terrorist weapon.

3.1 Toxicities.

The columns in Table 2 offer some ideas on how toxins could be classified. (In the last row, Soman, a classical CWA, is listed for comparison.) One obvious category is toxicity, expressed as LD50 (or in the case of nonlethal incapacitants, the effective dose for 50% or ED50). Toxins span the entire range of toxicities from relatively nontoxic (domoic acid) to equitoxic with (continued on page 22) (continued from page 21) classical nerve agents (tetrodotoxin) to 10 to 100,000 times more toxic than nerve agents (botulinum toxin, maitotoxin). Based on toxicity alone, toxins offer a far greater assortment of agents than the classical nerve/lung/blister chemical agents. It is easy to identify, at least 100 toxins having 10 times the toxicity of VX, the most toxic (weaponized) nerve agent. However, considerations other than toxicity may also play a major role in assessing whether, or not, a toxin is a threat.

3.2 Sources.

The sources of toxins vary from snakes and insects to plants, fungi and microbes and the structures also represent a wide array from relatively simple to very complex. Highly toxic toxins may be difficult to synthesize or extract from their sources. For example, palytoxin is exquisitely potent: the LD50 is less than 0.15 g/kg in mice, but its polyether structure is so complex that easy chemical synthesis is not feasible and bulk extraction from the producing organism (Palythoa sp.) is not currently a viable option on militarily significant scales. In fact production of adequate concentrations of toxins has been the major determinant of the military significance of toxin weapons. It still represents one of the more important hurdles to the incorporation of toxins into weapons of mass destruction. Recent advances in areas as diverse as computer modelling, biotechnology and protein chemistry, along with those that can reasonably be expected in the near future, however may change the importance of production capability.

3.3 Mechanism of Action and Target System.

The vast array of known toxins renders discussion of individual toxin threats and peculiarities premature and probably impossible. As with CW agents, toxins act on many different systems and processes in the body. Perhaps a view from the alternative perspective would offer more insights: what are the consequences if critical systems (process, nucleus, receptor) are affected by a toxin? Examined from this angle, groups based on mechanism of action emerge from among the myriad of toxins. For example, there are toxins that target critical pores in nerve membranes, which allow the cell to communicate with, and adapt to, its external environment. These toxins are often found in the venom of carnivorous animals and are usually specific and very fast acting, e.g., the Ca2+ channel blocking conotoxins found in the venom of fish eating cone snails. Other toxins, such as the exotoxins, botulinum and tetanus toxins, elaborated by anaerobic bacteria act on specific parts of the nerves that control the release of the chemical messenger from nerve endings. The onsets of action from these toxins are typically slower than the channel blockers described above, but extremely potent. Yet other classes of toxins act on specific receptors and either overstimulate or block critical processes, e.g., breathing (curare, …-bungarotoxin) or blood pressure (endothelin). The onset of actions from these toxins is also rapid. There are also other toxins that inhibit certain biochemical processes or cause nonlethal performance-degrading effects (hallucinations, ataxia, vertigo, etc.). So, grouping toxins according to their mechanism of action often puts seemingly unrelated compounds together in the same category, but allows a diverse and extremely large set to be studied more easily.

The vast diversity of mechanisms of action and target systems for toxins makes it difficult to develop medical countermeasures. The treatment of most toxin poisoning consists of supportive measures to relieve symptoms.

3.4 Category/Structures.

Toxins include some extremely complex chemical structures, including peptides, polypeptides and proteins. As discussed above, structure is not sufficient to categorize the toxicity of the toxins. This diversity makes detection and subsequent identification very difficult. The best detector may turn out to be man and the most reliable identification may be based on analysis of signs and symptoms.

