Emerging Infectious Diseases
[Volume 5 No.4 / July - August 1999]

Special Issue

Potential Biological Weapons Threats

Mark G. Kortepeter and Gerald W. Parker
U.S. Army Medical Research Institute of Infectious Diseases, Fort
Detrick, Maryland, USA

The list of agents that could pose the greatest public health risk in
the event of a bioterrorist attack is short. However, although short,
the list includes agents that, if acquired and properly disseminated,
could cause a difficult public health challenge in terms of our ability
to limit the numbers of casualties and control the damage to our
cities and nation.

The use of biological weapons has occurred sporadically for
centuries, culminating in sophisticated research and testing
programs run by several countries. Biological weapons proliferation
is a serious problem that is increasing the probability of a serious
bioterrorism incident. The accidental release of anthrax from a
military testing facility in the former Soviet Union in 1979 and
Iraq's admission in 1995 to having quantities of anthrax, botulinum
toxin, and aflatoxin ready to use as weapons have clearly shown
that research in the offensive use of biological agents continued,
despite the 1972 Biological Weapons Convention (1,2). Of the
seven countries listed by the U.S. Department of State as
sponsoring international terrorism (3), at least five are suspected to
have biological warfare programs. There is no evidence at this time,
however, that any state has provided biological weapons expertise
to a terrorist organization (4).

A wide range of groups or individuals might use biological agents
as instruments of terror. At the most dangerous end of the spectrum
are large organizations that are well-funded and possibly
state-supported. They would be expected to cause the greatest
harm, because of their access to scientific expertise, biological
agents, and most importantly, dissemination technology, including
the capability to produce refined dry agent, deliverable in milled
particles of the proper size for aerosol dissemination. The Aum
Shinrikyo in Japan is an example of a well-financed organization
that was attempting to develop biological weapons capability.
However, they were not successful in their multiple attempts to
release anthrax and botulinum toxin (4). On this end of the
spectrum, the list of biological agents available to cause mass
casualties is small and would probably include one of the classic
biological agents. The probability of occurrence is low; however,
the consequences of a possible successful attack are serious.

Smaller, less sophisticated organizations may or may not have the
intent to kill but may use biological pathogens to further their
specific goals. The Rajhneeshees, who attempted to influence local
elections in The Dalles, Oregon, by contaminating salad bars with
Salmonella Typhimurium, are an example (5). Rather than having a
sophisticated research program, these organizations could use
biological pathogens that are readily available.

The third type are smaller groups or individuals who may have very
limited targets (e.g., individuals or buildings) and are using
biological pathogens in murder plots or to threaten havoc. The
recent anthrax hoaxes are examples of this. Many biological agents
could be used in such instances and the likelihood of their
occurrence is high, but the public health consequences are low.

There are many potential human biological pathogens. A North
Atlantic Treaty Organization handbook dealing with biological
warfare defense lists 39 agents, including bacteria, viruses,
rickettsiae, and toxins, that could be used as biological weapons
(6). Examining the relationship between aerosol infectivity and
toxicity versus quantity of agent illustrates the requirements for
producing equivalent effects and narrows the spectrum of possible
agents that could be used to cause large numbers of casualities. For
example, the amount of agent needed to cover a 100-km2 area and
cause 50% lethality is 8 metric tons for even a "highly toxic" toxin
such as ricin versus only kilogram quantities of anthrax needed to
achieve the same coverage. Thus, deploying an agent such as ricin
over a wide area, although possible, becomes impractical from a
logistics standpoint, even for a well-funded organization (7). The
potential impact on a city can be estimated by looking at the
effectiveness of an aerosol in producing downwind casualties. The
World Health Organization in 1970 modeled the results of a
hypothetical dissemination of 50 kg of agent along a 2-km line
upwind of a large population center. Anthrax and tularemia are
predicted to cause the highest number of dead and incapacitated, as
well as the greatest downwind spread (8).

