Pathogens and Disease ISSN 2049-632X
MINIREVIEW
Biocontainment laboratory risk assessment: perspectives and considerations Amy Patterson1, Kelly Fennington1, Ryan Bayha1, Diane Wax2, Rona Hirschberg2, Nancy Boyd2 & Michael Kurilla2 1 Office of Science Policy, National Institutes of Health, Bethesda, MD, USA 2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Excellent review on risk assessment needed for biosafety level 3/4 facilities.
Keywords biocontainment laboratory; risk assessment; BSL4 laboratory. Correspondence Michael Kurilla, 5601 Fishers Lane, Bethesda, MD 20892, USA. Tel.: 301 402 4197 fax: 301 480 3235 e-mail: [email protected] Received 24 January 2014; accepted 17 February 2014. Final version published online 4 April 2014.
Abstract The ability to respond to public health emergencies involving infectious diseases as well as our ability to adequately prepare for as yet unknown or unrecognized emerging infectious diseases requires suitable facilities within which scientific investigations can take place. To ensure the safe conduct of such investigations so that laboratory workers and the general public are protected from potential consequences of accidental or intentional release of high consequence pathogens, special containment facilities have been designed and constructed. Evaluation of the adequacy of containment for these types of investigations requires a risk assessment (RA) as part of the overall construction project for these types of laboratories. A discussion of the RA process along with considerations that impact the design of such studies and the overall results is presented.
doi:10.1111/2049-632X.12162 Editor: Kelly Cole
Introduction This article discusses biocontainment laboratory risk assessment (RA) from the perspective of the decade-long experience of the National Institutes of Health (NIH) and its component the National Institute of Allergy and Infectious Diseases (NIAID) with a biocontainment laboratory construction program. The specific focus is on high-level biocontainment biosafety level 3 (BSL3) and level 4 (BSL4) laboratories designed and constructed for working with highly pathogenic human infectious agents. In response to Congressional mandate, in 2003 and 2005, NIAID awarded partial grant funding to several US academic research institutions for constructing biocontainment facilities to enhance the nation’s capability to do research on biologic agents. Specifically, awards were made for the construction of regional biocontainment laboratories (RBLs, BSL3 laboratories) and national biocontainment laboratories (NBLs, comprehensive BSL4 laboratories). The NBLs and RBLs were constructed so that improved diagnostics, therapeutics, and vaccines for protecting the public from emerging and reemerging infectious diseases could be developed. 100
This experience involved detailed oversight of the projects from planning to completion and beyond, including development and submission of environmental impact statements (EIS) and environmental assessments (EA) required by the National Environmental Policy Act (NEPA; United Environmental Protection Agency, 2013), as NIH partially funded the projects. This has provided a well-defined perspective in general on how best to approach and conduct RAs and the critical issues that must be considered and analyzed. The principles, processes, and analyses outlined in this paper have been successfully used in these projects. Discussion will begin with the conceptual framework for organizing a RA, including the process and key elements for conducting a RA, and then address ‘best practices’ derived from having engaged in RAs for construction of two NBLs and 12 RBLs. In general terms, a RA is an analysis of the probability and consequences (adverse effects to both humans and the environment) of reasonably foreseeable accidents or events that may occur as a result of various actions associated with the facility. Frequently, RAs analyze adverse effects such as radiation damage to tissues, other health effects such as cancer, loss of hearing, or lung or liver damage, traffic
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congestion, increased noise, displacement of people or activities, pollution of the environment or damage to native species. These can occur as a result of constructing and/or operating a building, particularly nuclear facilities or other industrial plants, bridges, dams, or activities that either use or produce dangerous chemicals, biologic materials, and radiation as part of their normal operations. This article is concerned with the unique situation of assessing risks that may be associated with operating high-level biocontainment laboratories where work with dangerous biologic agents and toxins takes place. There are two primary reasons to perform a RA for a biocontainment laboratory project. First and most important, it is essential to define the risks associated with the laboratory and its activities, particularly the potential adverse human health and/or environmental effects that could result from accidents involving the agents (primarily bacteria and viruses) that might be present and under investigation. When the risks have been defined and assessed, appropriate measures to minimize them can be implemented. This is known as risk mitigation and can include enhanced building design features, personal protective equipment, specific protocols and standard operating procedures (SOPs), and specialized training programs, among others. Second, projects involving federally funded or partially funded actions must meet NEPA standards. NEPA was originated in 1969 and established the broad national framework for protecting our environment. Its intent is to assure that all branches of government give proper consideration to the environment prior to undertaking any major federal action that might significantly affect the environment. EAs and EISs, which are assessments of the likelihood of impacts from alternative courses of action, are required from all federal agencies and are the most visible NEPA requirements. NEPA’s procedural requirements apply to all federal agencies in the executive branch so that NIH/NIAID’s construction projects need to be compliant with NEPA. Over the years, RA standards and guidance have been developed by federal government agencies, particularly the Environmental Protection Agency (EPA, 2013) and the Department of Energy (DOE, 2011), and it is important to conduct a RA consistent with these and other accepted approaches. Projects that involve the use of biological select agents and toxins as well as those that include recombinant DNA activities also require RAs, based on additional federal requirements. There may also be similar state and local environmental requirements for biocontainment laboratory construction and operation. EPA and DOE documents, the Centers for Disease Control (CDC)/NIH document Biosafety in Microbiological and Biomedical Laboratories [BMBL (Center for Disease Control, 2011), sections II and IV in particular], the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (National Institutes of Health, 2013) and the Select Agent Regulations (Centers for Disease Control, 2013) all provide guidance about the goals and principles of RA and conducting them. The broad principles of RA include transparency, clarity, consistency, and reasonableness. These basic principles should be kept in mind and assessed throughout the RA
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process. In general, a RA should be planned and conducted to address the question of what could go wrong and what would be the consequences of such events. Analyses must be conducted using existing guidance and established methods and approaches; the RA report must be able to survive rigorous scientific review and to the extent possible be based on well-established and scientifically validated peer-reviewed approaches. For complex and possibly controversial projects such as a BSL4 laboratory, the RA should be as comprehensive, scientifically sound, and rigorously conducted study as possible.
