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ILAR Journal Vol 46(1)

Facility Design Considerations for Select Agent Animal Research

Dan Frasier and Jeff Talka

Dan Frasier, P.E., is Director of Commissioning Services, Cornerstone Commissioning, Inc., Boxford, Massachusetts. Jeff Talka, A.I.A., is an Architect with CUH2A, Inc., Architecture Engineering Planning, Atlanta, Georgia.

Abstract

The events of September 11, 2001, have piqued US interest and investment in infectious disease research and the facilities that support the research. Since 1999, federal grants for biosafety level (BSL)-3, -3 agricultural (Ag), and -4 research have increased by more than 900%--to $13.1B in the fiscal years 2002 to 2004 compared with $1.2B from 1999 to 2001. This dramatic growth has forced experienced professionals from government agencies, universities, industry, design firms, commissioning firms, and contractors to work together to construct buildings that meet the demanding and unique needs of the research. This discussion pertains primarily to select agent research and provides (1) an overview of the guidelines and standards pertinent to the design and construction of biocontainment research facilities using animals, (2) design considerations appropriate for these facilities, (3) special requirements associated with BSL-3Ag agricultural research, and (4) information to prepare for the use of a state-of-the-art infectious disease research facility.

Key Words: biocontainment; biosafety; commissioning; containment; facility design; security; select agents; waste handling

Overview of Guidelines and Standards

Institutions that have plans to conduct or are already conducting research using the select agents listed in 42 Code of Federal Regulations (CFR¹) 73 (Federal Register 2002) and in 9 CFR 121 (USDA APHIS 2002) must comply with the regulations described therein. The CFR contains the statement that an institution or other entity possessing such agents "considers the requirements for handling toxins found in the appendices" of the current, 4th edition of Biosafety in Microbiological and Biomedical Laboratories (BMBL¹) (published jointly by the Centers for Disease Control and Prevention [CDC¹] and the National Institutes of Health [NIH¹] 1999). Readers are also referred to other important references, which include the following:

Department of Agriculture (USDA¹)

Animal Research Services, Facilities Design Standards 242.1M (USDA 2002a): This manual establishes agency policies, design standards, and technical criteria for application during the programming, design, construction, alteration, and renovation of Agricultural Research Service (ARS¹) buildings and facilities. This standard applies to agricultural (livestock) agents.

National Research Council (NRC¹)

Guide for the Care and Use of Laboratory Animals (NRC 1996): This publication is a primary reference for animal care and use in the United States. It provides information on the ethical care and use of animals, and on important functional and environmental recommendations for laboratory animal facilities.
Occupational Health and Safety in the Care and Use of Research Animals (NRC 1999): This primary reference addresses exposure to research animals that could adversely affect the health or safety of the animal care or research staff.

NIH

Guidelines for Research Involving Recombinant DNA Molecules (NIH 1998)
Design Policy and Guidelines for Laboratories and Vivaria (NIH 2003)
Model Commissioning Plan and Guide (NIH 2001)

References appropriate to particular facilities depend on numerous factors, including the agents being used, the source of funding, local codes, and user-mandated requirements.

Design Considerations for Containment Facilities

Select Agent Decisions

Risk Assessment and Standard Operating Procedures (SOPs¹) Preparation

The first step in developing a containment facility program is to perform a risk assessment as described in the BMBL, Section V, for the agents to be used. The "risk" is the probability of harm or infection arising from the use of the agent within the laboratory or animal holding areas (Richmond and McKinney 1999). The information obtained from the assessment is used to determine the facility features that can mitigate risk, and may include shower in/shower out facilities, effluent decontamination systems, exhaust high-efficiency particulate air (HEPA¹) filtration, and redundant infrastructure systems. The risk assessment should guide the facility design interactively with the SOPs. Therefore, early development of draft SOPs is necessary to advance the building design documents confidently.

SOPs for containment facilities are developed to assist in risk mitigation. They typically include immunization programs, the use of personal protective equipment appropriate for the agents, animals, and procedures, and effective training programs (Richmond and McKinney 1999). Facility features are required to support the SOPs and typically include such items as directional airflow, HEPA filtration, system redundancy, robust controls system, and emergency power.

