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8
Evaluation of Biosafety
Level 4 Assessment
The 2010 site-specific risk assessment (SSRA) of the proposed Na-
tional Bio- and Agro-Defense Facility (NBAF) did not adequately address
the unique issues and challenges associated with work in a maximum-
biocontainment environment, and the previous National Research Council
committee was therefore led to conclude that the 2010 SSRA did not
adequately characterize risks associated with biosafety level 4 (BSL-4) con-
tainment activities. An overall risk assessment of the NBAF BSL-4 would
need to include an evaluation of the additive risks posed by all BSL-4 work,
including the risk of a release from the BSL-4 associated with use of large
animals in the BSL-4 suite, the risk of a release associated with non-animal-
related activities in the BSL-4 suite, and the risk of a release from the BSL-4
suite associated with natural disasters. The epidemiological and economic
impacts of such a release would then need to be evaluated as part of the risk
assessment. The committee recognizes the inherent limitations in the avail-
able information regarding henipaviruses (see below) that formed the basis
of the BSL-4 review and regarding other agents that may be studied in the
BSL-4 suite. However, the risk assessment presented focuses on only one
component of the overall risk, namely, the unique risks of release from the
BSL-4 suite associated with the use of large animals. During the March
2012 meeting of the present committee, the Department of Homeland
Security (DHS) indicated that it assessed only BSL-4 risks associated with
large animals on the basis of its interpretation of the previous committee’s
evaluation, which was misunderstood. The uSSRA does not consider the
overall risk and presents a limited qualitative assessment, and therefore
the evaluation likely underestimates overall risk related to the BSL-4 suite.
69
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70 NBAF UPDATED SITE-SPECIFIC RISK ASSESSMENT
INADEQUACY OF THE SEMI-QUANTITATIVE APPROACH
The uSSRA responded to the congressional mandate by conducting a
semi-quantitative risk assessment on the only two exclusively BSL-4 agents
that are on the priority list for work at the NBAF: Hendra virus (HeV) and
Nipah virus (NiV). HeV and NiV are paramyxoviruses (Henipavirus genus)
that were recognized in the 1990s and produce high-mortality disease in
animals and humans (Eaton et al., 2006; Field et al., 2007).
The uSSRA states that the primary objective of the BSL-4 risk as-
sessment is “to identify and characterize the unique risks associated with
working with large animals in BSL-4 conditions.” The analysis therefore
focuses exclusively on risks associated with handling infected large animals
in BSL-4 containment. The uSSRA modeled four potential release pathways
(aerosol, solid, liquid, and transference) and developed scenarios in consul-
tation with an international panel of experts in high-containment settings
and pathogens (including representatives of the Australian Animal Health
Laboratory in Geelong and the Canadian Science Centre for Human and
Animal Health in Winnipeg). The committee commends DHS for consulting
an international expert panel to delineate the major and unique risks of the
BSL-4 environment.
Some risks are inherent to working in a BSL-4 environment, which
include the use or manipulation of dangerous pathogens that are highly
lethal to humans or animals and for which there are no preventive or
therapeutic interventions. Added to those risks are the combination of
the presence of large animals in the maximum-containment environment
coupled to the difficulty of maneuvering in biocontainment suits and with
separate air supplies. These difficulties raise the risk of injuries, disruptions
in air supply, and compromised suit integrity from holding pens, animal
bites, inoculations, and use of sharp implements during experiments and
necropsies. These hazards highlight the importance of having administrative
measures in place—including buddy requirements for BSL-4 systems—to
ensure recognition and reporting of such breaches and occupational health
programs to ensure proper management of personnel.
CONCERNS ABOUT BSL-4 ANALYSIS
The committee concurs with the finding in the uSSRA that transference
represents the major risk of inadvertent escape for BSL-4 pathogens rela-
tive to other release pathways. However, the committee has many concerns
about the analysis and found that the uSSRA does not adequately address
the overall risks related to work with BSL-4 pathogens; it elaborates on
those below.