For further indication of which pathogens make effective biological
weapons, one could look at the agents studied by the United States
when it had an offensive biological weapons research program.
Under that program, which was discontinued in 1969, the United
States produced the following to fill munitions: Bacillus anthracis,
botulinum toxin, Francisella tularensis, Brucella suis, Venezuelan
equine encephalitis virus, staphylococcal enterotoxin B, and
Coxiella burnetti (9). As a further indication of which pathogens
have the requisite physical characteristics to make good biological
weapons, one need only look next at the agents that former Soviet
Union biological weapons experts considered likely candidates. The
agents included smallpox, plague, anthrax, botulinum toxin, equine
encephalitis viruses, tularemia, Q fever, Marburg, melioidosis, and
typhus (10,11). Criteria such as infectivity and toxicity,
environmental stability, ease of large-scale production, and disease
severity were used in determining which agents had a high
probability of use. Both the United States before 1969 and the
former Soviet Union spent years determining which pathogens had
strategic and tactical capability.

The National Defense University recently compiled a study of more
than 100 confirmed incidents of illicit use of biological agents
during this century (W.S. Carus, pers. comm. [4]). Of the 100
incidents, 29 involved agent acquisition, and of the 29, 19 involved
the actual nongovernmental use of an agent, and most were used
for biocrimes, rather than for bioterrorism. In the context of this
study, the distinguishing feature of bioterrorism is that it involves
the use of "violence on behalf of a political, religious, ecologic, or
other ideologic cause without reference to the moral or political
justice of the cause." The balance of incidents involved an
expressed interest, threat of use, or an attempt to acquire an agent.
In the 1990s, incidents increased markedly, but most have been
hoaxes. The pathogens involved present a wide spectrum, from
those with little ability to cause disease or disability, such as Ascaris
suum, to some of the familiar agents deemed most deadly, such as
B. anthracis, ricin, plague, and botulinum toxins (Table). During
this period, the number of known deaths is only 10, while the total
number of casualties is 990. However, the numbers should not give
a false sense of security that mass lethality is not achievable by a
determined terrorist group. The sharp increase in biological threats,
hoaxes, information, and Internet sources on this subject seen in
recent years indicates a growing interest in the possible use of
biological pathogens for nefarious means (4).

In general, the existing public health systems should be able to
handle most attempts to release biological pathogens. A working
group organized by the Johns Hopkins Center for Civilian
Biodefense Studies recently looked at potential biological agents to
decide which present the greatest risk for a maximum credible event
from a public health perspective. A maximum credible event would
be one that could cause large loss of life, in addition to disruption,
panic, and overwhelming of the civilian health-care resources (12).

To be used for a maximum credible event, an agent must have some
of the following properties: the agent should be highly lethal and
easily produced in large quantities. Given that the aerosol route is
the most likely for a large-scale attack, stability in aerosol and
capability to be dispersed (17m to 5 m particle size) are
necessary. Additional attributes that make an agent even more
dangerous include being communicable from person to person and
having no treatment or vaccine.

