An Evaluation of Bioregulators as Terrorism and Warfare Agents

*Slavko Bokan, **John G. Breen, *Zvonko Orehovec
*MOD, Croatian Military Academy, Laboratory for NBC Protection, Ilica 256 b, HR-10000 Zagreb, Croatia
** Geneva, Switzerland

Introduction
          Within neuroscience over the last twenty years there has been an explosion of knowledge about the receptor systems on nerve cells that are of critical importance in receiving the chemical transmitter substances released by other nerve cells. Bioregulators or modulators are biochemical compounds, such as peptides, that occur naturally in organisms. They are a potential new class of weapons that can damage the nervous system, alter moods, trigger psychological changes and even kill. These compounds can act as neurotransmitters and modify neural response. Bioregulators are closely related to substances normally found in the body that regulate normal biological processes. Their potential military or terrorism use is similar to that of toxins. Some examples of potential application of bioregulators are to cause pain, as an anesthetic and to influence blood pressure.
          Together with increased research into toxins, the bioregulators have also been studied and synthesized. These substances can also be modified synthetically, whereupon they may obtain new properties. It is feasible to produce some of these compounds by chemical synthesis. It is apparent that the past decade has brought an enormous increase in knowledge about the pharmacology and structural biology of receptors.
          In the last ten years considerable advances have taken place in this in vitro synthesis of peptides, and, already commercial production in large quantities of various pharmaceutical peptides are freely available. Synthetic derivates or slightly modified forms of these compounds can have drastically altered toxic effects and these could be important in the development of new agents. Advances in discovery of novel bioregulators, especially bioregulators for incapacitation, understanding of their mode of operation and synthetic routes for manufacture have been very rapid in recent time. Some of these compounds may be potent enough to be many hundreds of times more effective than the traditional chemical warfare agents. Some very important characteristics of new bioregulators that would offer significant military advantages are novel sites of toxic action; rapid and specific effects; penetration of protective filters and equipment and militarily effective physical incapacitation.
          Peptide bioregulators are interesting regulatory molecules for many reasons. Their range of activity covers the entire living system, from mental processes (e.g. endorphins) to many aspects of health such as mood control, consciousness, temperature control, sleep, or emotions, exerting regulatory effects on the body.
          This paper presents an evaluation of bioregulators according to criteria, which are used for evaluation of toxin warfare agents, and describes the main human bioregulators or modulators that can be used as terrorism delivery system or biological agents in hostile activities. Materials and Methods
          As the list of bioregulators will be hard to define, we propose two tables of bioregulators, with important criteria to enable decision to include these compounds from a list of bioregulators with potential as terrorism or biological warfare agents.
          It is very hard to find in available literature all the data for all bioregulators, especially for the criterion: Agents known to have been developed, produced, stockpiled or used as weapons (in the tables - Weaponized). Therefore, we can not be 100% sure that data for this criterion are correct.
          Many biological agents, in this case bioregulators, have the capacity to cause disease and potentially be used to threaten civilian populations. From a public health standpoint, however, bioregulators which are less known, must be evaluated and prioritized in order to assure appropriate allocation of the limited funding and resources that are often found within public health systems.
          Potential terrorism bioregulators with an expected mortality of >50% were rated higher (+++) than agents with lower expected mortalities (21-49% = ++, and <21% = +).
          Bioregulators are rated higher (++) for morbidity if clinical disease requires hospitalization for treatment (including supportive care), and with lower rating (+) if outpatient treatment is possible for most cases.
          We evaluated expected mortality in the same way as toxins: LD₅₀ >50% were rated higher (+++) than agents with lower expected mortalities (21-49% = ++, and <21% = +).
          Agents received (+) to (+++) for dissemination potential based on their environmental stability after release (+), their ease of production in large quantities (+) and distributed (+) as a agent in quantities that could effect large populations. High level of intoxication by a variety of routes - we rated according of the kind of exposure: per oral route (+), respiratory route (++), or both (+++).
          Bioregulators also were ranked based on any special public health preparedness that might be required including: stockpiling of therapeutics (+), enhanced surveillance and education (+), improved laboratory diagnostics (+).
          Public fear associated with an agent and the potential mass civil disruptions that may be associated with even a few cases of disease were also considered (+ to +++).

