Safety and Security Requirements
for Select Agent Research
Bioterrorism
Definitions
• Biological terrorism (BT) – Use of biological agent on
a population to deter, hinder, or otherwise slow the
productivity of a community.
• Biological warfare (BW) - Use of biological agent to
harm or kill an adversary’s military forces, population,
food, and livestock.
• Select agents (SA): designated subset of biological
agents or toxins identified as having the potential to
be used in weapons of mass destruction (WMD’s)
Types of Biological Weapons
• Bacterial agents
• Viral agents
• Biological toxins
Advantages of BT
• Killing efficacy
• Cost effectiveness
• Vehicle
• Relative ease of production
• Interval between dissemination to infection
History
• Ancient – 20th century
• 20th century – 1972
• 1972 – today
Does the Siege at Caffa Correlate
with the Initiation of Black Death?
1346 - 1352
20th Century to 1972
• World War I
• Glanders and anthrax used on horses
• Geneva Protocol (1925)
- 40 violations from 1969-86 of prohibitions of
bioweapons used in war
• World War II
- Unit 731, Manchuria, China – weapons tests
on Chinese
20th Century to 1972
• US military bio-weapon program, 1950-72
• Ft. Detrick, Maryland
• Pine Bluff Arsenal, Arkansas
• 1966, B. subtilis in NYC subway
- Study dissemination patterns
• 1969, Serratia in San Francisco
- Study line-source dissemination
• Biological Weapons Convention, 1972
• Today, 148 signatories
- India, North Korea, Pakistan, Iran among those not signed
1972 - Today
•
1979, Sverdlovsk, Russia
• 66 fatalities from anthrax
release
• For 13 years USSR
government tells public it was
due to ingestion of
contaminated meat.
• 1992, Boris Yeltsin admits a
faulty HEPA exhaust filter as
the result of the release from
Building 19.
•
Science, 1994,
266(5188):1202-8.
1972 - Today
•1992, Aum Shinrikyo cult
•Weaponize anthrax
- 10 botched attempts
(1992)
•Travel to Zaire to find Ebola
•Sarin gas attacks in Japan
Where in the World is Safety Bob
and what is the public health significance of this place?
The former Shakey’s Pizza where the Bhagwan Shree Rajneesh cult conducted the first
known bio agent attack in the US in September 1984, spraying salmonella on the salad
bar to in an attempt to prevent citizens from voting in an upcoming election
The 2001 Anthrax Letters
• 23 reported cases of anthrax
• New York City (8), New Jersey (7), D.C. (5), Florida
(2), and Connecticut (1)
• 11 inhalation anthrax (5 deaths)
• 12 cutaneous anthrax
• 9/11 inhalation anthrax cases are linked to direct
exposure to contaminated mail
• 2 cases had no known exposure (61 y.o. woman in
NY, 94 y.o. woman in CT)
Anthrax
• Bacillus anthracis
• Gram (+) sporulating rod
• 3 antigens formed
• (EF), (LF), (PA)
• Presence of (LF) and (PA) = pathogenic
• 3 distinct clinical syndromes
• Cutaneous
• Inhalational
• Gastrointestinal
Inhalational Anthrax
• Infective Dose = 8,000 - 15,000 spores
• Incubation period = 1-6 days
• Duration of illness = 3-5 days
• Diagnostic Hallmark
• Widened mediastinum
• Treatment:
• Ciprofloxacin: 500mg bid x 4 wk
• Doxycycline: 100mg bid x 4 wk
Anthrax - Clinical Presentations
October 2001: Anthrax Mail Attacks:
UTHSC-H Experience
Ricin
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•
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Derivative from castor bean plant, Ricinus communis
Protein cytotoxin that inhibits protein synthesis through its 2
polypeptide chains
Marginal toxicity when compared to other biological toxins
• LD50 = 30 μg/kg
•
Recent history
•
•
•
•
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1978 – Bulgarian dissident
1996 – KC Oncologist intent to use
1997 – WI resident possession
2003 – Al Qaeda plot
2004 – Washington DC letter
Ricin, cont’d
Major clinical presentations:
• Inhalation
• Rapid onset (4-8 h) – fever, chest tightness, cough, dyspnea, nausea
• Respiratory failure (36-72 h) and pulmonary edema
• Injection
• Same onset as inhalation
• Local lymphoidal and muscle necrosis, GI hemorrhaging
• Ingestion
• Less toxic than above
• Onset of symptoms similar time – abdominal pain, vomiting, diarrhea,
progressing to GI hemorrhaging, hepatic, splenic, and renal necrosis
• Death 3-5 days – cessation of circulatory system
Smallpox
•
Variola major virus
• Orthopox virus
•
•
BW threat from aerosolization