RA process To guide the biocontainment laboratory RA process, the following questions should be posed as overall organizing thoughts: (1) What could go wrong; what is the likelihood of each kind of potential incident or accident; what would the consequences be should something go wrong? (2) What are the risks to the workers at the laboratory and to the public if something were to go wrong? (3) Would these risks be modified if the laboratory were to be located at a different site? The RA should contain a detailed analysis of potential health and environmental effects associated with the laboratory, and it should be designed to be realistic and to consider input from the affected community and relevant experts. The analysis should examine a series of scenarios describing the likely fates of specific pathogens that might be involved in plausible procedural failures, containment system failures, human errors, and malevolent actions. A major objective of the analysis should be to estimate the likely number of primary and secondary infections and possible fatalities that might occur among laboratory workers and/or the public if an accidental release of any of the studied pathogens were to occur. A second objective should be to evaluate the possibility that pathogens released from the laboratory could persist in the environment and cause adverse effects. The RA process will be further detailed in the section that follows. In general, RA involves the following: (1) Identifying possible hazards (this answers the question of what can go wrong). (2) Analyzing their likelihood (this addresses the probability of an accident occurring). (3) Evaluating the resulting consequences (infections, fatalities, other environmental effects). In the case of a biocontainment laboratory, where the primary concern is infections or fatalities resulting from loss of containment, the steps in a thorough RA include the following: (1) Define scope; (2) Identify pathogens; (3) Identify and analyze events; (4) Estimate initial infections; (5) Assess and model secondary infections; and (6) Evaluate site differences and population differences across the various sites.
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Define scope The scope of the RA deserves detailed and careful thought at the beginning, because once it is determined, all aspects of the subsequent work will be affected. Decisions about which biocontainment levels will be analyzed, what organisms will be included, whether alternative sites are to be included, as well as such issues as agent transport accidents, potential environmental persistence of agents if they are released from the laboratory, and particular characteristics of local populations that will be considered are all important. Threat RA (TRA) is another important and necessary component of a thorough RA which, although usually kept confidential (for obvious reasons), will influence the scope of the RA and mitigation strategies. TRA involves analysis of threats and vulnerabilities associated with a facility from natural or criminal/terrorist activities, followed by development of appropriate countermeasures. Guidance from EPA, DOE, CDC, NIH, and the BMBL will also impact the RA scope. The specific features of the building and its systems influence planning the RA. The process should begin with a detailed facility analysis that considers the facility’s design attributes, its building systems, security features, and the site and surrounding environment. Knowledge of how the facility will be operated and the kinds of research activities that are expected to be conducted is essential for a well-planned RA scope. SOPs, research project plans and protocols, and equipment specifications are important resources for this analysis and are the basis for determining facility and procedure hazards. If the facility design and operation are not yet well established, assumptions must be made and then modified during the RA process as more information is available. If alternative sites are under consideration, the similarities and differences among them need to be identified so that their impact on possible hazards can be factored into the RA plan. Identify pathogens The choice of pathogens to analyze for a biocontainment laboratory RA is one of the most critical scoping decisions. On the one hand, the pathogen list should be comprehensive enough to represent the actual risks associated with operating the facility; however, it must be limited enough to practically implement. Both goals can be accomplished by selecting agents with a variety of characteristics that encompass those of the total range of agents that are likely to be studied in the laboratory once it is operational. Important characteristics to include in determining the pathogen list include the following: transmissibility, pathogenicity, BSL3 or 4 assignment, mode of transmission including vector borne with reservoirs, case fatality rate, infection period, availability and efficacy of treatments and/ or means of prevention. In addition, the list should include agents of concern to the public, as well as take into account the recommendations of expert scientific advisors to the project (see below). At a practical level, the choice will be influenced by the availability of epidemiological data 102
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to support analyses, availability of appropriate models for conducting analysis (particularly for quantitative modeling of secondary transmission), and the extent to which an agent is a recognized public health concern. A detailed review of the literature that documents the characteristics of the selected pathogens should be done so that the hazards associated with working with them are clear. The scientific literature as well as CDC and NIAID/NIH guidance including that found in the BMBL are sources for agent hazard data. A final note on agent selection for analysis is to not limit the agent repertoire to merely those under consideration for immediate utilization within an operational facility since research and public health needs evolve as science advances. Therefore, representative pathogens that span the range of the various criteria highlighted above will allow for an adequate evaluation of currently intended research activities as well as remain relevant when newer, currently unknown pathogens are identified in the future. Identify and analyze events The next phase of the RA process involves identifying, selecting, and analyzing events that might cause the release of a pathogen and result in the exposure of laboratory workers or members of the public. These potential hazards include failures of equipment, building systems, personnel, and procedures. The events identified will be a function of the facility hazard, procedure hazard, and agent hazard information described above and should include a consideration of appropriate BSL level and recommended precautions to use for work with the agents and types of experiments. Event sequence analysis should include evaluation of staff proficiency and involve input by biosafety professionals at the institution. Based on knowledge of laboratory operations and the nature of the work that will be done, combined with historical data about laboratory accidents, including real-world operating experience in existing BSL3 and BSL4 laboratories, a comprehensive list of possible accidents can be generated; it should be as inclusive as possible to start. Several hundred possible events might be identified and then considered, evaluated, and grouped into categories comprising similar or related events for further detailed examination. The final selection of specific events to analyze in detail should include frequent to rare event types, low to high consequence events, and ‘maximum reasonably foreseeable’ events. It is very important to include a reasonable range to be sure the RA meets the standard of comprehensiveness and reasonability. The list selected for detailed analysis might include a group of events such as a needle-stick accident (relatively frequent, perhaps annually, but generally low consequence), a centrifuge malfunction creating an aerosol release (moderate frequency, moderate consequence), an earthquake (very low frequency, but high consequence), and a transportation mishap (low frequency, low consequence). The many other events identified but not analyzed in detail should all be bounded or encompassed by those chosen in terms of probability and consequences. It is