Criteria for Selection of Bioregulators as Terrorism Agents

1. High level of morbidity: higher rating (++) if clinical disease requires hospitalization for treatment including supportive care and lower rating (+) if outpatient treatment is possible for most cases.
2. High level of mortality or incapacity: agents with an expected mortality of =50% were rated higher (+++), and with lower expected mortalities (21-49%=++, and <21%=+).
3. Stability in the environment after release (+)
4. Ease of production and transportation (+)
5. High level of dissemination and contamination in quantities that could effect large populations especially by aerosol (+) .
6. High toxicity or potency or low toxic dose: LD₅₀ <0.000025 mg/kg (+++), LD₅₀ from 0.000025 to 0.0025 mg/kg (++) and LD₅₀ >0.0025 mg/kg (+).
7. High level of intoxication by variety route: per oral route (+), respiratory route (++), or both (+++).
8. Stockpiling of prophylactics and antidotal therapy (+)
9. Enhanced surveillance and education (+)
10. Difficult to diagnose or identify at the early stage or improved laboratory diagnostics (+).
11. Public perception: Public fear associated with an agent and the potential mass civil disruptions that may be associated with even a few cases of disease were also considered (+ to +++).

Criteria for Selection of Bioregulators as Warfare Agents

1. Agents known to have been developed, produced, stockpiled or used as weapons (+).
2. Likely methods and high level of dissemination or contamination a large area: by aerosol (+++) and sabotage (food and water supply) (++).
3. High toxicity or potency or low toxic dose: LD₅₀ <0,000025 mg/kg (+++), LD₅₀ from 0,000025 do 0,0025 mg/kg (++) and LD₅₀ >0,0025 mg/kg (+).
4. High level of morbidity: higher rating (++) if clinical disease requires hospitalization for treatment including supportive care and lower rating (+) if outpatient treatment is possible for most cases.
5. High level of intoxication by variety route: per oral route (+), respiratory route (++), or both (+++).
6. High level of mortality or incapacity: agents with an expected mortality of =50% were rated higher (+++), and with lower expected mortalities (21-49%=++, and <21%=+).
7. No effective prophylaxis and therapy commonly available and widely in use (+). (cont. p. 18 - Bioregulators) (Bioregulators - from p. 17)
8. Stability in the environment (+).
9. Difficulty to diagnose/detect or identify at early stage (+).
10. Ease of production and transportation (+).

Results and Discussion
          Our opinion is that if some bioregulator satisfies the bulk of the criteria, it should be recommended for inclusion in the list. Rankings of potential bioregulators according to important criteria are shown in:
          Table 1. Bioregulator assessment according to criteria for selecting bioregulators as warfare agents, and
          Table 2. Bioregulator assessment according to criteria for selecting bioregulators as terrorism agents.

Conclusion
          It is very hard to make a final decision on criteria and the final list of the molecular agents (bioregulators) as terrorism and warfare agents. We propose that the list and criteria for bioregulators be well studied and that opinions by scientists and experts be obtained. The list should be scientifically based. Although many bioregulators can be used to cause illness, they can truly threaten civilian populations on a large scale. If released upon a civilian population, these agents would pose a significant challenge for public health and medical responses.

Tables and Figures

          Table 1. Bioregulator assessment according to criteria for selecting bioregulators as warfare agents.

          Table 2. Bioregulator assessment according to criteria for selecting bioregulators as terrorism agents.

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Editor's Note: This paper describes criteria Dr. Bokan has used before in evaluating potential terrorism and biological weapon agents. See ASA 01-2.