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EVALUATION OF BIOSAFETY LEVEL 4 ASSESSMENT
Lack of Consideration for Full Array of BSL-4 Activities
The uSSRA focuses exclusively on risks associated with handling of
large animals in BSL-4 containment and neglects risks posed by other activi-
ties in BSL-4 containment. Work in a BSL-4 laboratory that does not house
large animals is not risk-free as implied by the uSSRA. Due to the nature of
BSL-4 pathogens, work that would normally be conducted in BSL-3 special
procedure or BSL-3 Enhanced areas of the facility are required to be con-
ducted in BSL-4 if it involves live virus. The 20-year record for safe opera-
tion of major BSL-4 laboratories in the United States is excellent (Johnson,
2003) and the use of biosafety cabinets and other biosafety measures in the
BSL-4 laboratory setting can reduce the risk of release from non-animal-
related activities, but it does not reduce the risk to zero. Consequently, by
omitting the risk of activities in non-large-animal BSL-4 space, the uSSRA
does not address “overall risks” as this committee had expected because it
ignores these risks.
Magnitude of Risks Associated with Unknown
or Uncharacterized Pathogens
The uSSRA notes that NiV and HeV are not the only pathogens that
would be examined in the BSL-4 laboratory. As part of its mission to serve
as a world-class laboratory, the NBAF is expected to conduct essential and
cutting-edge research both on known BSL-4 agents and on unknown and
uncharacterized pathogens. There is a possibility that experiments would
involve large animals for hemorrhagic fever agents, variant influenza vi-
ruses, or pox viruses, and work on these pathogens will pose risks. As the
microbiological and epidemiological features of these agents differ from
those of henipaviruses, it is likely the risks associated with working on these
agents would also be different from those of henipaviruses. The committee
concurs that it is difficult, if not impossible, to model the risks associated
with unknown agents. However, the uSSRA provides only a minimal risk
estimate, and the present committee echoes the previous committee’s con-
cern that the risk assessment did not adequately discuss “the magnitude of
risk and the strategy or process flow to identify and mitigate risk in future
research areas” (NRC, 2010, p. 94).
Scenarios Not Fully Developed or Characterized
The uSSRA modeled 109 scenarios in the BSL-4 assessment, but the
risks associated with some of them were not fully developed. For example,
the necropsy scenario does not consider what the procedure entails with re-
gard to livestock, including the use of knives, saws, rib cutters, and various
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72 NBAF UPDATED SITE-SPECIFIC RISK ASSESSMENT
other surgical instruments for collecting fluids and tissues. Those activities
pose among the highest risks of exposures in the BSL-4 laboratory, but these
events are covered in only a single scenario in the uSSRA.
Failure to Consider Natural Disasters
For FMDv, the risk analysis includes potential releases associated with
tornadoes and earthquakes. The uSSRA concludes that the overall risk of
release for FMDv, although low, is higher for these natural disasters than
for any non-disaster scenarios. Although the relative risks in the BSL-4 en-
vironment are likely to differ because of the potential for escape via human
infection (transference), if one accepts the contention that natural hazards
create the greatest risk of releases from the BSL-3 laboratories, the risks
associated with natural disasters are also likely to be higher for the BSL-4
laboratories than those associated with the other pathways modeled in the
risk assessment. The potential for natural disasters to affect the BSL-4 por-
tions of the facility is not mentioned in the assessment of BSL-4 risks, and
the committee wonders why the uSSRA fails to consider natural disasters as
part of the BSL-4 risk assessment. Although the facility would be designed
to withstand many natural disasters, there is a potential for loss of contain-
ment because of pressure fluctuations that can occur during a tornado or
loss of structural integrity during an earthquake; this constitutes a signifi-
cant omission and leads to an understatement of the risks associated with
the BSL-4 containment suite.
CONCERNS ABOUT USE OF METHODS AND MODELS
Because the BSL-4 semi-quantitative assessment used an approach simi-
lar to the epidemic modeling of foot-and-mouth disease virus (FMDv), the
modeling concerns expressed in Chapter 6 of the present report regarding
the assessment of FMDv also pertain to the BSL-4 assessment. For example,
the uSSRA calculated probabilities as the simple product of individual risks,
which fails to recognize the potential interdependence of risks; for example,
a single mechanism of failure may simultaneously impact multiple nodes,
meaning these nodes are not completely independent and cannot be illus-
trated as a simple product. In addition, the uSSRA treats all mechanical
errors and human errors as equivalent by using a single numeric value for
each in all the risk calculations in the BSL-4 section of the uSSRA. Taken
together, these factors may have artificially lowered the calculated risk
probabilities.
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EVALUATION OF BIOSAFETY LEVEL 4 ASSESSMENT
Inappropriate Extrapolation of Data and Assumptions
The committee recognizes that limited data are available on NiV and
HeV and that no studies have been performed for some of those data gaps.