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important to note that accepted guidance does not require consideration of beyond reasonably foreseeable events or ‘worst-case scenarios’ (a term which is not considered meaningful in the field of RA). Events should be chosen so that those eliminated are unlikely to pose more risk relative to those chosen for further detailed analysis. For example, a hurricane event might be considered but not included in the RA because it can be similar to an earthquake in the resultant structural damage caused to the building, but a severe earthquake is more likely to have greater consequences. Once events are chosen, analysis is then performed to estimate how often the selected events would be likely to occur; this is based on available data about laboratory accidents (such as industrial data regarding equipment failures) and past experience of those familiar with the work likely to occur in the laboratory. Depending on the specific situation, events might be analyzed that involve BSL3 and BSL4 operations or only one. Next, human exposure numbers and levels are estimated using the event frequency estimates combined with estimates of the quantities of various pathogens likely to be involved with the specific activity and the hazard under consideration along with the number of people likely to be exposed and the nature of the event. Each pathogen needs to be analyzed separately for each event as available amounts and other agent characteristics will influence final exposure. The results of the event sequence analysis are the potential consequences of various pathogen-event pairs (a specific hazard paired with a specific agent creates a potential accident for analysis), expressed in terms of how many laboratory workers or members of the public are likely to be exposed following an accident and the amount of exposure in terms of units of pathogen. The results also include the range of likely frequency for the event pair. The number of people directly exposed as a result of an accident can range from zero to many. However, most laboratory incidents have the potential to directly expose only one to at most a few laboratory workers. For example, the number of workers permitted at one time in BSL4 space is typically limited which places an upper limit on the number of potential exposures in the event of an equipment failure such as a centrifuge malfunction, while the exposure amounts would vary. In contrast, events such as a major earthquake may directly expose many members of the public, although the exposure would in most cases be very low in amount. Estimate initial infections Not all exposures to pathogens will necessarily lead to infection and disease. Whether an infection occurs depends on several factors: the specific pathogen, the amount of pathogen exposure, the dose–response relationship for that pathogen. In addition, the health of the specific individual and mitigating features such as vaccination status and antimicrobial drugs availability may influence infections. Estimating the number of initial infections that might result from an accident involves taking the exposure data and applying dose–response analysis. Higher exposure doses
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are more likely to cause infection, but this relationship varies by pathogen and the circumstances of a given exposure, such as route. If the exposure is in the low range of the dose–response curve, infection is unlikely; conversely, if it is in the high part, infection is more likely. Dose–response relationships define the probability of infection from a known exposure level. The data are derived from naturally occurring human epidemics and outbreaks, from experimental data using animals or human volunteers and from estimates and extrapolations by experts in the field of infectious disease research and epidemiology. Dose–response estimates based on both human and animal experiences are robust for some pathogens and extremely uncertain for others. For most diseases, direct experimentation in humans is not possible, and predicting human dose– response relationships from animal dose–response data is not straight-forward. In some cases, actual outbreak or experimental data may be supplemented by expert opinion through a process designed to reach consensus from available data. There is no direct correlation between the number of people exposed and those infected. One person might be exposed to a high dose and therefore be highly likely to be infected. One the other hand, a large number might be exposed to very low doses and result in few or no infections. The results of initial infection analysis are estimates (ranges) of the number of infections likely to result from a given pathogen-event pair over a specific time period. With predictions from exposure data, along with a consideration of the possible implementation of appropriate medical intervention, along with data about case fatality rates for specific pathogens, potential fatalities can also be estimated. Assess and model secondary infections An infected person (either a laboratory worker or member of the public) may in some cases transmit the infection to other people, leading to secondary infection(s). This aspect of RA involves, first, determining whether the particular pathogen being considered can be transmitted from person-to-person, and second – for those that are transmissible – assessing the size and scope of outbreaks that might result. In some cases, there is sufficient existing information to allow detailed, quantitative mathematical modeling of transmission. In other cases, only qualitative assessment is possible. Modeling infectious diseases is a complex undertaking. The more sophisticated approaches utilize an agent-based mathematical analysis (Luke & Stamatakis, 2012) where detailed characteristics of specific populations are incorporated into the model (work related details, commuting patterns, social interactions, etc.) to model the likely spread of an infectious agent through the population. The results of quantitative modeling are the likelihood of outbreaks of various sizes per time for a particular pathogen, expressed as infections and/or deaths. Qualitative analysis of secondary transmission can predict whether such spread is possible and, based on available literature and data, may provide some indication of whether small or large outbreaks are reasonable to expect.
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Characterize risk This part of the RA summarizes the likely numbers of possible exposures, infections, and fatalities that could potentially result from the events analyzed. Risk is a function of probability and consequences, and final decisions are based on both the risk and the benefits of the proposed action. It is important to note that characterization of risk is not a prediction of what will happen, but rather an estimation of potential consequences with associated frequencies. In most cases, the reported frequencies for specific accidents seem extremely remote (one event per every 100 000 years or even less), but the key point is that risk includes not only the frequency, but the potential consequences. In this manner, a low-frequency event with high consequences may pose a greater overall risk than an event with a greater likelihood, but low consequences. An additional consideration is the risk of external factors such as an earthquake. While this type of natural disaster presents the greatest chance for loss of containment that would put the general public at risk, the stringent construction requirement for these types of laboratory facilities is such that an event sufficient to topple the facility will probably render much of the adjacent public and private infrastructure destroyed as well. Finally, in evaluating risk, an operating lifetime for a facility is generally assumed to be about 50 years, but not because the facility will necessarily be decommissioned at that point. Rather, there is an expectation that after 50 years, evolution and advancement in construction technology as well as building operations and safety systems, and the results of the present-day analysis will no longer be applicable due to continual and ongoing improvements. While it is the not intent of this article to focus on any particular risk assessment or RA results, the kind of results that can typically be expected is worth discussing. Both qualitative (describes or characterizes, but does not measure) and quantitative (counts or measures) data go into the analyses of a typical RA so that both qualitative and quantitative results will be obtained. Where clear, complete epidemiological data are available, and experience with similar events has been catalogued and documented, precise estimates of initial infections are possible, and detailed, quantitative modeling of secondary infections will be possible. In other cases, results are qualitative descriptions of a likely range of possibilities that may happen. But in either case, the results are estimates, not definitive predictions. Any particular event may or may not happen, and the outcome will be variable. Uncertainty is introduced at several levels during the analysis, so that the outcome of a RA is a range of results, not a definitive number. The level of uncertainty will depend on the event, the organism being studied, mitigating factors, and steps taken to prevent both the initial event and secondary spread of infection. Typical RA outcomes will provide a range of frequencies for the various pathogens under consideration with potential consequences of exposures, infections, and fatalities.