Acute stages often confused with Varicella (chickenpox)
• Differentiation:
•
•
•
•
Smallpox typically evolves distally
Lesions generally all is same stage
Febrile illness prodromal stage
Eradicated by WHO in 1980
• US & UN delay destruction of reserves until 7-02
• Delayed longer
•
Treatment
• No known cure
•
•
Vaccinia Immune globulin
Cidofovir
Smallpox Presentation
Given the Threat – What to Do?
• Preparedness Needs
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•
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Detection - Health Surveillance
Rapid Laboratory Diagnosis
Epidemiological Investigations
Implementation of Public Health Control Measures
Communication network
Research and Development
• PPE, respirators
• Triage and decontamination methods
• Vaccines, prophylaxis
Web Resources
• www.bt.cdc.gov
• http://www.osha.gov/SLTC/biologicalagents/index
.html
• http://www.usps.com/news/2001/press/pr01_101
0tips.htm
• http://www.texasbiosecurity.org/
• www.aphl.org
• www.defenseofhouston.org
• http://www.cdc.gov/od/sap/
The Select Agent Rule
Foundation for Select Agents
• Antiterrorism and Effective Death Penalty Act of 1996
(PL 104-132)
• Invoke transport requirements, and prohibited
possession as weapons
• USA PATRIOT Act (PL 107-56)
• Effective 10/16/01
• Controlled the possession of 49 Select Agents/Toxins for any
use: peaceful, research, or intentional
• Outlawed use if a “restricted person”
Public Health Security and Bioterrorism
Preparedness and Response Act of 2002
• (PL 107-188) effective 6/12/02
• Covers both human and plant/animal select
agents; joint program between HHS (CDC) and
USDA (APHIS)
• 9/10/02 - CDC notification of possession or use
of SA by facilities required; negative
certification also required
• 12/12/02 – Interim final rule published
• 02/14/03 – Interim final rule enacted as law
• 03/18/05 – Final Rule released
What is a Select Agent?
• List of agents can be found on the CDC and APHIS
websites
http://www.cdc.gov/od/sap/docs/salist.pdf
• Includes infectious agents and biological toxins of
WMD concern; often termed “dual use”
• There are some exemptions for certain strains and
amounts of toxin per PI
42 CFR 73 – Select Agent Regulations
• 73.7 Registration & related security risk assessment
• 73.9 Responsible Official
• 73.10 Restricting access to Select Agents
• 73.11 Security plan
• 73.12 Biosafety plan
• 73.14 Incident Response
• 73.15 Training
• 73.18 Inspections
• 73.19 Notification for Theft, Loss, or Release
CFR 73.7 - Registration
• You must be registered prior to beginning work
• Registration good for 3 years
• Facility must meet CDC/NIH BMBL guidelines in
addition to security requirements
CFR 73.7 – Related Security Risk
Assessment
• Registration information required to be submitted
so that Attorney General may perform risk
assessment of work at institution with Select
Agents
CFR 73.9 – Responsible Official
• Responsible Official (RO) and an Alternate
Responsible Official (ARO) must be designated
• This individual must have resources available to
ensure compliance
CFR 73.10 – Restricting Access
• Must be an authorized person to have unrestricted,
unsupervised access to Select Agents
-training & experience required
-must be approved by Attorney General
• Authorization granted for a period of five years
Statement of Eligibility
• Denied SA possession if ‘Yes’ to any of following:
•
•
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Jail >1 year
Fugitive from justice
Controlled substance use
Citizen of one of UN recognized terrorist countries
Committed to a mental institution
Dishonorably discharged
CFR 73.11 – Security
• Inventory Control Measures
• Physical Security
- Looking for at least 3 levels
• Cyber Security
• Provisions for visitors, housekeeping, and
maintenance
• Procedures for lost passwords, keys, IDs,
personnel leaving, unauthorized personnel
CFR 73.12 - Biosafety Plan
• Biosafety and containment procedures set forth
following BMBL and NIH rDNA Guidelines
• i.e. entry protocols; PPE; general and special practices
and procedures
• Plan must be tested at least annually using drills to
evaluate the effectiveness of plan or after any
incident
CFR 73.14 - Incident Response
•
Do you have an institutional Emergency Situations Response Plan
(ESRP)? Where is it located?