USDA agents requiring biosafety level (BSL¹)-3 agricultural (Ag¹) containment also assess risk beyond the laboratory, where the infectious agents may have significant impact on the animal-based food supply and economy. The facilities supporting BSL-3Ag work use most features of BSL-4 applications because those features are required for the safe performance of pathogen research in animals that cannot be contained in laminar flow isolation cages or biosafety cabinets, as mandated for animal biosafety level (ABSL¹)-3 research (USDA 2002a).

Budget Decisions

Adequate project budgets should be established early in the planning process for the inclusion of necessary safeguards to support the SOPs. An accurate budget number requires properly developed SOPs and an educated evaluation of the building features to minimize risk. Administrators of institutions that use multiple agents may consider the use of stand-alone suites dedicated to individual agents, each furnished with shower-out and autoclave-out capabilities. This arrangement provides improved cross-contamination protection for the access corridor and may also reduce the need for multiple vaccinations to combat all anticipated agents, thus making the suite approach advantageous from a budgetary and operational perspective.

Containment facility operation is essential through emergency conditions to provide safety for users and the community, and it requires the use of costly emergency generators and redundant systems (NIH 2003). However, project cost reductions must never compromise the safety of the occupants and experiments, even when budget requirements mandate design modifications. For this reason, it is important to retain generators and system redundancy during value engineering exercises.

Flexibility

Flexibility may be desirable to allow fit-out of spaces for housing a variety of animal species, perhaps even as dramatically as converting rodent housing rooms for use with large animals, which may have significant budget impact. Rooms equipped to connect ventilated rodent housing systems to building exhaust demand a much different air distribution arrangement than is required for ventilation of large animal rooms. Animal watering systems for rodents also differ frin watering systems for livestock animals. Room layouts are substantially different, with gating systems for large animals and small cages for rodents (Ruys 1991).

Flexibility may be more readily achieved by including several levels of containment in one facility, such as BSL-3, ABSL-3, and BSL-3Ag. This hierarchy of containment typically results in a project having a lower construction cost than a comparably sized project dedicated only to BSL-3Ag. Research using certain agents listed by USDA may be conducted in a facility with a lower containment level classification through the use of proper protocols, biosafety cabinets, and glove boxes. Such research also requires final authorization from the appropriate certifying agency (Blaine 2004).

Impact on Design After September 11, 2001 (9/11¹)

Even before the events of 9/11, the US government had initiated steps to develop security measures for federal buildings to protect building occupants. On October 19, 1995, an executive order had established the Interagency Security Committee (ISC¹), with the mandate to develop construction standards primarily for new federal office buildings referred to as the ISC Security Design Criteria (ISC 2001). After 9/11, in support of the newly created National Institute for Allergy and Infectious Diseases Program for Regional and National Biocontainment Laboratories (RBL/NBL¹), the NIH developed security design guidelines for these facilities. (NIH 2003). These criteria supplement the ISC criteria.

An underlying premise for determining the security requirements for a facility is the threat and risk assessment (TRA¹). This assessment determines the factors that may contribute to a specific threat to a facility by certain groups, as well as the risk of harm and the consequences of attack. The TRA, which is a sensitive document, is a condition of the RBL/NBL program and may have applications elsewhere. Prospective users of select agents should contact NIH for applicability of the TRA for their specific project.

Security and Setbacks

Setbacks, charge weights, and hardening, which are factors for the design of a facility that result from a TRA, are established on a case-by-case basis (NIH 2003). The ISC and the Department of Defense have developed guidelines on these facility features. Users should consult the appropriate funding agency to obtain proper direction for security.

Other security system devices are gaining popularity in animal facilities, and specifically BSL-3Ag facilities. They include the following:

Closed circuit television (CCTV¹) systems around the building perimeter, supplemented by sufficient lighting levels.
CCTV within the animal rooms for surveillance of animals under study. Cameras are protected by plastic bubbles in containment areas, and staff can gain access to the camera from outside the containment barrier.
Zoned security access design, progressing from least restricted to more secure. Devices to support security include card readers and biometric devices. Care must be taken in their selection and specification, and protocol development for some security devices may not work well in biocontainment laboratories due to decontamination concerns such as some biometric devices that may not sense hand readings by a gloved hand.
Perimeter access and enclosures, which can act detrimentally by advertising a security concern.