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Critical issues in conducting biocontainment laboratory RAs A variety of issues, both scientific and other, influence how a RA should be conducted and what should be analyzed and considered. These issues should be identified at the beginning of the project to avoid difficulties later in the process. These issues vary from project to project, but typically may includes ‘data sources and quality, risk mitigation, environmental justice and community engagement, qualifications of the RA team and independent review and advice from external scientific advisors’. Data sources and quality Central to a RA is the data that are used for the analyses. To the extent possible, real data from peer-reviewed sources and real-world experience should be used, such as data from actual human disease outbreaks. For some diseases, no appropriate studies have been completed or the diseases are so rare that data do not exist. Where such information is unavailable, estimates, reasonable assumptions, and expert group opinion can be elicited. The sources of data used and any data limitations must be clearly indicated and described in the report. For most RAs, not all desired data will be available, so decisions must be made about how to best proceed. While the goal may be quantitative modeling of infection and secondary transmission, such an analysis may not be possible, and the RA may have to accept qualitative approaches. But in any case, clarity and transparency about data should be provided. In instances where no definitive quantitative information to estimate potential risk exists, the standard practice is to use estimates at the higher end of values that are available. This practice generally results in overestimates for risk. The need to use broad estimates for data leads to uncertainty and impacts the precision of results. In a RA, results are generally expressed as ranges of values to account for this uncertainty. Variability means that the same event may have different outcomes if it occurs a number of different times, because of random chance. This is another reason that the RA results are often presented as ranges. Analyzing the impact of uncertainty and variability associated with the results should be part of a thorough RA; this is an important part of meeting the standards of transparency and clarity. Risk mitigation Many of the possible events or circumstances that might lead to release of pathogens and subsequent infections are known or foreseeable. Exactly what these events may be depends on the facility (the building and its systems as well as the environment around the site) and the work being done. Generally, system failures or SOP failures are the cause of events that lead to loss of containment. A thorough evaluation of the facility, procedures, and agents can identify likely risks, and a variety of precautions and steps can be taken to reduce them or mitigate the risks. Mitigation may be
Pathogens and Disease (2014), 71, 100–106, Published 2014. This article is a US Government work and is in the public domain in the USA.
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accomplished through the use of specialized building design features, personnel protective equipment, and personnel training and administrative procedures. Recommended strategies are discussed in BMBL. Redundancy in building systems is important and common for high-level biocontainment laboratories. Other risk reduction steps include access control, directional airflow, biologic safety cabinets, eye and face protection, gloves, gowns, and safety suits, decontamination procedures/equipment, thorough and ongoing personnel training, detailed accident response and reporting systems, strong security, redundancies, and sealed laboratories. All of these can greatly reduce probability of accidents and decrease the frequency of exposure or infections in the event of an accident. A well-conducted RA will lead to a strong mitigation plan which in turn reduces risk. Environmental justice and community engagement Federal agencies must consider environmental justice (EJ) in activities under NEPA (United Environmental Protection Agency, 2013). Minimally, the agency must determine if EJ communities are present (this includes low income, minorities, and other groups) and whether the project would result in disproportionately high adverse human health or environmental effects on these populations. As health disparities are common in EJ communities, an RA should be particularly sensitive to additional health impacts. Public concerns must be gathered and addressed, and opportunities for public involvement in the NEPA process must be provided. In the course of conducting NIH’s biocontainment RAs, principles and best practices for community engagement and communications were developed (National Institutes of Health, 2009), and these may be broadly applicable for other projects. Qualifications of the RA team For many projects that require an EA or EIS be conducted, it is desirable to employ the services of consultants that have experience with these reviews and preparing RA reports. A team consisting of the contractor’s personnel, relevant agency personnel with knowledge of the project, and (in the case of the RBL/NBLs) personnel from the university should be formed to facilitate the required work. The contractor takes the lead and has overall responsibility for the RA analyses and producing an objective report. Other team members provide data and specific knowledge regarding the project that is needed regarding the facility, procedures, and agents for risk evaluation. A variety of very specific expertise may be needed on the team as well. Some examples include experts in the fields of infectious disease modeling, wind dispersion analysis, security, knowledge about sources of data and literature reviews, and NEPA guidance. It is also extremely important that the contractor not be invested in the project and serve as an impartial, neutral body. For controversial projects, this is very critical so that the RA report will be recognized as valid. A well-qualified contractor and appropriate members on the overall team are important for a successful RA.
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Independent review and advice from external scientific advisors For some projects, it may be prudent to have a group of external expert advisors with a variety of expertise to provide input about the RA. Their input may take place at the beginning of the project as well as during execution of the RA. Typically, such a group could be asked to provide independent and scientifically based advice regarding the scope of the RA, including questions to be addressed, as well as infectious agents and scenarios to consider. They might also be asked to review background documents, evaluate scenarios, organisms, methodologies, and assumptions for the RA. Members of an advisory group with appropriate expertise might provide advice and oversight at key milestones in the conduct of RA studies regarding progress and sufficiency of approaches and results. Other advisors might have insight about how to address public comments or concerns and formulate the content of final reports. In addition to experts on infectious diseases and modeling, expertise relating to EJ, community engagement, and risk communication might be desirable.
Conclusions Our ability to respond to public health emergencies due to emerging and re-emerging highly infectious and/or pathogenic agents requires appropriate infrastructure in which to safely study and evaluate known and potential pathogens with high public health consequences. A properly executed RA is a critical step in ensuring that everyone involved, laboratory workers, facility workers, and the general public, are adequately protected so that the necessary work can proceed in safe and secure manner. The potential benefits derived from the study of these dangerous pathogens will lead to new modalities for diagnosis, treatment, and prophylaxis for some of most feared diseases in human history. The decision to proceed with a high-level biocontainment laboratory project is complex and involves considering pros and cons and balancing risks with benefits; ultimately what is best is a judgment call with many factors contributing to the decision. References Center for Disease Control (2011) Biosafety in Microbiological and Biomedical Laboratories (BMBL), 5th edn. Biosafety, Retrieved on December 19, 2013 from www.cdc.gov/biosafety/publications/ bmbl5/. Centers for Disease Control (2013) What’s new. National Select Agent Registry. Retrieved on December 19, 2013 from www. selectagents.gov/index.html. Luke DA & Stamatakis KA (2012) Systems science methods in public health: dynamics, networks, and agents. Annu Rev Public Health 33: 357–376. National Institutes of Health (2009) Fundamental principles and best practices for public and local community engagement and communications for high- and maximum-containment regional and National Biocontainment Laboratories funded through the NIAID/ NIH Emerging Infectious Diseases and Biodefense Program.
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Community engagement recommendations. Retrieved on December 19, 2013 from nihblueribbonpanel-bumc-neidl.od.nih.gov/ docs/2009/July/Final%20BRP_Community-Engagement-Reccomendations_July-13-2009.pdf. National Institutes of Health (2013) NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. Office of Biotechnology Activities, Retrieved on December 19, 2013 from oba.od.nih.gov/rdna/nih_guidelines_oba.html.
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United Environmental Protection Agency (2013) National Environmental Protection Act (NEPA). National Environmental Protection Act (NEPA). Retrieved on December 19, 2013 from www.epa. gov/compliance/nepa/. United States Department of Energy (2011) General guidance on NEPA. Office of NEPA Policy and Compliance. Retrieved on December 19, 2103 from energy.gov/nepa/guidance-requirements.