When the potential agents are reviewed for these characteristics,
anthrax and smallpox are the two with greatest potential for mass
casualties and civil disruption. 1) Both are highly lethal: the death
rate for anthrax if untreated before onset of serious symptoms
exceeds 80%; 30% of unvaccinated patients infected with variola
major could die. 2) Both are stable for transmission in aerosol and
capable of large-scale production. Anthrax spores have been known
to survive for decades under the right conditions (13). WHO was
concerned that smallpox might be freeze-dried to retain virulence
for prolonged periods (8). 3) Both have been developed as agents
in state programs. Iraq has produced anthrax for use in Scud
missiles and conducted research on camelpox virus, which is closely
related to smallpox (2). A Soviet defector has reported that the
former Soviet Union produced smallpox virus by the ton (11). 4)
Use of either agent would have a devastating psychological effect
on the target population, potentially causing widespread panic. This
is in part due to the agents' well-demonstrated historical potential to
cause large disease outbreaks (14). 5) Initial recognition of both
diseases is likely to be delayed. For anthrax, this is secondary to the
rare occurrence of inhalation anthrax. Only 11 cases of inhalation
anthrax have been reported in the United States from 1945 to 1994
(15), and recognition may be delayed until after antibiotic use
would be beneficial. For smallpox, given that few U.S. physicians
have any clinical experience with the disease, many could confuse it
for more common diseases (e.g., varicella and bullous erythema
multiforme) early on, allowing for second-generation spread
(12,16). 6) Availability of vaccines for either disease is limited.
Anthrax vaccine, licensed in 1970, has been used for persons at
high risk for contact with this disease. The U.S. military has
recently begun vaccinating the entire force; however, there is
limited availability of the vaccine for use in the civilian population.
Routine smallpox vaccination was discontinued in the United States
in 1971. Recent estimates of the current number of doses in storage
at CDC range from 5 to 7 million (12), but the viability of stored
vaccine is no longer guaranteed.

Table.  Biological agents involved in bioterrorism or biocrimes(sup a)

---------------------------------------------------------------------
                Traditional                Agents associated
                biological                 with biocrimes
                warfare agents             and bioterrorism
---------------------------------------------------------------------
Pathogens       Bacillus anthracis(sup b)  Ascaris suum
                Brucella suis              Bacillus anthracis(sup b)                                 
                Coxiella burnetii(sup b)   Coxiella burnetii(sup b)
                Francisella tularensis     Giardia lamblia
                Smallpox                   HIV
                Viral encephalitides       Rickettsia prowazekii
                Viral hemorrhagic fevers   (typhus)
                  (sup b)
                Yersinia pestis(sup b)     Salmonella Typhimurium
                                           Salmonella typhi
                                           Shigella species
                                           Schistosoma species
                                           Vibrio cholerae
                                           Viral hemorrhagic
                                             fevers (Ebola)b
                                           Yellow fever virus
                                           Yersinia enterocolitica
                                           Yersinia pestis(sup b)
Toxins         Botulinum(sup b)            Botulinum(sup b)
               Ricin(sup b)                Cholera endotoxin
               Staphylococcal		       Diphtheria toxin
                 enterotoxin B             Nicotine
                                           Ricin(sup b)
                                           Snake toxin
                                           Tetrodotoxin
Anti-crop      Rice blast
agents         Rye stem rust
               Wheat stem rust
---------------------------------------------------------------------
(sup a)Includes agents which were used, acquired, attempted to
acquire, involved in a threat of use or an expressed interest in using. 
Reprinted with permission from Carus WS.   Table 6: Biological
agents involved. In: Carus WS. Bioterrorism and biocrimes: the
illicit use of biological agents in the 20th Century. Working Paper,
Center for Counterproliferation Research, National Defense
University. August 1998, revised March 1999.
(sup b)These agents appear on both lists.

Obtaining smallpox virus as opposed to other agents (e.g., anthrax,
plague, and botulinum toxin) would be difficult, but if obtained and
intentionally released, smallpox could cause a public health
catastrophe because of its communicability. Even a single case
could lead to 10 to 20 others. It is estimated that no more than 20%
of the population has any immunity from prior vaccination (12).
There is no acceptable treatment, and the communicability by
aerosol requires negative-pressure isolation. Therefore, these
limited isolation resources in medical facilities would be easily
overwhelmed.

Anthrax can have a delayed onset, further leading to delays in
recognition and treatment. In the outbreak of inhalation anthrax in
Sverdlovsk in 1979, some patients became ill up to 6 weeks after
the suspected release of anthrax spores (1). The current
recommendation for prophylaxis of persons exposed to aerosolized
anthrax is treatment with antibiotics for 8 weeks in the absence of
vaccine or 4 weeks and until three doses of vaccine have been given
(17). The amount of antibiotics required for postexposure
prophylaxis of large populations could be enormous and could
easily tax logistics capabilities for consequence management.

