BW-ch23.pdf

Biosurety

Chapter 23

Biosurety

Gretchen L. Demmin, P h D *

iNtroDuCtioN

reGuLAtory AGeNCies

CeNters For DiseAse CoNtroL AND PreVeNtioN sAFeGuArDs

us ArMy Biosurety

surety Program Concepts

Physical security

Biosafety

Biological Personnel reliability Program

Agent Accountability

suMMAry

* Lieutenant Colonel, Medical Service Corps, US Army; Deputy Commander, Safety, Biosurety, Operations Plans and Security, US Army Medical

Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland 21702

543

Medical Aspects of Biological Warfare

iNtroDuCtioN

the influence of infectious disease on the course of

history has been continuous. endemic diseases such as

malaria and human immunodeficiency virus have con-

tributed to the endemic poverty of many third World

countries. Although humans have coexisted with in-

fectious diseases for centuries, their potential for use

as weapons against humans has become a matter of

particular concern. Use of infectious diseases against

enemies is not a new idea. throughout history there

have been well-documented and deliberate attempts

to use noxious agents to influence battles, assassinate

individuals, and terrorize the masses. South Ameri-

can aboriginal hunters often use arrow tips dipped in

curare and amphibian-derived toxins. Additionally,

there are reports from antiquity that crude wastes and

animal carcasses were catapulted over castle walls and

dropped into wells and other bodies of water to con-

taminate water sources of opposing forces and civilian

populations. these practices precede written records

but demonstrate the human race’s long involvement

in the use of biological weapons. One of the earliest

well-documented cases of using infectious agents in

warfare dates back to the 14th century siege of Kaffa

(now Feodosia, Ukraine). During the attack, the tartan

forces experienced a plague outbreak. turning their

misfortune into advantage, they began to hurl the

cadavers of the deceased into Kaffa using a catapult.

Defending forces retreated in fear of contracting the

plague. the abandoned city was easily taken by the

tartan forces, and the hasty retreat from Kaffa resulted

in the spread of the plague epidemic to constantinople,

Genoa, Venice, and other mediterranean port cities

where the retreating forces found safe harbor. 1-3

tactics such as these, and the understanding that

disease, or even fear of disease, can be as detrimental

to fighting forces as bullets, led military leaders to

seek ways in which they could prevent disease among

their soldiers as well as use it against their enemies.

Although the first vaccine for smallpox was not used

until 1796, variolation was practiced long before that

time and provided lifelong immunity. Variolation

was the procedure of deliberately inoculating people

using scabs from smallpox infections either blown

into the nose or rubbed into a puncture on the skin.

General George Washington ordered the variolation

of all soldiers in 1777. Because they were able to pro-

tect their own forces, commanders were free to use

infectious disease in more deliberate ways. the Brit-

ish military reportedly used smallpox as a weapon

against the Delaware indians when General Jeffery

Amherst ordered that blankets and handkerchiefs

from smallpox-infected patients at Fort Pitt’s infirmary

be presented to them during a peace meeting. 1,2,4,5

During the 19th century there were many advances

in the understanding of bacterial agents. For the first

time bacteria were isolated from diseased individuals

and animals and grown in artificial culture outside the

body using various growth media. Armed with these

new methods of growing large volumes of bacteria,

German scientists and officers began a large biological

campaign against the Allied Forces during World War i.

instead of targeting the soldiers in this campaign, they

targeted the livestock that were destined for shipment

to the Allied Forces with the agents causing anthrax

and glanders. Large numbers of horses and mules

were reported to have died from these infections. 1,2,6,7

these biological campaigns are considered to have

had a negligible effect on the outcome of the war. the

Germans were far more successful in their campaigns

with chemical agents.

the devastating effects of German chemical warfare

efforts led to the drafting of the Protocol for the Prohi-

bition of the Use in War of Asphyxiating, Poisonous or

Other Gases and of Bacteriological methods of Warfare,

signed at Geneva, Switzerland, on June 17, 1925. 8,9

this treaty prohibited the use of both biological and

chemical agents in warfare but did not provide for any

inspections to verify compliance. nor did the treaty

prohibit the use of biological or chemical agents in

research, production of agents, or possession of biologi-

cal weapons. many countries agreed to the measure

in 1925 with the stipulation that they had the right to

retaliate against biological or chemical weapon attacks

with their own arsenals. many countries proceeded to

work with both biological and chemical weapons, and

50 years passed before any agreement on biological

and toxin weapons was ratified by the US Senate. the

Japanese aggressively advanced biowarfare in World

War ii by using chinese prisoners to study the effects

of anthrax, cholera, typhoid, and plague. more than

10,000 people were killed from the use of these agents

on both military prisoners and civilian populations. 1,2,10

Despite their best efforts at the time, the Japanese never

developed an effective means of infecting large num-

bers of persons using biological munitions.