Special Requirements for Agriculture Facilities: Designing for Overlap Agents

As noted in 42 CFR 73, not all select agents are classified as BSL-3Ag. Overlap agents are listed among the select agents that are intended to be researched in both nonagricultural and agricultural laboratories. Animal disease centers funded by the US Department of Health and Human Services are required to develop a biological countermeasures program that focuses on high-consequence biological threats. These threats include agricultural diseases that could result in high-volume contamination of food supplies.

Both the CDC and the USDA use definitions and guidelines for containment and the principles of primary and secondary containment. In the traditional sense, primary containment is achieved in a biosafety cabinet. Secondary containment is achieved in the laboratory enclosure, or room, where engineering principles such as directional airflow and bubble tight dampers are used to maintain secondary containment in the event of a failure or spill outside the biosafety cabinet. However, in the case of large animals infected with the select agent, the BSL-3Ag room itself becomes the primary containment element (USDA 2002a, section 9.4.4). As mentioned above, the nature of the BSL-3Ag space closely resembles the BSL-4 construction outlined in the BMBL. Examples of such building features are double HEPA exhaust (Figure 1), effluent decontamination, and pressure decay testing of the envelope (Figure 2). In Table 1, the information from the ARS Guideline is presented for reference.

Figure 1 Example of mechanical floor, immediately above the containment spaces to minimize the length of potentially contaminated ductwork. All service to mechanical equipment is performed outside the containment barrier.

Figure 2 Example of dirty corridor showing air pressure-resistant doors. The surfaces of the corridor allow for high-temperature wash down as well as for chemical decontamination. All contaminated material or animal flow is through this corridor to a decontamination chamber, to a sterilizer, or to necropsy.

Critical Path Decision-making

When considering the process for establishing a containment facility, one should first assess which agents are to be studied with associated risks, and then develop a protocol for handling. Some of the recommended steps are outlined below:

1. Assess the agent and the risk. To accomplish this task, ask the following questions:

What is the nature of the agents used?
What is the potential of exposure to personnel?
What are the processes used with the agent?
What is the potential for cross-contamination?
What are the waste products?
How will various medical waste be handled?

Evaluation of medical waste handling should include references to agency requirements and should involve the development of a waste management program (we recommend following the outline provided by Salkin and colleagues [2000]).

2. Consider issues relating to primary containment, including the important biosafety cabinet, which provides primary containment as well as protection of the agents used, and the isolation box. The nature of the agent used determines operator protection. Blood- and air-borne agents determine biosafety level (according to the guidelines of CDC/NIH or ARS, or the Select Agent Rule).

3. For secondary containment, consider including the following:

Room enclosure;
Airflow volume and direction;
Anterooms and vestibules;
Sterilization of materials exiting the laboratory;
Decontamination chamber for large equipment;
Wash down for personnel;
Liquid biowaste treatment; and
Solid waste (which may include prions) with sodium hydroxide.

4. For personnel protective equipment, evaluate the following:

Location of gowning and degowning;
Extent of standardization;
Requirements related to specific tasks (e.g., double gloving); and
Selection of breathing apparatus.

5. For decontamination requirements, the following items should also be reviewed:

Method for decontamination (e.g., formaldehyde, vaporized hydrogen peroxide);
Frequency of decontamination;
Dwell times for decontaminant;
Capability of facility environmental control system to meet the relative humidity and airflow setpoints required for effective decontamination;
Integration of the decontamination with the building automation system; and
Method to test the efficacy of decontamination procedures.

According to Abraham and colleagues (1997), "Methods for testing the efficacy of decontamination procedures must be precise and reproducible when using a test organism" (p. 30-38).