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MINIREVIEW
Biocontainment laboratory risk assessment: perspectives and considerations Amy Patterson1, Kelly Fennington1, Ryan Bayha1, Diane Wax2, Rona Hirschberg2, Nancy Boyd2 & Michael Kurilla2 1 Office of Science Policy, National Institutes of Health, Bethesda, MD, USA 2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Excellent review on risk assessment needed for biosafety level 3/4 facilities.
Keywords biocontainment laboratory; risk assessment; BSL4 laboratory. Correspondence Michael Kurilla, 5601 Fishers Lane, Bethesda, MD 20892, USA. Tel.: 301 402 4197 fax: 301 480 3235 e-mail: [email protected] Received 24 January 2014; accepted 17 February 2014. Final version published online 4 April 2014.
Abstract The ability to respond to public health emergencies involving infectious diseases as well as our ability to adequately prepare for as yet unknown or unrecognized emerging infectious diseases requires suitable facilities within which scientific investigations can take place. To ensure the safe conduct of such investigations so that laboratory workers and the general public are protected from potential consequences of accidental or intentional release of high consequence pathogens, special containment facilities have been designed and constructed. Evaluation of the adequacy of containment for these types of investigations requires a risk assessment (RA) as part of the overall construction project for these types of laboratories. A discussion of the RA process along with considerations that impact the design of such studies and the overall results is presented.
doi:10.1111/2049-632X.12162 Editor: Kelly Cole
Introduction This article discusses biocontainment laboratory risk assessment (RA) from the perspective of the decade-long experience of the National Institutes of Health (NIH) and its component the National Institute of Allergy and Infectious Diseases (NIAID) with a biocontainment laboratory construction program. The specific focus is on high-level biocontainment biosafety level 3 (BSL3) and level 4 (BSL4) laboratories designed and constructed for working with highly pathogenic human infectious agents. In response to Congressional mandate, in 2003 and 2005, NIAID awarded partial grant funding to several US academic research institutions for constructing biocontainment facilities to enhance the nation’s capability to do research on biologic agents. Specifically, awards were made for the construction of regional biocontainment laboratories (RBLs, BSL3 laboratories) and national biocontainment laboratories (NBLs, comprehensive BSL4 laboratories). The NBLs and RBLs were constructed so that improved diagnostics, therapeutics, and vaccines for protecting the public from emerging and reemerging infectious diseases could be developed. 100
This experience involved detailed oversight of the projects from planning to completion and beyond, including development and submission of environmental impact statements (EIS) and environmental assessments (EA) required by the National Environmental Policy Act (NEPA; United Environmental Protection Agency, 2013), as NIH partially funded the projects. This has provided a well-defined perspective in general on how best to approach and conduct RAs and the critical issues that must be considered and analyzed. The principles, processes, and analyses outlined in this paper have been successfully used in these projects. Discussion will begin with the conceptual framework for organizing a RA, including the process and key elements for conducting a RA, and then address ‘best practices’ derived from having engaged in RAs for construction of two NBLs and 12 RBLs. In general terms, a RA is an analysis of the probability and consequences (adverse effects to both humans and the environment) of reasonably foreseeable accidents or events that may occur as a result of various actions associated with the facility. Frequently, RAs analyze adverse effects such as radiation damage to tissues, other health effects such as cancer, loss of hearing, or lung or liver damage, traffic
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congestion, increased noise, displacement of people or activities, pollution of the environment or damage to native species. These can occur as a result of constructing and/or operating a building, particularly nuclear facilities or other industrial plants, bridges, dams, or activities that either use or produce dangerous chemicals, biologic materials, and radiation as part of their normal operations. This article is concerned with the unique situation of assessing risks that may be associated with operating high-level biocontainment laboratories where work with dangerous biologic agents and toxins takes place. There are two primary reasons to perform a RA for a biocontainment laboratory project. First and most important, it is essential to define the risks associated with the laboratory and its activities, particularly the potential adverse human health and/or environmental effects that could result from accidents involving the agents (primarily bacteria and viruses) that might be present and under investigation. When the risks have been defined and assessed, appropriate measures to minimize them can be implemented. This is known as risk mitigation and can include enhanced building design features, personal protective equipment, specific protocols and standard operating procedures (SOPs), and specialized training programs, among others. Second, projects involving federally funded or partially funded actions must meet NEPA standards. NEPA was originated in 1969 and established the broad national framework for protecting our environment. Its intent is to assure that all branches of government give proper consideration to the environment prior to undertaking any major federal action that might significantly affect the environment. EAs and EISs, which are assessments of the likelihood of impacts from alternative courses of action, are required from all federal agencies and are the most visible NEPA requirements. NEPA’s procedural requirements apply to all federal agencies in the executive branch so that NIH/NIAID’s construction projects need to be compliant with NEPA. Over the years, RA standards and guidance have been developed by federal government agencies, particularly the Environmental Protection Agency (EPA, 2013) and the Department of Energy (DOE, 2011), and it is important to conduct a RA consistent with these and other accepted approaches. Projects that involve the use of biological select agents and toxins as well as those that include recombinant DNA activities also require RAs, based on additional federal requirements. There may also be similar state and local environmental requirements for biocontainment laboratory construction and operation. EPA and DOE documents, the Centers for Disease Control (CDC)/NIH document Biosafety in Microbiological and Biomedical Laboratories [BMBL (Center for Disease Control, 2011), sections II and IV in particular], the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (National Institutes of Health, 2013) and the Select Agent Regulations (Centers for Disease Control, 2013) all provide guidance about the goals and principles of RA and conducting them. The broad principles of RA include transparency, clarity, consistency, and reasonableness. These basic principles should be kept in mind and assessed throughout the RA
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process. In general, a RA should be planned and conducted to address the question of what could go wrong and what would be the consequences of such events. Analyses must be conducted using existing guidance and established methods and approaches; the RA report must be able to survive rigorous scientific review and to the extent possible be based on well-established and scientifically validated peer-reviewed approaches. For complex and possibly controversial projects such as a BSL4 laboratory, the RA should be as comprehensive, scientifically sound, and rigorously conducted study as possible.