By the end of World War ii, the Americans and So-

viets were investing heavily in the weaponization of

biological agents. Advances in science and technology

allowed researchers to develop efficient ways to dis-

perse infectious agents, often using routes quite differ-

ent from the way people normally contracted the dis-

ease. infectious agents were placed in missiles, bombs,

and aerosol delivery systems capable of targeting large

numbers of people. the ability to create aerosol clouds

of infectious disease agents and infect large numbers

of people simultaneously changed the perceived risk

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Biosurety

associated with biological agents. Scientists estimated

that casualties caused by the release of agents from

aircraft ranged from 400 to 95,000 dead and 35,000 to

125,000 incapacitated depending on the agents used. 2,11

Agents that had been encountered only in manage-

able, naturally occurring outbreaks acquired the po-

tential to kill or incapacitate large numbers of people.

the lethal and unpredictable nature of biological

weapons and their ability to affect noncombatants

galvanized the global community against their use

in warfare, and led to over 100 nations, including

the United States, iraq, and the former Soviet Union,

signing the 1972 Biological Weapons convention. 9,12

this treaty prohibited the use of biological agents

as weapons but stopped short of ending defensive

research. the ability of some countries to continue

aggressive weapons development programs despite

having signed the convention demonstrated its inef-

fectiveness as a means of controlling the proliferation

of biological and chemical weapons. During the 1990s

an attempt was made to strengthen the Biological

Weapons convention by adding a verification regime

referred to as the Biological Weapons convention Pro-

tocol. this protocol would have added to the original

agreement the ability to inspect both declared and

suspected sites for biological weapons manufacture.

this would have meant that a significant number of

facilities that could be considered “Dual Use” (eg,

vaccine production facilities, university research cen-

ters, and beer brewing plants) would now be subject

to inspection from international weapons inspection

teams. the Bush administration eventually rejected

the protocol in 2001 because it felt that the inspection

of these potential “Dual Use” facilities would not as-

sist in uncovering illicit activity and create an undue

burden on US commercial facilities.

President richard m nixon ordered the disman-

tling of the US offensive biological weapons program

and diverted its funding to other vital efforts such as

cancer research in 1969. Although the United States

and Great Britain were busy destroying their weapon

stockpiles, other countries and extremist organizations

continued to develop and use both biological and

chemical weapons. in the 1970s the Soviet Union and

its allies were suspected of having used “yellow rain”

(trichothecene mycotoxins) during campaigns in Laos,

cambodia, and Afghanistan. 1 An accidental release of

Bacillus anthracis spores (the causative agent of anthrax)

from a Soviet weapons facility in Sverdlovsk killed

at least 66 people in 1979. 13-15 After the Persian Gulf

War and United nations Special commission inspec-

tions, iraq disclosed that it had bombs, Scud missiles,

122-mm rockets, and artillery shells armed with botuli-

num toxin, B anthracis spores, and aflatoxin. According

to a 2002 report from the center for nonproliferation

Studies, six countries (iran, iraq, Libya, north Korea,

russia, and Syria) were known to possess biological or

toxin weapons based on clear evidence of a weaponiza-

tion program. An additional 11 nations (Algeria, china,

cuba, egypt, ethiopia, israel, myanmar, Pakistan, Su-

dan, taiwan, and Vietnam) were suspected of having

biological weapons programs with varying certainty.

this list includes nations that also had former weapons

programs. 16 Because of the lack of verification in any of

the international agreements, it is difficult to determine

whether the massive quantities of agents produced

by those nations have been destroyed. Although the

Biological Weapons convention attempted to restrain

nations in the biological weapons race, other events

make it clear that the greater threat may now come

from extremist organizations that exploit political

instability worldwide to gain access to the agents and

technologies that will further their agendas.