4. Hazard Assessment

In terms of detection, identification and most importantly medical or therapeutic countermeasures, toxins would present considerable problems if they were actually used in the military or terrorist sphere. Do toxins represent a significant threat? As an armamentarium of weapons right now, the answer is no. On the other hand, as the experience in Iraq has shown, some toxins (botulinum toxin for example) have indeed been produced and weaponized. Additionally, recent experiences in Japan, the U.S. and Europe show that relatively open societies are vulnerable to terrorist attacks not just from explosives but also from CBW agents that could easily include toxins. Toxin research is not prohibited under terms of the Biological Toxin Weapons Convention (BTCW) and there are many valid and important toxin research programs under way in all parts of the world. This valid interest in toxin research, by pharmaceutical and agricultural companies in particular, is spurring developments in parallel fields (modeling, targeting, gene transfer) that contribute to the feasibility of developing a toxin as a drug or a poison. Of course, if toxins are available for commercial use, they are available for other less admirable intentions. Given that the field of toxinology is vast and active then, the question is how can defense R&D select which toxins (or classes) to study?

4.1 Toxicity.

One seemingly obvious criterion is toxicity. Initial considerations suggest defense R&D concentrate on those toxins whose lethal dose is at least 10 times less than that of VX. The term toxicity should be interpreted with caution and certainly should include agents that are nonlethal, but militarily incapacitating. Such toxins might include SEB (a nausea producing agent), frog skin toxins (both lethal, batrachotoxin and hallucinogenic, the "hunting magic" of Amazon Indians (Daly, 1995)), mycotoxins which are both contact and systemic irritants and cholera toxin, a diarrhea producing agent. However, the potency of these toxins could still be a determining factor in judging whether they pose a significant threat.

4.2 Technology.

Rapidly advancing technology has been having a major impact on both the perception and the fact of toxin threat. This technology incorporates not just biotechnology, with recombinant DNA, plasmid transfers, designer bacterial synthesis, etc., but also advances in mainstream technology, such as solid phase peptide synthesis and computer science. The molecular and structural complexity of toxins has contributed to their relative obscurity and the perceived lack of a menace. As complexity is reduced by technology’s rapid advances, the ability of many countries to afford and build designer toxins has increased. The technologies most important to the availability of toxins are fermentation, peptide synthesis, delivery and penetration, and computer science.

4.2.1 Fermentation: This is still the same "low tech" method that can be and is being used to produce weaponizable quantities of easily obtained bacterial toxins, e.g., cholera, botulinum and SEB. New simple and commonplace gene splicing techniques can be used to force bacteria or yeast (prokaryotes) to grow toxins that are normally only produced in eukaryotes, which is in animal and plant cells. Although the toxin backbone can be easily produced, many toxins undergo significant post-translational modification that confers special properties (potency, specificity, etc.) to the toxin and prokaryotic organisms normally do not have the correct "machinery" to provide this step. Thus the toxins produced in this manner may lack several unique qualities of the native toxin but nevertheless may still be a useful weapon.

4.2.2 Peptide Synthesis: Peptide synthesis is now an automated technique and custom synthesis of many complex polypeptides is increasingly affordable. Recently, a peptide with a length of more than 100 peptide bonds was synthesized, using solid phase synthetic techniques. Other techniques, such as "combinatorial libraries" (an automated method of producing random analogues of peptides or nucleotides based on a parent structure) are commercially available. An increasing number of pharmaceutical companies are using these methods to discover, synthesize and develop new drugs. Thus, previously difficult to obtain peptide or protein toxins are rapidly becoming relatively commonplace and easily affordable to obtain.

4.2.3 Delivery and Penetration: Many very potent and lethal toxins have evolved to reach the site of action by ingestion (botulinum or cholera toxin) or, in the case of predation or self-defense, by injection (envenomation, as in crotoxin and sarafotoxin from snakes). In order to be an effective weapon, toxins must be delivered in a form that can cause the desired effect. As mentioned earlier, with the exception of certain mycotoxins, toxins are not normally active cutaneously. The agent, therefore would have to gain access to the body through one of the other three routes: inhalation, ingestion, or through mucous membranes of the eyes. Production of particles of optimal size for deep lung penetration is now routinely and economically achievable so that delivery of toxins in this manner is not a problem. The oral route of entry may be very important for food or water contamination (vide infra), but the ocular route is not as likely for a toxin weapon.