RA process To guide the biocontainment laboratory RA process, the following questions should be posed as overall organizing thoughts: (1) What could go wrong; what is the likelihood of each kind of potential incident or accident; what would the consequences be should something go wrong? (2) What are the risks to the workers at the laboratory and to the public if something were to go wrong? (3) Would these risks be modified if the laboratory were to be located at a different site? The RA should contain a detailed analysis of potential health and environmental effects associated with the laboratory, and it should be designed to be realistic and to consider input from the affected community and relevant experts. The analysis should examine a series of scenarios describing the likely fates of specific pathogens that might be involved in plausible procedural failures, containment system failures, human errors, and malevolent actions. A major objective of the analysis should be to estimate the likely number of primary and secondary infections and possible fatalities that might occur among laboratory workers and/or the public if an accidental release of any of the studied pathogens were to occur. A second objective should be to evaluate the possibility that pathogens released from the laboratory could persist in the environment and cause adverse effects. The RA process will be further detailed in the section that follows. In general, RA involves the following: (1) Identifying possible hazards (this answers the question of what can go wrong). (2) Analyzing their likelihood (this addresses the probability of an accident occurring). (3) Evaluating the resulting consequences (infections, fatalities, other environmental effects). In the case of a biocontainment laboratory, where the primary concern is infections or fatalities resulting from loss of containment, the steps in a thorough RA include the following: (1) Define scope; (2) Identify pathogens; (3) Identify and analyze events; (4) Estimate initial infections; (5) Assess and model secondary infections; and (6) Evaluate site differences and population differences across the various sites.
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Define scope The scope of the RA deserves detailed and careful thought at the beginning, because once it is determined, all aspects of the subsequent work will be affected. Decisions about which biocontainment levels will be analyzed, what organisms will be included, whether alternative sites are to be included, as well as such issues as agent transport accidents, potential environmental persistence of agents if they are released from the laboratory, and particular characteristics of local populations that will be considered are all important. Threat RA (TRA) is another important and necessary component of a thorough RA which, although usually kept confidential (for obvious reasons), will influence the scope of the RA and mitigation strategies. TRA involves analysis of threats and vulnerabilities associated with a facility from natural or criminal/terrorist activities, followed by development of appropriate countermeasures. Guidance from EPA, DOE, CDC, NIH, and the BMBL will also impact the RA scope. The specific features of the building and its systems influence planning the RA. The process should begin with a detailed facility analysis that considers the facility’s design attributes, its building systems, security features, and the site and surrounding environment. Knowledge of how the facility will be operated and the kinds of research activities that are expected to be conducted is essential for a well-planned RA scope. SOPs, research project plans and protocols, and equipment specifications are important resources for this analysis and are the basis for determining facility and procedure hazards. If the facility design and operation are not yet well established, assumptions must be made and then modified during the RA process as more information is available. If alternative sites are under consideration, the similarities and differences among them need to be identified so that their impact on possible hazards can be factored into the RA plan. Identify pathogens The choice of pathogens to analyze for a biocontainment laboratory RA is one of the most critical scoping decisions. On the one hand, the pathogen list should be comprehensive enough to represent the actual risks associated with operating the facility; however, it must be limited enough to practically implement. Both goals can be accomplished by selecting agents with a variety of characteristics that encompass those of the total range of agents that are likely to be studied in the laboratory once it is operational. Important characteristics to include in determining the pathogen list include the following: transmissibility, pathogenicity, BSL3 or 4 assignment, mode of transmission including vector borne with reservoirs, case fatality rate, infection period, availability and efficacy of treatments and/ or means of prevention. In addition, the list should include agents of concern to the public, as well as take into account the recommendations of expert scientific advisors to the project (see below). At a practical level, the choice will be influenced by the availability of epidemiological data 102
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to support analyses, availability of appropriate models for conducting analysis (particularly for quantitative modeling of secondary transmission), and the extent to which an agent is a recognized public health concern. A detailed review of the literature that documents the characteristics of the selected pathogens should be done so that the hazards associated with working with them are clear. The scientific literature as well as CDC and NIAID/NIH guidance including that found in the BMBL are sources for agent hazard data. A final note on agent selection for analysis is to not limit the agent repertoire to merely those under consideration for immediate utilization within an operational facility since research and public health needs evolve as science advances. Therefore, representative pathogens that span the range of the various criteria highlighted above will allow for an adequate evaluation of currently intended research activities as well as remain relevant when newer, currently unknown pathogens are identified in the future. Identify and analyze events The next phase of the RA process involves identifying, selecting, and analyzing events that might cause the release of a pathogen and result in the exposure of laboratory workers or members of the public. These potential hazards include failures of equipment, building systems, personnel, and procedures. The events identified will be a function of the facility hazard, procedure hazard, and agent hazard information described above and should include a consideration of appropriate BSL level and recommended precautions to use for work with the agents and types of experiments. Event sequence analysis should include evaluation of staff proficiency and involve input by biosafety professionals at the institution. Based on knowledge of laboratory operations and the nature of the work that will be done, combined with historical data about laboratory accidents, including real-world operating experience in existing BSL3 and BSL4 laboratories, a comprehensive list of possible accidents can be generated; it should be as inclusive as possible to start. Several hundred possible events might be identified and then considered, evaluated, and grouped into categories comprising similar or related events for further detailed examination. The final selection of specific events to analyze in detail should include frequent to rare event types, low to high consequence events, and ‘maximum reasonably foreseeable’ events. It is very important to include a reasonable range to be sure the RA meets the standard of comprehensiveness and reasonability. The list selected for detailed analysis might include a group of events such as a needle-stick accident (relatively frequent, perhaps annually, but generally low consequence), a centrifuge malfunction creating an aerosol release (moderate frequency, moderate consequence), an earthquake (very low frequency, but high consequence), and a transportation mishap (low frequency, low consequence). The many other events identified but not analyzed in detail should all be bounded or encompassed by those chosen in terms of probability and consequences. It is