The uSSRA attempts a semi-quantitative approach, which would be com-
mendable; however, some assumptions and extrapolations are inappropri-
ate, including the calculations of infectious dose and relative impact.
The calculation of infectious dose (which is a critical factor in this
modeling) uses data based on intraperitoneal injections into Syrian ham-
sters to estimate infectious dose in large animals and humans. The uSSRA
extrapolates the infectious dose in large animals and humans on the basis
of weight. Allometric scaling is used in chemical risk assessment but is
not an accepted practice in microbial risk assessment, in which the initial
inoculum can replicate. The extrapolation fails to recognize that the infec-
tious dose–response curve may not be linear. In addition, the uSSRA uses
lethal dose (LD50) instead of an infectious dose–response analysis because
of unavailability of data on which to model the latter. The committee recog-
nizes that because these agents are associated with high mortality, the LD50
may not vary substantially from the infectious dose, but the use of LD50 is
likely to cause artificially high estimates of the dose necessary to produce
infection in humans and large animals. As a result, the threshold Q values
included in Table 9.9.2-2 of the uSSRA appear to be speculative at best and
are probably inappropriate.
The current practice in microbial risk assessment uses dose–response
modeling when data are available, as opposed to the minimum infectious
dose (MID) approach used in the uSSRA. As previously mentioned in Chap-
ter 6 (see the section “Dose-Response Modeling and Minimum Infectious
Dose”), the committee finds the use of MID to be unacceptable. Data-
driven dose–response modeling (including model selection via goodness-
of-fit testing) may be limited by the availability of suitable data, but a
discussion of uncertainty would cover the accepted one-hit (no-threshold)
concept (NRC, 2005) with extrapolation at very low doses for infectious
dose–response.
The relative impact section (Section 9.9.2.2 of the uSSRA) uses data
from the 30 recognized outbreaks of HeV in Australia and the 14 rec-
ognized NiV outbreaks in Malaysia, Bangladesh, and India. The uSSRA
acknowledges that conditions in those locations are substantially different
from conditions in Kansas, especially animal husbandry practices and the
availability and quality of human health care. However, the committee is
perplexed that the uSSRA would use the mean value to make calculations,
such as the number of animals affected in a possible release and the number
of human illnesses. For NiV, the initial outbreak in Malaysia resulted in
the culling of more than a million pigs, whereas none were culled in any
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74 NBAF UPDATED SITE-SPECIFIC RISK ASSESSMENT
of the other outbreaks, because these outbreaks occurred in settings where
pigs were not present and were due to different modes of transmission. The
uSSRA uses an average number of 71,400 animals per outbreak in subse-
quent calculations, which disregards the statistical principle of excluding
outliers. Similarly, the uSSRA uses a value of 0.23 humans affected per
outbreak of HeV (the average of 7 human cases in 30 outbreaks). The com-
mittee finds that these values are not soundly derived and thus not valid.
Given these significant limitations, the calculations in the more quan-
titative sections of the BSL-4 assessment seem highly speculative. And the
committee reaches this conclusion without even further addressing the
limited epidemiological and economic information that was included in the
uSSRA relative to BSL-4 pathogens.
Wildlife Reservoirs
In assessing the potential consequences of a BSL-4 pathogen release
from the NBAF, the impact assessment briefly mentions the possibility of
introducing the agent into a natural reservoir that may sustain transmis-
sion. The committee finds this possibility was understated and is a concern
regarding non-endemic agents that produce high mortality in animals and
humans. The uSSRA discusses work that will be conducted at the NBAF
to determine whether henipaviruses can infect North American bat spe-
cies, and the committee concurs that such work is important. However, if
henipaviruses affect native bat populations, this would affect the overall
risk assessment and elevate the risk. There is also a potential for NiV to
be introduced and transmitted in feral swine populations, which could be
virtually impossible to control. Concerns about impact on native wildlife
reservoirs should be part of a comprehensive risk assessment, but the
uSSRA fails to fully address these risks to native wildlife reservoirs and their
potential impact on animal and human health.