If a toxin exists that is stable in the atmosphere, the technology to deliver respirable particles easily, economically and reproducibly, already exists. It is important to note here that the technology exists not only for large-scale dissemination, for example many square kilometers, but also in miniaturized form that could find application in the fictional news story that opened this article. Further, the technology, which is primarily agricultural, is neither restricted nor monitored.

Naturally, toxins were not intended to be inhaled. But given the ease of incorporation into respirable particles, can an absorbed toxin reach its target, for instance the central nervous system? In many cases, tetanus toxin is one example, there exists an active transport for the toxin to its central site of action. For others the barriers massed by the body, not the least of which is the lung/blood barrier, are quite formidable. Here again, there are instances whereby biotechnology and other technological advances have provided interesting potential and actual solutions. For example, American Cyanamid has submitted proposals to the U.S. Environmental Protection Agency to field test a viral/toxin combination that kills beet armyworm. [3. Adler] A lethal scorpion toxin is inserted into a baculovirus, a virus that specifically infects larval stages of lepidoptera. The expression of the scorpion toxin after infection of the lepidopteran hosts, the beet armyworm, increases the toxicity and halves the onset time of action by factors of two to three. In fact the larvae die with the convulsions and paralysis induced by the toxin. Interestingly, the specificity of this insect control is at two levels: the virus only infects lepidoptera and the scorpion toxin elaborated by the introduced gene only kills insects.

It does not require a great leap of imagination to think of a vector that will infect susceptible organisms or people. Let us think, for example, of a new flu virus strain: "Hong Kong X3A." This virus could be delivered to a naive population. Once inside people, the virus would express a toxin protein, say botulinum toxin, within a specified time period. Vaccine protection against the virus would be provided for the users, so safety would be essentially complete. The toxin produced after infection could be lethal, as with botulinum toxin, or debilitating. Such a scenario has not been accomplished in the field of CBW agents, but if it is being done and commercialized in agriculture, certainly the technology is available, the methods proven and the training/education accessible.

This begs the question: Would a harmless viral or bacterial vector, containing a toxin producing gene, but no toxin, contravene the Chemical Weapons Convention (CWC) or the Biological and Toxin Weapon Convention (BTWC)? This speculative example combines both biological (viral vector) and chemical (toxin) warfare agents, but in ways that may not have been considered in treaty negotiations. In addition to the described example of baculovirus and toxin, there are also proven technologies, such as encapsulation of toxins in liposomes or oligomeric liposomes with known biological dwell times. These encapsulation technologies are feasible, inexpensive, reproducible and generally available. There is also the possibility of so-called "eco-terrorism." "Flavor saver" tomatoes represent a class of food that has been genetically altered. Similar alterations are equally possible with other staple foods, for instance wheat or rice.

In addition to the high tech method of genetic insertion of toxin producing genes, there are other more mundane possibilities. As recently as the 1950’s there was an outbreak of St. Anthony’s fire or ergotism in Europe, mycotoxicosis caused by eating rye flour infected with the ergot producing fungus. In Canada, there was a mini outbreak of ciguatera poisoning caused by eating ciguatoxin-containing swordfish. And there are the relatively common instances of saxitoxin, or paralytic shellfish poisoning, from the west coast of North America. It would be relatively easy to contaminate a food source, such as flour, shellfish or vegetables with toxins. Further, the toxin could be exotic and unexpected, as in the case of ciguatoxin in North America, or out of place, for example, saxitoxin contamination of cultured shellfish.