Distinction Between BSL-3, -4, and -3Ag

Institutional administrators who are considering the study of select agents categorized as BSL-3 or ABSL-3 may be tempted to consider overlap agents that would require BSL-3Ag facility features. First, it is important to note that agents studied in 3Ag facilities are not necessarily select agents, nor do all select agents require BSL-3Ag facilities. Second, BSL-3Ag are most often required as a result of animal size. A comparison of the facility features required or recommended for all biosafety levels reveals that BSL-3Ag is much like a BSL-4 facility in terms of construction and operating costs. Therefore, it is important for design and planning teams to understand the budgetary and site implications involved in the construction of a BSL-3Ag facility. The USDA Animal and Plant Health Inspection Service (APHIS¹) 9 CFR 121 regulation is an important reference that lists animal agents and toxins (USDA APHIS 2002b). In Table 1, containment facility features associated with BSL-1 through BSL-4 and BSL-3Ag buildings are listed.

Unique Building Features and Issues

As mentioned above, the animal holding or procedure room is the primary containment in BSL-3Ag facilities, where livestock animals are too large to be contained in a separate enclosure such as a biosafety cabinet. Design details must therefore be refined, discussed, and reviewed to construct a very reliable and durable facility. The design must address the issues inherent in the movement of large animals through the facility to provide safety for the animals, caregivers, and researchers.

Design Points to Consider

It is important to consider the following aspects in the design of large animal facilities:

The placement of mechanical spaces is one such consideration. Locating mechanical spaces above and below containment allows for improved inspection of piping for effluent below and accessible HEPA housings above. This arrangement also reinforces the containment facility "box in a box" concept and can minimize contaminated duct and pipe runs (Figure 3).
The utilization of appropriate materials for containment enclosures is another important consideration. One example of appropriate materials are poured concrete formed walls, which are more durable than concrete masonry unit construction.
Planning of the design should begin with early and thorough study of the animal movement. Understanding the movement of animals through the facility provides insight into the design of penning and gating and promotes animal handler safety (Figure 4).
It is important to study maintenance routines and protocols early and thoroughly. This study should include the identification of methods or designs that allow maintenance staff to conduct activities such as changing filters outside containment areas.
The agents to be handled should be identified. Proper and early identification permits accurate documentation of the program with the appropriate levels of containment (BSL-3, BSL-3Ag), and the inclusion of features that permit flexibility and contingency (e.g., use of a BSL-3Ag animal room as a laboratory for certain agents by the simple addition of moveable benches or biosafety cabinets).
Adequate cost models should also be prepared. Security and waste disposal are two key areas for which this applies (e.g., the use of biometrics and CCTV are common considerations in BSL-3Ag facilities).
It is necessary to provide alternative solid waste (carcass) disposal methods. Incineration has become very problematic for new facilities due to environmental considerations and has led to thermal and alkaline tissue digestion systems. Each system requires extensive planning and infrastructure.
The provision of adequate high-quality space for staff to relax is also necessary. Work in a high-containment facility involves some degree of stress, and staff welcome a place to relax.

Figure 3 Example of high-efficiency particulate air filter banks. The redundant filter housing allows filters to be changed while the room is in use. In-place filter challenges can also be accomplished.

Figure 4 Example of animal gating in a typical holding room. The gating separates the animals from the handler. The gating also includes head gates to keep the animal still during the performance of procedures.

Animal Movement and Personnel Safety

It is important to consult the animal husbandry staff when developing protocols as well as handling and care routines for a facility. A good resource for initiating design is the Handbook of Facilities Planning (Ruys 1991). We also recommend consulting the Guide for the Care and Use of Laboratory Animals (NRC 1996).

Configuration of penning and gating systems is among the more challenging design tasks related to BSL-3Ag facilities. It may be necessary to use pens and gates to accommodate multiple animals and different species in holding rooms. Gating systems are used to assist in leading animals from the point of delivery through corridors to the animal room in a sequential manner, similar to a ship moving through a series of locks in a canal. A properly designed system provides barriers to protect the animal handler from the potential danger of a charging animal.

Within the animal rooms, gating is used for animal holding and separation as well as for restraint during procedures. Head gates, squeeze chutes, and stocks are used to restrain the animals during procedures. Gating should be configured to afford safety to the animal handler while providing safe access to the animal in the locations needed. During the design phase, mock-ups of gating configurations should be constructed and tested with the appropriate animal species so that any necessary modifications can be made before the final design. Material selection is also critical. The selected material must be strong and durable to withstand the chemical decontamination processes. We recommend considering materials such as galvanized steel, stainless steel, and aluminum. Coated products may be evaluated; however, it is imperative to inspect the moving parts in the gating systems to avoid worn coatings on or near hinges and latches.