Human Illness
The committee finds that the uSSRA qualitatively understates aspects
that deal with potential human illness. Particular concerns include (1) the
ability and capacity of Mercy Regional Health Center to recognize and
handle human illness associated with zoonotic pathogens held in the NBAF
(such as NiV, HeV, and Rift Valley fever virus), and (2) the capabilities of
the Kansas Department of Health and Environment (KDHE) and local
health departments. It will be critical to quickly recognize and diagnose
an infection caused by a BSL-4 agent, and the surveillance, diagnostic, and
response capabilities of local and state partners may be insufficient for the
NBAF in Manhattan, Kansas.
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EVALUATION OF BIOSAFETY LEVEL 4 ASSESSMENT
Similar to the previous committee, the present committee is concerned
that the medical capabilities that are present at other locations with BSL-4
laboratories (e.g., Galveston and Atlanta) seem to be absent in Manhattan,
Kansas. Although Mercy Regional Health Center has isolation rooms, the
uSSRA states that there is only a single infectious disease physician and
does not assess other medical capabilities in the area. Early recognition of
a human zoonotic disease is crucial for proper treatment and could be the
key in preventing a potential outbreak. For example, in 2000, a U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID) scientist
who was conducting research on Burkholderia mallei, the causative agent
for glanders, was presented to a primary care physician with signs and
symptoms consistent with glanders, but it took nearly two months for the
proper diagnosis to be made (CDC, 2000). Similarly in 2009, it took at
least two weeks for tularemia to be diagnosed in a USAMRIID researcher
working with Francisella tularensis (Eckstein, 2009).
The ability of providers in the Manhattan area or other rural areas of
Kansas to recognize the diseases caused by the suite of pathogens at the
NBAF will need to be assessed and will likely need to be improved. The
single infectious disease physician and the nursing staff and allied health
professionals would be challenged to rapidly diagnose and provide the
necessary care for patients with level 3 and 4 infections. HeV and NiV can
have relatively long incubation periods, and NiV is known to be transmitted
from person to person (Chadha et al., 2006; Gurley et al., 2007; Blum et
al., 2009; Homaira et al., 2010). Although some BSL-4 agents are not stable
in the environment and are difficult to transmit from person to person, the
agent modeled in the uSSRA (NiV) has been transmitted through environ-
mental exposures (from palm sap on trees) and has been transmitted from
person to person in family and healthcare settings (Luby et al., 2009). Fur-
thermore, humans are highly mobile (as noted in the FMDv portion of the
uSSRA in which Biosecurity Research Institute personnel were questioned
about mobility); therefore, patients could be present almost anywhere in
Kansas or surrounding states. There may also be secondary cases that are
not directly connected to the NBAF. For example, in 2006, a patient was
presented to a major Washington, DC, hospital-affiliated primary care cen-
ter with signs and symptoms of tularemia (a BSL-3 organism) but was not
tested for the disease and was eventually discharged without further test-
ing even though the patient informed the medical staff of the characteristic
symptoms of tularemia infection (Dudley, 2010).
The uSSRA fails to fully consider the capabilities of KDHE and local
health departments. Available information suggests that only emergency
management officials in KDHE were contacted for the uSSRA. However, an
unrecognized transference event involving human infection would require
disease surveillance and diagnostic capacity that depend on KDHE epide-
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76 NBAF UPDATED SITE-SPECIFIC RISK ASSESSMENT
miology and laboratory personnel more so than on emergency response
personnel; this fact was overlooked in the uSSRA. Such capacities should
have been assessed and modeled in the overall risk assessment.
Outbreaks involving either human or animal disease caused by a BSL-4
agent would almost certainly be a national problem rather than a regional
one. Experience with other high-profile incidents—such as the incidents
with anthrax in 2001 and severe acute respiratory syndrome (SARS) in
2003—demonstrates that although the overall number of domestic human
cases was small, virtually all locations in the United States were required
to investigate and test for potential illness once one case emerged (Perkins
et al., 2002; CDC, 2003). If a domestically acquired case of HeV or NiV
infection were recognized, there may be a nationwide investigation for
disease prevalence in horses and pigs, respectively, but the qualitative por-
tions of the uSSRA do not mention this. The uSSRA uses simple calcula-
tions to determine the cost of a human life or the cost of a pig or horse to
estimate economic impact, but the costs associated with even a single case
would be far greater than suggested due to the nature of the pathogen and
the national attention that would ensue. The committee thus finds that the
outbreak impact scoring (which is a relative weighting given the lack of a
full quantitative analysis) provides false impressions of the impact of an
accidental BSL-4 pathogen release from the NBAF.
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