extremist organizations have used biological agents

to further their agendas since the 1980s. Food and wa-

ter contamination may be a highly effective means to

deliver a chemical or biological attack. Over 750 people

were infected with Salmonella typhimurium through

contamination of restaurant salad bars in Oregon by

followers of the Bhagwan Shree rajneesh in 1984. 1,2,17

A Japanese sect of the Aum Shinrikyo cult attempted

an aerosolized release of the anthrax agent from tokyo

building tops in 1994. 1,2,18 this cult also unsuccessfully

attempted to obtain ebola virus during an outbreak in

Africa during the 1990s, and it released sarin nerve gas

into a subway system in tokyo. Several national and

international groups have been found in possession of

ricin toxin with the intent to disperse the toxin in an

attack. 1,2 the anthrax mailings sent in October 2001 in

the United States demonstrated that individuals were

able to use biological agents as bioterrorism experts

had warned for more than two decades. Although the

anthrax attacks were not successful in causing large

numbers of casualties and fatalities, they did have

a significant economic and emotional impact. the

centers for Disease control and Prevention (cDc)

reported the effects of this one attack included 5 fatali-

ties, 17 illnesses, a cost of $23 million to decontaminate

one Senate office building, $2 billion in lost revenue

to the US Postal Service, and as much as $3 billion for

the decontamination of the US Postal Service buildings

and procurement of mail sanitizing equipment. 19

As the potential use of these agents by extremist

organizations and individuals came into the spotlight,

congressional interest in regulating the research com-

munity increased. it was evident that a fundamental

change in the US policy toward the regulation of these

agents was required. the need for change was made

apparent by the case of Larry Wayne harris, micro-

biologist and suspected white supremacist, who was

545

Medical Aspects of Biological Warfare

arrested in 1995 after receiving freeze-dried cultures of

Yersinia pestis (the agent that causes plague) from the

American type culture collection. Because it was not

a crime to possess these materials, he was only able to

be charged for mail fraud and sentenced to 18 months

of probation and 200 hours of community service in

spite of the fact that there was a clear intent to use these

materials in a malicious manner. At the time that his

crime was committed, it was not a federal offense or

even illegal to be in possession of these agents. 20 in con-

trast, once the laws were changed, a professor in texas

who was conducting valid research without malicious

intent was convicted and sentenced to 2 years in prison

for improper handling of plague samples. the pros-

ecutor in the case was seeking 10 years in prison and

millions in fines; however, the sentence was reduced

because of the great contributions that thomas Butler

had made to the scientific community. there was no

indication that he planned on using these specimens

for bioterrorism. 21,22 Since that conviction, there has

been concern in the scientific community regarding

the risks of engaging in research that could put one in

jail for relatively minor infractions of the law.

the US government and other nations have under-

taken a variety of approaches to combat the extremist

threat. export controls on key precursor materials and

equipment have been implemented since 2001. new

technical sensors to detect and identify specific agents

or categories of agents have been developed and de-

ployed. these systems have been used during events

where large populations have assembled such as the

Olympic games and the Super Bowl. in direct response

to the anthrax mailings of 2001, the US Postal Service

has implemented a continuous surveillance of major

distribution centers to protect both their workers and

the general public from another attack. new systems to

monitor public health, such as syndromic surveillance

systems, have been developed. Syndromic surveillance

assists in highlighting areas in which an epidemic or

outbreak might occur so that a containment and treat-

ment strategy can be developed. Finally, to prepare for

situations in which detection and surveillance efforts

fail to warn of an attack, agencies in the federal gov-

ernment are focusing efforts to develop, improve, and

stockpile medical countermeasures to the recognized

biowarfare threat agents. 23

reGuLAtory AGeNCies

After the Oklahoma city bombing, congress passed

the Anti-terrorism Act of 1996. this act provides law

enforcement activities with a broad range of new tools

to be used in investigating and prosecuting potential

acts of terrorism in the United States. With this act,

congress declared that the responsibility for develop-

ing regulations to control access to and possession of

biowarfare threat agents would be the US Department

of health and human Services (DhhS) and the US

Department of Agriculture (USDA).

the first regulatory framework for working with

and transferring select agents and toxins was pub-

lished by the cDc in 1997. in these regulations the

cDc had four goals:

as select agents requiring regulation.

On December 13, 2002, DhhS and the USDA each

published interim regulations in the Federal Register

that addressed the possession, use, and transfer of

select biological agents and toxins (select agents). the

final rule, which was published on march 18, 2005,

is updated periodically to include emerging threats.

the DhhS regulations are published in title 42 code

of Federal regulations (cFr) Part 73, 19 and the USDA

regulations are published in title 7 cFr Part 331 24 and

title 9 cFr Part 121. 25 these rules apply to all academic

institutions and biomedical centers; commercial manu-

facturing facilities; federal, state, and local laboratories;

and research facilities. regulated agents and toxins

appear in chapter 18, Laboratory identification of

Biological threats, exhibit 18-1.

the original list published in December 2002 re-

mains largely unchanged in the regulation, which

was published on march 18, 2005. the list is not

limited to the infectious agent or toxin itself but also

regulates the agents’ genetic elements, recombinant

nucleic acids, and recombinant organisms. if the

DnA or rnA of an agent on the listing can be used

to recreate the virus from which it was derived, then

the genetic material is also subject to the regulation.