Alternative Solid Waste (Carcass) Disposal

With the increasing rigidity of environmental regulation and difficulty involved in obtaining a license for new incinerators, tissue digesters (both alkaline hydrolysis and thermal digestion) have become a standard feature in the design of new high-containment facilities (Richmond et al. 2003). Various available systems utilize similar technologies, and most are designed primarily to eliminate prions. Thermal hydrolysis and hot alkaline hydrolysis, two prevalent technologies, use high temperatures and pressures to break down the prion molecules. The resulting outputs include a high-temperature liquid and sterilized solid residue. The design team should research and accurately assess these technologies to make an informed choice. It is especially important to evaluate the infrastructure that is required to support the digestion process. The fully integrated digester system usually includes additional facility components to bring the system into operational compliance. For example, the digester effluent may be highly alkaline and in excess of 150°C, requiring waste neutralization (acid) and temperature treatment systems (cooling tower or domestic cold water) before the effluent is released into the municipal waste system. The decision-making process should include a review of case studies and site visits of operating systems.

Preparing for Facility Operation

Certainty of Outcome

Certainty of outcome is a concept that focuses on the successful completion and implementation of the design to achieve the desired objective--successful containment and APHIS approval of the facility for work with a specific biological agent. As mentioned above, the ARS Guidelines published by USDA are internal guidelines for internal projects. However, when a non-USDA entity such as a university endeavors to conduct research on select animal agents and toxins, the APHIS inspector determines whether the institution has followed the Guidelines and should be accepted. If the goal of the facility is to perform as a containment facility, the detailing of its enclosure must pass the pressure decay test mandated by the ARS Guidelines. Requirements include robust walls, coatings that will withstand abuse and chemical cleaning, and proper filtration in mechanical systems.

Predetermination of Facility Performance

Mock-ups and computational fluid dynamics (CFD¹) have become standard methods to predetermine the integrity of the building structure and the effectiveness of environmental control strategies for high-containment laboratories and animal facilities. Mock-ups of building envelope, structural members, and doors are useful to evaluate the constructability and feasibility of facility features. It is also effective to analyze imbeds, penetrations, and aesthetics using this method. The cost and time savings can significantly outweigh the expense and effort of constructing mock-ups because the disruption of demolition and rework is exorbitant, particularly with the complexity of constructing level 3Ag and level 4 facilities.

CFD is the study of fluid motion through particle analysis to model airflow, temperature, and particle movement in a defined space. Its application in laboratories and animal facilities has increased as the accuracy of CFD software and its application has improved to simulate closely the actual conditions developed by heating, ventilating, and air-conditioning systems and by effluents, gaseous anesthetics, and other fluid flows. Figures 5 and 6 are examples of airflow and temperature modeling in animal holding areas.

Figure 5 Computational fluid dynamics modeling of airflow in a static cage rodent holding room. Image courtesy of Scott Reynolds, Computer Aided Engineering Solutions, Binghamton, New York.

Figure 6 Computational fluid dynamics modeling of temperature gradients in a static cage rodent holding room. Image courtesy of Scott Reynolds, Computer Aided Engineering Solutions, Binghamton, New York.

Verification of Facility Performance

Commissioning is the quality-oriented process that is required to verify that the performance of a biocontainment facility and its systems meet predefined objectives and criteria. The effectiveness of the commissioning process greatly depends on the clarity of the operational objectives and functional performance criteria. A well-documented program of requirements and the project intent provide the necessary pass-fail criteria to test, accept, and certify the facility for its intended use.

The following elements are necessary for a successful biocontainment facility commissioning process:

Design document reviews from a commissioning perspective, focused on biosafety, control system sequences of operation, and specialty system integration;
Mutual, willing participation of all members of the commissioning team: owner, commissioning authority, architects/engineers, contractors, vendors;
Agreement on a comprehensive list of systems and components to be commissioned;
Conclusive system testing, including thorough failure analysis;
Training of appropriate staff on facility systems by qualified instructors; and
Effective documentation of deficiencies from discovery through resolution.