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important to note that accepted guidance does not require consideration of beyond reasonably foreseeable events or ‘worst-case scenarios’ (a term which is not considered meaningful in the field of RA). Events should be chosen so that those eliminated are unlikely to pose more risk relative to those chosen for further detailed analysis. For example, a hurricane event might be considered but not included in the RA because it can be similar to an earthquake in the resultant structural damage caused to the building, but a severe earthquake is more likely to have greater consequences. Once events are chosen, analysis is then performed to estimate how often the selected events would be likely to occur; this is based on available data about laboratory accidents (such as industrial data regarding equipment failures) and past experience of those familiar with the work likely to occur in the laboratory. Depending on the specific situation, events might be analyzed that involve BSL3 and BSL4 operations or only one. Next, human exposure numbers and levels are estimated using the event frequency estimates combined with estimates of the quantities of various pathogens likely to be involved with the specific activity and the hazard under consideration along with the number of people likely to be exposed and the nature of the event. Each pathogen needs to be analyzed separately for each event as available amounts and other agent characteristics will influence final exposure. The results of the event sequence analysis are the potential consequences of various pathogen-event pairs (a specific hazard paired with a specific agent creates a potential accident for analysis), expressed in terms of how many laboratory workers or members of the public are likely to be exposed following an accident and the amount of exposure in terms of units of pathogen. The results also include the range of likely frequency for the event pair. The number of people directly exposed as a result of an accident can range from zero to many. However, most laboratory incidents have the potential to directly expose only one to at most a few laboratory workers. For example, the number of workers permitted at one time in BSL4 space is typically limited which places an upper limit on the number of potential exposures in the event of an equipment failure such as a centrifuge malfunction, while the exposure amounts would vary. In contrast, events such as a major earthquake may directly expose many members of the public, although the exposure would in most cases be very low in amount. Estimate initial infections Not all exposures to pathogens will necessarily lead to infection and disease. Whether an infection occurs depends on several factors: the specific pathogen, the amount of pathogen exposure, the dose–response relationship for that pathogen. In addition, the health of the specific individual and mitigating features such as vaccination status and antimicrobial drugs availability may influence infections. Estimating the number of initial infections that might result from an accident involves taking the exposure data and applying dose–response analysis. Higher exposure doses
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are more likely to cause infection, but this relationship varies by pathogen and the circumstances of a given exposure, such as route. If the exposure is in the low range of the dose–response curve, infection is unlikely; conversely, if it is in the high part, infection is more likely. Dose–response relationships define the probability of infection from a known exposure level. The data are derived from naturally occurring human epidemics and outbreaks, from experimental data using animals or human volunteers and from estimates and extrapolations by experts in the field of infectious disease research and epidemiology. Dose–response estimates based on both human and animal experiences are robust for some pathogens and extremely uncertain for others. For most diseases, direct experimentation in humans is not possible, and predicting human dose– response relationships from animal dose–response data is not straight-forward. In some cases, actual outbreak or experimental data may be supplemented by expert opinion through a process designed to reach consensus from available data. There is no direct correlation between the number of people exposed and those infected. One person might be exposed to a high dose and therefore be highly likely to be infected. One the other hand, a large number might be exposed to very low doses and result in few or no infections. The results of initial infection analysis are estimates (ranges) of the number of infections likely to result from a given pathogen-event pair over a specific time period. With predictions from exposure data, along with a consideration of the possible implementation of appropriate medical intervention, along with data about case fatality rates for specific pathogens, potential fatalities can also be estimated. Assess and model secondary infections An infected person (either a laboratory worker or member of the public) may in some cases transmit the infection to other people, leading to secondary infection(s). This aspect of RA involves, first, determining whether the particular pathogen being considered can be transmitted from person-to-person, and second – for those that are transmissible – assessing the size and scope of outbreaks that might result. In some cases, there is sufficient existing information to allow detailed, quantitative mathematical modeling of transmission. In other cases, only qualitative assessment is possible. Modeling infectious diseases is a complex undertaking. The more sophisticated approaches utilize an agent-based mathematical analysis (Luke & Stamatakis, 2012) where detailed characteristics of specific populations are incorporated into the model (work related details, commuting patterns, social interactions, etc.) to model the likely spread of an infectious agent through the population. The results of quantitative modeling are the likelihood of outbreaks of various sizes per time for a particular pathogen, expressed as infections and/or deaths. Qualitative analysis of secondary transmission can predict whether such spread is possible and, based on available literature and data, may provide some indication of whether small or large outbreaks are reasonable to expect.
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Characterize risk This part of the RA summarizes the likely numbers of possible exposures, infections, and fatalities that could potentially result from the events analyzed. Risk is a function of probability and consequences, and final decisions are based on both the risk and the benefits of the proposed action. It is important to note that characterization of risk is not a prediction of what will happen, but rather an estimation of potential consequences with associated frequencies. In most cases, the reported frequencies for specific accidents seem extremely remote (one event per every 100 000 years or even less), but the key point is that risk includes not only the frequency, but the potential consequences. In this manner, a low-frequency event with high consequences may pose a greater overall risk than an event with a greater likelihood, but low consequences. An additional consideration is the risk of external factors such as an earthquake. While this type of natural disaster presents the greatest chance for loss of containment that would put the general public at risk, the stringent construction requirement for these types of laboratory facilities is such that an event sufficient to topple the facility will probably render much of the adjacent public and private infrastructure destroyed as well. Finally, in evaluating risk, an operating lifetime for a facility is generally assumed to be about 50 years, but not because the facility will necessarily be decommissioned at that point. Rather, there is an expectation that after 50 years, evolution and advancement in construction technology as well as building operations and safety systems, and the results of the present-day analysis will no longer be applicable due to continual and ongoing improvements. While it is the not intent of this article to focus on any particular risk assessment or RA results, the kind of results that can typically be expected is worth discussing. Both qualitative (describes or characterizes, but does not measure) and quantitative (counts or measures) data go into the analyses of a typical RA so that both qualitative and quantitative results will be obtained. Where clear, complete epidemiological data are available, and experience with similar events has been catalogued and documented, precise estimates of initial infections are possible, and detailed, quantitative modeling of secondary infections will be possible. In other cases, results are qualitative descriptions of a likely range of possibilities that may happen. But in either case, the results are estimates, not definitive predictions. Any particular event may or may not happen, and the outcome will be variable. Uncertainty is introduced at several levels during the analysis, so that the outcome of a RA is a range of results, not a definitive number. The level of uncertainty will depend on the event, the organism being studied, mitigating factors, and steps taken to prevent both the initial event and secondary spread of infection. Typical RA outcomes will provide a range of frequencies for the various pathogens under consideration with potential consequences of exposures, infections, and fatalities.