Any organism that has been genetically altered must

also be regulated. Finally, recombinant nucleic acids

that encode for functional forms of toxins that can be

expressed in vivo or in vitro are subject to regulation

1. identify the agents that are potentially haz-

ardous to the public health;

2. create procedures for monitoring the acquisi-

tion and transfer of the restricted agents;

3. establish safeguards for the transportation of

these infectious materials; and

4. create a system for alerting the proper au-

thorities when an improper attempt is made

to acquire a restricted agent.

in June 2002, the cDc convened an interagency

working group with diverse representation, including

Department of Defense (DoD) experts, to determine

which infectious diseases and toxins should be listed

546

Biosurety

to safeguard this material.

Some notable exceptions to the regulation allow for

the unencumbered handling of diagnostic specimens

by clinical laboratories. title 42 cFr 73.5 states:

As with diagnostic testing, the recipient of these mate-

rials must safeguard them from theft, loss, or release;

transfer or destroy the testing materials within 90 cal-

endar days of receipt; and report identification of the

agent or toxin within 90 calendar days. Both of these

exceptions are important in that they allow exemp-

tion of clinical laboratories that may only handle such

agents for short periods of time during diagnostics or

proficiency testing periods. these laboratories, which

are already registered and inspected by the college of

American Pathologists, generally only handle small

quantities of agent at any given time.

in addition to the specific allowances provided

for clinical labs, there are guidelines for agents with

general exclusions as follows:

“clinical or diagnostic laboratories and other entities

that possess, use or transfer a DhhS select agent or

toxin that is contained in a specimen presented for

diagnosis or veriication will be exempt from the re-

quirements of this part for such agent or toxin pro-

vided that:

1. Unless directed otherwise by the hhS secretary,

within 7 calendar days after identification, the

select agent or toxin is transferred in accordance

with 73.16 or destroyed on-site by a recognized

sterilization or inactivation process.

2. the select agent or toxin is secured against theft,

loss, or release during the period between identi-

fication of the select agent or toxin and transfer or

destruction of such agent or toxin, and any theft

loss or release of such agent or toxin is reported,

and

3. the identification of the select agent or toxin is

reported to the cDc or the Animal and Plant

health inspection Service (APhiS) and to other

appropriate authorities when required by federal

state or local law.“ 19

• Any select agent or toxin that is in its naturally

occurring environment provided it has not

been intentionally introduced, cultivated, col-

lected, or otherwise extracted from its natural

source.

• nonviable select agent organisms or nonfunc-

tional toxins.

• Formalin-fixed tissues.

• Agents that have been granted exception as a

result of their proven attenuations.

the identification of certain agents in diagnostic

specimens is of great concern to the cDc, and certain

agents must be reported within 24 hours of identifica-

tion. exhibit 23-1 lists select agents and toxins with im-

mediate reporting requirements, which is different from

the reporting requirements for public health activities.

Additional variances are granted to the clinical labo-

ratory to allow handling proficiency testing materials.

Attenuated virus and bacteria strains are listed on the

cDc Web site. this is not a general exclusion for all

“attenuated strains” of viruses or bacteria. if research-

ers want exemption from the provisions for a particular

strain, a written request for exclusion with supporting

scientific information on the nature of the attenuation

must be submitted. Agents that have already received

exclusion are listed in table 23-1.

eXHiBit 23-1

iMMeDiAte rePortiNG reQuireMeNts For seLeCt AGeNts

DHHs select Agents and toxins

overlap select Agents and toxins *

ebola viruses

Bacillus anthracis

Lassa fever virus

Botulinum neurotoxins

marburg virus

Brucella melitensis

South American hemorrhagic fever viruses (Junin ,

Francisella tularensis

machupo, Sabia, Flexal, Guanarito)

hendra virus

Variola major virus (Smallpox virus)

nipah virus

Variola minor (Alastrim)

rift Valley fever virus

Yersinia pestis

Venezuelan equine encephalitis virus

DhhS: Department of health and human Services

* Biological agents and toxins that affect both humans and livestock are termed overlap agents.

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