Some Toxic Chemicals as Potential Chemical Warfare Agents - The Threat for the Future?
J. Bajgar, Purkyne Military Medical Academy, Hradec Kralove, Czech Republic
The intent of this article is to comment on some trends in toxicology that make it possible for chemicals, which are not usually regarded as chemical warfare agents (CWAs), to be used as CWAs (1). Although the Chemical Weapons Convention (CWC) is very comprehensive, some of these chemicals are not likely to be included based solely on their toxicities. To this end, we describe some of the considerations in evaluating whether or not a country or group is developing or adapting a chemical for CW use.
Evaluation of Technology and Production.
For the development of new chemical weapons, many factors are necessary, e.g., a research base, including scientists, with a good instrumental basis, access to information, a developed chemical and arm industry, and, of course, funding to develop new chemical weapons. It is clear that this is possible not only for states, but also for terrorists.
In the beginning of a CW program, it can be difficult to distinguish between offensive or defensive research. Both types of research begin with the synthesis of a toxic chemical. G. Schrader originally synthesized organophosphates in a program dedicated to the development of new pesticides. The synthesis of V compounds, however was part of a program to develop new CWAs.
After synthesis, the next step is to characterize the chemical (toxicity, physicochemical properties, etc.) and possibly modify some of its militarily important properties (e.g., stability, volatility etc.). In the next step, the compound may be characterized in more detail, such as using more convenient species and routes of administration, etc. Even at this stage, it is practically impossible to decide if the research is offensive or defensive, although there may be some indications that the research is offensive, e.g., when a focus is percutaneous or inhalation efficacy.
All further steps in a weaponization program become increasingly obvious, but full evidence may still be ambiguous. For example, studies of methods of dispersion in field conditions may be part of an offensive program or they may be tests of protective means under real conditions. However, further steps, such as production in large quantities and weaponization, are clearly offensive. The remaining question is "How large are large quantities?" This can be solved following the approach used in the CWC. The quantities can also be compared with contamination densities prescribed for different CWA, such as those in Table 2. Of course for terrorist purposes, synthesis and small production scales are important and large quantities are not necessary.
The above evaluation works for chemicals, but with newer engineering and improvements in "delivery" or packaging technology, many of the militarily important properties can be improved. Some examples follow:
a. Microencapsulation for less stable or highly volatile substances.
b. Improved skin penetration such as with DMSO (O-isopropyl S-2-diisopropylaminoethyl methyl phosphonothiolate has an LD50 in rats of 59.1 µg/kg, but when mixed with DMSO, the LD50 is almost a factor of six lower [10.1 µg/kg]).
c. Although binary technologies are the most practical, syntheses requiring several steps can not be dismissed entirely. Alternate syntheses, even if more expensive or using different catalysts, can be useful. A search for compounds either used or synthesized can also be useful.
d. Toxic chemicals from other fields (not necessarily pesticides) can be used, if delivery is improved and if immediacy is not needed. If medicinal compounds are considered, there are highly toxic chemicals such as cardiac glycosides (digoxin), sympathomimetics (noradrenaline) and myorelaxans (succinylcholine, curare derivatives). Other possible compounds include insulin, cantharidin, aconitine,, gallamine, pancuronium, pipecuronium, some derivatives of D vitamins (cholecalciferol), some antibiotics, cytostatics, etc. Other possible candidates would be centrally acting alpha 2-adrenergics, with antihypertensive and sedative properties. Their use may be limited, e.g., injection of insulin or delayed acute effect of cytostatics. However, new vectors and new packaging and combinations may change the classic view of chemical warfare agents.
Possible toxic chemicals from other fields.
All these examples are more or less hypothetical and require further testing. There are some groups of compounds where the possibility of misusing is more probable and some of these chemicals are suspected (not proven) of being introduced into military arsenals. We present the following further illustrative, but not exhaustive, information.
Carbamates have a broad spectrum of toxicities - from relatively non toxic (Carbaryl) to highly toxic compounds comparable with nerve agents (T-1123) (Fig. 1). Other carbamates were described in detail by Badawi and Hassan (2). They are well absorbed by lungs, gastrointestinal tract and the skin. The clinical picture of poisoning is similar to that for nerve agents, perhaps with more expressed peripheral signs because of the presence of the quaternary nitrogen makes penetration through blood brain barrier difficult (3). The basic mechanism of action is reversible inhibition of cholinesterases. However, inhibition in case of carbamates is based on carbamylation of the active center of the acetylcholinesterase. Spontaneous decarbamylation occurs relatively quickly (ca 24 h) and carbamylated cholinesterases are resistant to effect of reactivators. Therefore the treatment is symptomatic only using preferably atropine. These difficulties in therapy can be a reason for military use.
Dioxins and dibenzofurans, of environmental risk notoriety, are some of the most toxic, low molecular compounds (Fig. 1) - e.g., the LD50 for oral administration of 3,6,7,8 TCDD in guinea pigs is 0.6 µg/kg. There are no specific antidotes. Dioxins have hepatotoxic, nephrotoxic, teratogenic, embryotoxic effects and causes symptoms known as porphyria cutanea tarda, which are characterized by increased synthesis of porphyrines. Treatment is very difficult and symptomatic only. The effects of even acute dioxin poisoning are delayed. (4).