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Critical issues in conducting biocontainment laboratory RAs A variety of issues, both scientific and other, influence how a RA should be conducted and what should be analyzed and considered. These issues should be identified at the beginning of the project to avoid difficulties later in the process. These issues vary from project to project, but typically may includes ‘data sources and quality, risk mitigation, environmental justice and community engagement, qualifications of the RA team and independent review and advice from external scientific advisors’. Data sources and quality Central to a RA is the data that are used for the analyses. To the extent possible, real data from peer-reviewed sources and real-world experience should be used, such as data from actual human disease outbreaks. For some diseases, no appropriate studies have been completed or the diseases are so rare that data do not exist. Where such information is unavailable, estimates, reasonable assumptions, and expert group opinion can be elicited. The sources of data used and any data limitations must be clearly indicated and described in the report. For most RAs, not all desired data will be available, so decisions must be made about how to best proceed. While the goal may be quantitative modeling of infection and secondary transmission, such an analysis may not be possible, and the RA may have to accept qualitative approaches. But in any case, clarity and transparency about data should be provided. In instances where no definitive quantitative information to estimate potential risk exists, the standard practice is to use estimates at the higher end of values that are available. This practice generally results in overestimates for risk. The need to use broad estimates for data leads to uncertainty and impacts the precision of results. In a RA, results are generally expressed as ranges of values to account for this uncertainty. Variability means that the same event may have different outcomes if it occurs a number of different times, because of random chance. This is another reason that the RA results are often presented as ranges. Analyzing the impact of uncertainty and variability associated with the results should be part of a thorough RA; this is an important part of meeting the standards of transparency and clarity. Risk mitigation Many of the possible events or circumstances that might lead to release of pathogens and subsequent infections are known or foreseeable. Exactly what these events may be depends on the facility (the building and its systems as well as the environment around the site) and the work being done. Generally, system failures or SOP failures are the cause of events that lead to loss of containment. A thorough evaluation of the facility, procedures, and agents can identify likely risks, and a variety of precautions and steps can be taken to reduce them or mitigate the risks. Mitigation may be
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accomplished through the use of specialized building design features, personnel protective equipment, and personnel training and administrative procedures. Recommended strategies are discussed in BMBL. Redundancy in building systems is important and common for high-level biocontainment laboratories. Other risk reduction steps include access control, directional airflow, biologic safety cabinets, eye and face protection, gloves, gowns, and safety suits, decontamination procedures/equipment, thorough and ongoing personnel training, detailed accident response and reporting systems, strong security, redundancies, and sealed laboratories. All of these can greatly reduce probability of accidents and decrease the frequency of exposure or infections in the event of an accident. A well-conducted RA will lead to a strong mitigation plan which in turn reduces risk. Environmental justice and community engagement Federal agencies must consider environmental justice (EJ) in activities under NEPA (United Environmental Protection Agency, 2013). Minimally, the agency must determine if EJ communities are present (this includes low income, minorities, and other groups) and whether the project would result in disproportionately high adverse human health or environmental effects on these populations. As health disparities are common in EJ communities, an RA should be particularly sensitive to additional health impacts. Public concerns must be gathered and addressed, and opportunities for public involvement in the NEPA process must be provided. In the course of conducting NIH’s biocontainment RAs, principles and best practices for community engagement and communications were developed (National Institutes of Health, 2009), and these may be broadly applicable for other projects. Qualifications of the RA team For many projects that require an EA or EIS be conducted, it is desirable to employ the services of consultants that have experience with these reviews and preparing RA reports. A team consisting of the contractor’s personnel, relevant agency personnel with knowledge of the project, and (in the case of the RBL/NBLs) personnel from the university should be formed to facilitate the required work. The contractor takes the lead and has overall responsibility for the RA analyses and producing an objective report. Other team members provide data and specific knowledge regarding the project that is needed regarding the facility, procedures, and agents for risk evaluation. A variety of very specific expertise may be needed on the team as well. Some examples include experts in the fields of infectious disease modeling, wind dispersion analysis, security, knowledge about sources of data and literature reviews, and NEPA guidance. It is also extremely important that the contractor not be invested in the project and serve as an impartial, neutral body. For controversial projects, this is very critical so that the RA report will be recognized as valid. A well-qualified contractor and appropriate members on the overall team are important for a successful RA.
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Independent review and advice from external scientific advisors For some projects, it may be prudent to have a group of external expert advisors with a variety of expertise to provide input about the RA. Their input may take place at the beginning of the project as well as during execution of the RA. Typically, such a group could be asked to provide independent and scientifically based advice regarding the scope of the RA, including questions to be addressed, as well as infectious agents and scenarios to consider. They might also be asked to review background documents, evaluate scenarios, organisms, methodologies, and assumptions for the RA. Members of an advisory group with appropriate expertise might provide advice and oversight at key milestones in the conduct of RA studies regarding progress and sufficiency of approaches and results. Other advisors might have insight about how to address public comments or concerns and formulate the content of final reports. In addition to experts on infectious diseases and modeling, expertise relating to EJ, community engagement, and risk communication might be desirable.
Conclusions Our ability to respond to public health emergencies due to emerging and re-emerging highly infectious and/or pathogenic agents requires appropriate infrastructure in which to safely study and evaluate known and potential pathogens with high public health consequences. A properly executed RA is a critical step in ensuring that everyone involved, laboratory workers, facility workers, and the general public, are adequately protected so that the necessary work can proceed in safe and secure manner. The potential benefits derived from the study of these dangerous pathogens will lead to new modalities for diagnosis, treatment, and prophylaxis for some of most feared diseases in human history. The decision to proceed with a high-level biocontainment laboratory project is complex and involves considering pros and cons and balancing risks with benefits; ultimately what is best is a judgment call with many factors contributing to the decision. References Center for Disease Control (2011) Biosafety in Microbiological and Biomedical Laboratories (BMBL), 5th edn. Biosafety, Retrieved on December 19, 2013 from www.cdc.gov/biosafety/publications/ bmbl5/. Centers for Disease Control (2013) What’s new. National Select Agent Registry. Retrieved on December 19, 2013 from www. selectagents.gov/index.html. Luke DA & Stamatakis KA (2012) Systems science methods in public health: dynamics, networks, and agents. Annu Rev Public Health 33: 357–376. National Institutes of Health (2009) Fundamental principles and best practices for public and local community engagement and communications for high- and maximum-containment regional and National Biocontainment Laboratories funded through the NIAID/ NIH Emerging Infectious Diseases and Biodefense Program.
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Community engagement recommendations. Retrieved on December 19, 2013 from nihblueribbonpanel-bumc-neidl.od.nih.gov/ docs/2009/July/Final%20BRP_Community-Engagement-Reccomendations_July-13-2009.pdf. National Institutes of Health (2013) NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. Office of Biotechnology Activities, Retrieved on December 19, 2013 from oba.od.nih.gov/rdna/nih_guidelines_oba.html.
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United Environmental Protection Agency (2013) National Environmental Protection Act (NEPA). National Environmental Protection Act (NEPA). Retrieved on December 19, 2013 from www.epa. gov/compliance/nepa/. United States Department of Energy (2011) General guidance on NEPA. Office of NEPA Policy and Compliance. Retrieved on December 19, 2103 from energy.gov/nepa/guidance-requirements.
Pathogens and Disease (2014), 71, 100–106, Published 2014. This article is a US Government work and is in the public domain in the USA.
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