4.2.4 Computer Science: Without doubt, computer science is the field of research that is going to have a very significant impact on toxins and mid-spectrum agents as CBW threats. The major drawback to new or exotic toxins weapons is the toxin’s availability. However, if the bulk of the research required to verify or develop "proof of concept" quantities of some particularly toxic or desirable or novel toxin could be carried out without actually ever producing the toxin or conducting laboratory experiments, the caveats mentioned above would disappear. Further, if the costs of conducting this "theoretical" research were exceptionally modest, the advantages of having and stockpiling toxin agents mentioned in Table 2, not the least of which are non-detectability, identification and compliance with the CBW treaty, become enormous.

This type of speculation is no longer fantasy. Faced with increasing costs of laboratory research, many pharmaceutical companies now routinely use what is called "structure based" drug design. [4. Kuntz] With this approach, the target structure (e.g., a receptor or an enzyme) is known and likely stored along with thousands of others in the Protein Data Bank. A so-called "docking program" then screens a database of compounds and finds those that have good geometrical and chemical complementarity for the target. Computers solve these molecular jig saw puzzles and provide a list of about 100 compounds (from a starting list of >100,000) for further investigation. Using computer graphics, several of these "hits" (rather than hundreds) are then selected for classical laboratory investigation. This type of approach has led to several "new" drugs (anti-AIDS, antimalarials) that are currently in clinical trials. [2. Moore]

An alternative method uses computers to design new molecules to fit directly into the target site. With this approach completely novel "scaffolds" can be developed. For example, non-peptide based chemicals have been developed that mimic the action of a very potent bioregulator, angiotensin II, and which are now in clinical trials. Computer programs capable of designing de novo compounds for specific targets include GROW, GrowMol and Legend. It is important to remember that these programs, which actually design hitherto unknown or unsynthesized chemicals, are easily and commercially available and run on rather modest computer systems. Alternative software, including BUILDER, LUDI and FOUNDATION/SPLICE take preformed fragments and link them together, again with a specific target in mind. Nor are the targets difficult to obtain: several thousand are stored in the Protein Data Bank. Advances in this field are moving rapidly. Already libraries of peptides and peptoids are being planned from which "biased" databases can be built and expanded to ensure the maximum diversity and number of possible structures. There are many databases and modeling software packages available through the Internet, and a number of commercial sources of design and synthesis software packages that use the power and low price of the modern PC computer platforms. It is apparent that a significant program of new threat (toxin or mid-spectrum) agent development could be undertaken with a very modest outlay of resources (something along the lines of "virtual" CW development.) Furthermore, the research, for the most part, could be done anywhere by a very small team with validation needed only in the final stages.

5. Discussion and Recommendations

What are the implications of the foregoing discussion for CBW research and development? First, even with unlimited resources, defense R&D will not be able to investigate every potential toxin threat, let alone those that may develop because of targeted synthesis and molecular modeling software. Evaluations using defining categories, such as toxicity, can be used to reduce the potential number of emerging toxin/mid-spectrum threats to hundreds of compounds. Risk analyses using information, such as that in Table 3, can suggest some ways to

quantitate the potential risk and recommend which toxins should be of interest to the CBW R&D community. Other possible actions are listed below.

5.1 The Generic Approach.

In this concept, critical physiological systems are studied with respect to function. This includes studying the effects of activators and blockers on the systems controlled by the channels and ways to restore function or prevent dysfunction in the event of poisoning. The purpose of this type of research is to use the signs of poisoning of a physiological system to direct the therapeutic response. Subsequent attempts at detection and identification may be assisted as classes of toxins can be excluded based on the known pharmacology of toxins. In recent years, research in three important channels in nerve membranes, which are very common targets of quite potent toxins, has been undertaken in Canada, and in several other countries. Much active defense R&D toxin research is aimed at defining the role of cation channels in excitable cells, such as neurons, heart and muscle cells. Cooperation among various countries has expanded the knowledge base among all partners that allows a rational attempt at reasonable therapeutic measures, even if the identity of the specific toxin is not known.