Inspection of BSL-3Ag and BSL-4 Containment Facilities

Before a facility is approved to use a specific agent, the facility must apply to the appropriate agency: the CDC for Department of Health and Human Services agents, or APHIS for USDA agents (Blaine 2004). Either agency is appropriate for the use of overlap agents. The Select Agent Rule, 42 CFR 73.16, and 9 CFR 121 address inspection of facilities for select agents (DHHS 2002; Federal Register 1999). Inspections ensure that facilities meet certain minimum safety requirements for work with infectious agents and toxins. In the case of select animal agents and toxins, APHIS is the inspecting agency.

Before inspection, the applying agency should be familiar with the requirements for that agent and perform an internal audit for compliance. According to 42 CFR 73.11, a security plan that addresses policies and procedures for the areas that will contain the select agent should be in place. A responsible official (RO¹) should be identified to serve as the point of contact for the organization. The RO should be familiar with the requirements of the Select Agent Rule and have the authority and responsibility to act on behalf of the organization.

Development of SOPs

SOPs should be developed during the planning process for the facility. The procedures will inform the design team of the level of containment work planned as well as the anticipated movement of personnel, animals, and materials. The RO should be included in the group authoring the SOPs to have appropriate input regarding design and use of the facility to conform to the Select Agent Rule. SOPs should be developed for each agent used based on a risk assessment for each agent, as well as plans for amenities and enhancements to containment.

Staff Training

It is not possible to overemphasize the importance of training staff in protocols and safety. With the recent move toward more BSL-3, 3Ag, and BSL-4 space, more people are required to work in these facilities. The National Laboratory Training Network is a training resource sponsored by the Association of Public Health Laboratories and the CDC. The National Center for Infectious Disease through the Emerging Infectious Disease Laboratory Fellowship Program also assists in training scientists for work on infectious disease. Additional information on these programs is available online (www.phppo.cdc.gov/nltn and www.cdc.gov/ncidod/eidlsp.html).

Summary

The design, construction, and operation of biocontainment level 3 and higher laboratory animal facilities are extremely demanding tasks that require concerted efforts from many dedicated individuals. It is imperative that the research is understood and agreed upon so that appropriate decisions can be made before a facility is taken beyond the program or planning phase. Knowing where to obtain pertinent information and building a team of experienced team members are paramount to the success of a biocontainment facility.

¹Abbreviations used in this article: 9/11, September 11, 2001; ABSL, animal biosafety level; Ag, agricultural; APHIS, Animal and Plant Health Inspection Service; ARS, Agricultural Research Service; BMBL, Biosafety in Microbiological and Biomedical Laboratories; BSC, biological safety cabinet; BSL, biosafety level; CCTV, closed circuit television; CDC, Centers for Disease Control and Prevention; CFD, computational fluid dynamics; CFR, Code of Federal Regulations; DDC, direct digital controls; HEPA, high-efficiency particulate air; HVAC, heating, ventilation, and air conditioning; ISC, Interagency Security Committee; NIH, National Institutes of Health; NRC, National Research Council; RBL/NBL, regional and national biocontainment laboratories; RO, responsible official; SOP, standard operating procedure; TRA, threat and risk assessment; USDA, US Department of Agriculture.

References

Abraham G, Leblanc Smith PM, Nguyen S. 1997. The effectiveness of gaseous formaldehyde decontamination assessed by biological monitoring. J Am Biolog Safety Assoc Vol 2, No 1: p 30-38.

Blaine J. 2004. Facility Inspections Under the CDC Select Biological Agents and Toxins Rule. Presented at the Centers for Disease Control and Prevention, Atlanta, Georgia, January 27, 2004.

CDC [Centers for Disease Control and Prevention] and NIH [National Institutes of Health]. 1999. BioSafety in Microbiological and Biomedical Laboratories. 4th ed. Washington DC: GPO. Available online (http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm).

DHHS [Department of Health and Human Services]. 2002. Federal Register. 42 CFR 73. List of Select Agents. Washington DC: GPO.

DHHS [Department of Health and Human Services]. 2004. Staff article. Available online (http://www.dhs.gov/dhspublic/interapp/press_release/press_release_0380.xml).