Bicyclic phosphates were used as flame retardants, antioxidants, stabilizers or for spectroscopic studies. At present, they have been replaced (when possible) by other not so highly toxic compounds. When R- (see Fig. 1) is substituted by the isopropyl group, the toxicity is very near to sarin (LD50 = 0.18 mg/kg, i.m., rat). The time course of poisoning is quick, in minutes, following parenteral administration. Perturbations, muscle weakness, hyperactivity, muscle tremor, later convulsions passing to paralysis are observed. Intoxication is slightly similar to nerve agent poisoning, but with a different mechanism of action, very probably connected with GABA receptors. Specific antidotal therapy does not exist, but relatively good effects were observed following administration of benzodiazepines (4).
Perfluoroisobutylene (PFIB) is produced by thermal decomposition of Teflon. PFIB (Fig. 1) has a high inhalation toxicity. Pulmonary edema was observed in developed intoxication. The therapy is symptomatic. PFIB was characterized in more details in recent ASA Newsletter (5).
Organophosphates (OP) other than the classic nerve agents also have relatively high toxicities, such as amiton (TetramÂ), ArminÂ, dimefox (Hanane, TerrasytamÂ), paraoxon (E 600Â), TEPP (TetronÂ), etc. These compounds could be used for military and terrorist purposes. However, if a military used these to replace existing munitions filled with CWAs, the munitions would not be complete and would not be "full-value". However, new groups of OP compounds have been described and characterized. This class of OP can be described in general as 2-dialkylaminoalkyl-(dialkylamido)-fluorophosphates. These are structurally similar with the groups of G-compounds (i.e., sarin, soman, tabun) and V-compounds (i.e., VX and others). These chemicals were designated as GP or GV compounds (6,7).. The volatility of GV compounds is between VX and sarin and therefore these agents are effective when penetrating through uniforms.Toxicities for the most toxic derivative are shown in Table 3. Intoxication with this compound is practically the same as is observed for nerve agents. Treatment with reactivators and atropine is difficult because the complex formed with cholinesterase is irreversible(8).. The lack of reactivation is different from that observed for soman (aging, dealkylation) and may be caused by steric hindrance in the cavity of cholinesterase.
Toxins are prohibited by Biological and Toxins Weapons Convention (BTWC). A good review of toxins and their potential use as BW or bioterrorism weapons appeared in ASA 98-3 (9). Their isolation from natural sources is sometimes difficult but some toxins are possible to synthesize. Their toxicities can be very high, e.g., inhalation LD50 of botulinum toxin and tetanus toxin lies in tenth of mg.kg.m-3.
Aziridines are 2-(trisubstituted phenyl) ethyl aziridines and induce changes in behavior and motor functions based on their influencing of neurotransmission. Their toxicity is not so high and they have been used to model of some diseases. The effect is long lasting, mostly irreversible without specific antidotal treatment. Some of them, e.g., N-(3,5-dimethoxy-4-propoxy-phenylethyl )-aziridinium (Fig. 1) have convulsive properties. Convulsions are treatable with benzodiazepines (10, 11).
Tremorin is a relatively simple compound (Fig. 1) inducing in mice and monkeys symptoms similar to Parkinson‚s disease: Symptoms have a short delay, 15-30 min following administration, salivation, miosis, lacrimation, muscle weakness, bradycardia can be manifested. Typical symptoms are muscle twitch or fine tremor of the head and extremities, decrease in body temperature and analgesia. This stage is lasting more hours. Therapy is symptomatic only and not very effective (4)..
¤¤-Iminodipropionitrile (IDPN) (Fig. 1) isolated from Lathyrus sativus, also called "lathyrogenic substances". The toxicity of IDPN (and also of aziridines and tremorine) expressed as LD50 is not so high - it lies in the range of tens of mg/kg. Following administration of lower doses of IDPN, a so called "waltzing syndrome" is observed (circling movement in both ways, sometimes movement of the head similar to chorea, also a hyperkinetic syndrome). High doses of IDPN produce conjunctivitis, edema of eye lids, etc.. In severe cases, hemorrhages in retina, with possibility of blindness, occur. The hyperkinetic syndrome is irreversible and does not react to therapy(4).
Another possible threat is the modification of commonly used chemicals or biological agents to elicit a reaction similar to an allergic sensitization: the first administration is without any toxic effect and the second administration of the same (or other) compound causes damage.
Exploitation of the present genetic material of human population could be also misused. Some examples are given below:
Glucoso-6-phosphate dehydrogenase - enzyme catalyzed dehydrogenation of glucoso-6-phosphate to 6-phosphogluconate is genetically determined. In some people (more frequently black people or Scandinavians) its activity is decreased genetically. It is connected with the male chromosome and in these men, hyperbilirubinemia is observed. Following administration of some normal medicaments like acetylsalicylic acid, sulphamidine, chinine, chloramphenicol etc., a hemolytic syndrome is induced.
Individuals with chronic methemoglobinemia are more sensitive to drugs able to increase the level of methemoglobin, i.e., to analgesics, antipyretics, nitrates etc.
Plasma cholinesterase activity is also genetically determined and individuals with decreased cholinesterase activity are more sensitive to myorelaxants. It is very probable that these people will be more sensitive to nerve agents.
All these examples show that misuse of pharmacological and toxicological knowledge is possible. Our task is to be informed, to know the best protection and therapies, and, when necessary, to control activities connected with the synthesis and production of possible candidate chemicals and limit their availability to nonqualified people.
As it was mentioned before, these examples are not meant to be exhaustive. However, in all cases, the time is running and we will find what will be real in the future.
Table 1: Time periods from synthesis to production or use of toxic agents
Table 2: Contamination densities prescribed for different CWA [according to Robinson (12).]
Table 3: LD50 values of GV in mice and rats with various routes of administration
Figure 1: Chemical formulas of some toxic chemicals.