Other bacterial agents capable of causing a maximum credible event
include plague and tularemia. Plague, like smallpox and anthrax,
can decimate a population (as in Europe in the Middle Ages). An
outbreak of plague could easily cause great fear and hysteria in the
target population (as in the 1994 outbreak in India), when hundreds
of thousands were reported to have fled the city of Surat, various
countries embargoed flights to and from India, and importation of
Indian goods was restricted (18). Both plague and tularemia are
potentially lethal without proper treatment; however, the availability
of effective treatment and prophylaxis may reduce possible damage
to a population. Both are infectious at low doses. Pneumonic
plague's person-to-person communicability and untreated
case-fatality rate of at least twice that of tularemia make it more
effective than tularemia as an agent to cause mass illness.

Other agents of concern include the botulinum toxins and viral
hemorrhagic fevers. Once again, both are highly lethal. Botulinum
toxin is a commonly cited threat, and Iraq has admitted to
producing it. Since intensive care would be required in treating both
illnesses and ventilator management is life-saving for botulinum,
both would easily tax existing medical care facilities. However,
botulinum toxin may be a less effective agent because of relatively
lower stability in the environment and smaller geographic coverage
than other agents demonstrated in modeling studies. Producing and
dispensing large amounts are also difficult (W.C. Patrick, pers.
comm.,19).  

A number of different viruses can cause hemorrhagic
fever. These include (but are not limited to) Lassa fever, from the
Arenaviridae family; Rift Valley fever and Crimean Congo
hemorrhagic fever, from the Bunyaviridae family; and Ebola
hemorrhagic fever and Marburg disease, from the Filoviridae
family. These organisms are potential biological agents because of
their lethality, high infectivity by the aerosol route shown in animal
models, and possibility for replication in tissue culture (16).

In summary, we know that biological pathogens have been used for
biological warfare and terrorism, and their potential for future use is
a major concern. Therefore we must be prepared to respond
appropriately if they are used again. The technology and intellectual
capacity exist for a well-funded, highly motivated terrorist group to
mount such an attack. Although the list of potential agents is long,
only a handful of pathogens are thought to have the ability to cause
a maximum credible event to paralyze a large city or region of the
country, causing high numbers of deaths, wide-scale panic, and
massive disruption of commerce. Diseases of antiquity (including
anthrax, smallpox, and plague), notorious for causing large
outbreaks, still head that list. In addition, other agents, such as
botulinum toxin, hemorrhagic fever viruses, and tularemia, have
potential to do the same. By focusing on a smaller list of these
low-likelihood, but high-impact diseases, we can better prepare for
potential intentional releases, and hope to mitigate their ultimate
impact on our citizens.

Many other pathogens can cause illness and death, and the threat
list will always be dynamic. We must, therefore, have the
appropriate surveillance system and laboratory capability to identify
other pathogens, and we must improve our public health and
medical capabilities to respond to the short list of the most
dangerous naturally occurring biological pathogens that could be
used as bioterrorism weapons.

---------------------------------------------------------------------

Dr. Kortepeter is a preventive medicine officer in the Operational
Medicine Division at the U.S. Army Medical Research Institute of
Infectious Diseases, where he teaches the medical management of
biological weapons casualties.

 Dr. Parker is Commander, U.S. Army Medical Research Institute
of Infectious Diseases (USAMRIID) at Fort Detrick, MD.
USAMRIID conducts research to develop vaccines, medications,
and diagnostics to protect U.S. service members from biological
warfare threats and endemic infectious diseases.

 Address for correspondence: Mark G. Kortepeter, Operational
Medicine Division, U.S. Army Medical Research Institute of
Infectious Diseases, Fort Detrick, MD 21702-5011, USA; fax:
301-619-2312; e-mail: Mark_Kortepeter@DET.AMEDD.
ARMY.MIL.
 
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Emerging Infectious Diseases
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