•
Planning and coordination with outside parties
•
What are the emergency hazards associated with select agent?
• Oral, Contact (dermal), Inhalational hazards
•
What are the hazards associated with response that could lead to the
spread of select agent?
•
Do you have appropriate site security and control during emergency?
•
Where do you find information about the specific hazards associated
with the select agent?
• Biosafety Plan
CFR 73.15 - Records
• Current, accurate list of individuals approved for access to
select agent
• Current, accurate inventory of select agent
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Name, characteristics, and source data
Quantity acquired and date of acquisition
Quantity destroyed and date of destruction
Quantity transferred, date of transfer, and to whom it was transferred
(EA-101)
• Records of APHIS/CDC Form 2 (EA-101) transfers
• Access to area where select agent is used or stored
CFR 73.19 – Notification for Theft, Loss, or
Release
• Must have a procedure for any of the above events
• Must complete report to USDA or CDC using
APHIS/CDC Form 3
Penalties
• 42 CFR 1003 imposes strict penalties for
violations of 42 CFR Part 73
• Imprisonment of up to 5 years
• “….. $250,000 in the case of an individual”
• “……$500,000 in the case of any other person”
• Failure to completely comply also carries
significant reputational risk
Foreseeable Trends
• Increasing regulatory requirements, inspections,
scrutiny
• Opportunities for research
• The FY03 budget for Department of Homeland
Security was $37,450,000,000
Commentary
• Additional bureaucratic controls for select agents are
imminent
• These rules will not always be based on sound
science
• Incompatibilities with universities:
•
•
•
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Designed as traditionally open environments
Internationally diverse populations
Population eschews being told what to do
Openly shares information
• But the work is important –so an infrastructure is
needed to support this type of activity
Commentary (con’t)
• When looking at positions, suggest asking about
the support infrastructure in place - specifically:
Who does EH&S report to?
Who is the designated “responsible official”?
Is “select agent” work currently underway?
What facilities exist and are planned?
Summary
• Biosafety is much more than just research protocol
reviews or bloodborne pathogens
• Risk assessment process the key to properly
classifying and reviewing research with infectious
agents or rDNA
• Safety department must rely on the expertise of the
committee for assistance
• Select agent work is highly regulated and scrutinized
References
•42 CFR 73 (CDC)
http://www.cdc.gov/od/sap/42_cfr_73_final_rule.pdf
•7 CFR 331 and 9 CFR 121 (APHIS)
http://a257.g.akamaitech.net/7/257/2422/01jan20051800/edocket
.access.gpo.gov/2005/pdf/05-5063.pdf
•Biosafety in Microbiological and Biomedical Laboratories, 4th ed.
CDC/NIH 1999
•Guidelines for Research Involving Recombinant DNA Molecules
(NIH Guidelines) April 2002
•Health Canada MSDS for Biological Agents
http://www.phac-aspc.gc.ca/msds-ftss/index.html#menu?