5.2 Education.

Both defense and civilian medical personnel will be requested to provide essential services to emergency response organizations. These health care workers, physicians, nurses and medics will require training in fields relevant to the CBW. This should include not only areas as tropical medicine, but also CW, BW and mid-spectrum/toxin poisoning. Emphasis should be on classes of agents and the drugs currently approved for use (rather than new or experimental drugs) that may be useful in treatment until positive identification is made and a specific “antidote” is available. It is important to remember that, increasingly, civilian populations are at risk, whether through terrorist attacks or specifically targeted. Military medical personnel, particularly CBW trained, will be expected to provide, if not actual primary care, then at least advice.

5.3 Collaboration.

The continued and rapid evolution of computer aided drug design should be a major interest of CBW R&D. The academic community and the pharmaceutical industry are devoting large amounts of resources to this new area of research. Along with the opportunity to tailor-make new drugs more quickly and cheaply, the opportunity exists to use the same, freely available technology for more nefarious motives. Collaborative programs with industry, academia and other countries, should be entertained to provide CB defense R&D with the expertise and information required to evaluate the adaptability of these technologies to mid-spectrum agents. This type of collaborative program in computer modeling could also provide significant benefits in terms of other unresolved problems in CW, e.g., in designing or modeling therapeutic modalities for agents such as phosgene, mustard and potentially other medical or health related questions unique to the CBW community.

5.4 Detection and Identification

A final area that requires significant effort is that of detection and identification. Treatment strategies and often specific drug indications are greatly simplified when the nature of the chemical insult is known. Until then, treatment is supportive and reactionary. Once the identity of the toxin is known, physicians and other medical personnel can plan treatments based on recognized pharmacological profiles of therapeutic compounds. The use of nanotechnology in the development of diagnostic capabilities, literally on a glass microscope slide, will of course provide medical professionals with the timely information needed to effectively treat outbreaks of toxicoses from any source.

The news from Montreal, after some education in toxins and CBW:

Montreal, Canada (Canadian Press) - Police say that they still have no idea who planted the device that delivered a deadly fog during an international meeting taking place in this Canadian city two days ago. Twelve deaths have been reported following the surprise attack by terrorists during the busy lunch hour period at the Palais de Congres in this eastern Canadian city. “The deaths were caused by cardiovascular collapse, which is similar to a heart attack,” says a hospital official. “We were very worried that many more casualties would succumb until we identified the toxic component of the fog and were able to administer a specific drug to counteract the substance's effects.”

The toxic material was identified by a special team from the Department of National Defence. Based on the signs of poisoning, the DND experts were able to identify the toxin contained in the fog using sophisticated immunological methods. After the compound had been identified, the DND team was able to advise the use of a specific drug to counteract the toxin's effects. “The poison used was a chemical derived from the venom of a snake” said a senior DND official. “It is related to a compound produced by our own bodies, which is why it is so potent and specific.”

“Our research had previously shown that moderate exposures to this particular class of poisons could be treated with a commonly available blood pressure medicine. More severe cases require a very specific antidote, which is available only in limited quantities. Luckily, there were very few severely poisoned people, who probably were sitting quite close to the ventilation shaft where the toxin cloud was released.”

Police are continuing their investigation but they wish to remind people that there is no danger of infection or spreading the disease. “This was not an attack with viruses or bacteria, so it is not infectious,” says the DND spokesman. “This was a chemical attack with a bioengineered, very potent toxin, but it behaves exactly like a poisonous chemical and will not cause any new or exotic disease.”

References

1. Taylor, T. Iraq's biological weapons program. CBIAC 2(2), 1996.

2. Moore, G.J. Designing peptide mimetics. Trends in Pharmacological Sciences 15: 124-129 (1994)

3. Adler, T. Researchers engineer insect-killing viruses. Science News 146:154-155 (1994)

4. Kuntz, I.D. and Roe, D.C. What is structure based drug design? Pharmaceutical News 2: 13-15 (1995).

5. Daly, J.W. The chemistry of poisons in amphibian skin. Proc. Nat'l. Acad. Sci USA. 92: 9-18 (1995).