EPA [Environmental Protection Agency]. 1999. PA 40 CFR Part 60.51c; OSHA; 29 CFR Part 1910.1030[b]; US Public Health Service 42 CFR Part 72.3. Washington DC: GPO.

Federal Register. 1999. 42 CFR 73. Select Agent Rule. Washington DC: GPO.

ISC [Interagency Security Committee]. 2001. ISC Security Design Criteria for New Federal Office Buildings and Major Modernization Projects. (In Press).

NIH [National Institutes of Health]. 1998. Guidelines for Research Involving Recombinant DNA Molecules. Federal Register 59 FR 34496. Washington DC: GPO. Available online (http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html).

NIH [National Institutes of Health]. 2003. Physical Security Design Guidelines for NIAID National and Regional Biocontainment Laboratories. (In Press).

NIH ORS DES [National Institutes of Health, Office of Research Services, Division of Engineering Services]. 2001. Available online (http://des.od.nih.gov/eWeb/research/farhad2/Commissioning/nih_cx_guide/ComGuideTitle.htm).

NIH ORS DES [National Institutes of Health, Office of Research Services, Division of Engineering Services]. 2003. Available online (http://des.od.nih.gov/eWeb/policy/html/policy-index.html).

NRC [National Research Council]. 1996. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington DC: National Academy Press.

NRC [National Research Council]. 1997. Occupational Health and Safety in the Care and Use of Research Animals. Washington DC: National Academy Press.

Richmond JY, Hill RH, Weyant RS, Nesby-O'Dell SL, Vinson PE. 2003. What's hot in animal biosafety? ILAR J 44:20-27.

Richmond JY, McKinney RW, eds. 1999. Biosafety in Microbiological and Biomedical Laboratories. 4th ed. Washington DC: US DHHS.

Ruys T. 1991. Handbook of Facilities Planning, Vol 2. Laboratory Animal Facilities. City: Van Nostrand Reinhold.

Salkin I, Krisiunas E, Thumberg W. 2000. Medical and Infectious Waste Management. Anthology of Biosafety II. Mundelein IL: American Biological Safety Association. p 140-160.

USDA APHIS [US Department of Agriculture, Animal and Plant Health Inspection Service]. 2002. Available online (http://www.cdc.gov/od/sap/docs/btarule.pdf).

USDA ARS [US Department of Agriculture, Animal Research Services]. 2002. ARS Facilities Design Standards, 242.01. Facilities Division, Facilities Engineering Branch, AFM/ARS. Washington DC: GPO. Available online (http://www.afm.ars.usda.gov/ppweb/242-01m.htm).

Additional Pertinent Resources

The following recommended reading may be useful for the planning and design of biocontainment research facilities: Hessler JR. 1995. Methods of biocontainment. In: Bayne KAL, Greene M, Prentice ED, eds. Current Issues and New Frontiers in Animal Research. Greenbelt MD: Scientists Center for Animal Welfare. p 61-68.

Hessler JR, Broderson JR, King CS. 1998. Small animal research facilities. In: Richmond JY, ed. An Anthology of Biosafety: Perspectives on Laboratory Design. Mundelein IL: American Biological Safety Association. p 191-217.

Hessler JR, Höglund H. 2002. Laboratory animal facilities and equipment for conventional, barrier, and containment housing systems. In: Hau J, Van Hoosier G, eds. Handbook of Laboratory Animal Science, Selection and Handling of Animals in Biomedical Research. Vol 1, 2nd ed. London: CRC Press. p 907-953.

Hessler JR, Leary SL. 2002. Design and management of animal facilities. In: Fox J, Lowe F, eds. Laboratory Animal Medicine. 2nd ed. New York: Academic Press. p 127-172.

King CS, Hessler JR, Broderson JR. 1998. Small animal research facility management. In: Richmond JY, ed. An Anthology of Biosafety: Perspectives on Laboratory Design. Mundelein IL: American Biological Safety Association. p 219-231.

Quimby F. 1998. Large animal research facilities. In: Richmond JY, ed. An Anthology of Biosafety: Perspectives on Laboratory Design. Mundelein IL: American Biological Safety Association. p 233-254.

Richmond JY, ed. 1998. An Anthology of Biosafety: Perspectives on Laboratory Design. Mundelein IL: American Biological Safety Association.