1
Introduction

Biological warfare agents (BWAs) possess properties that complicate defensive measures against them. First, the effective concentrations can be sufficiently low that an airborne attack need not be obvious or even directly sensible. Secondly, latencies or incubation periods between exposure and the onset of physiological reactions or symptoms are typically long (hours to days). By the time symptoms appear and clinical diagnosis is possible, the most effective treatment period may have passed. Simple awareness of an attack allows for the possibility of taking preventive action, such as donning protective equipment, to minimize exposure and initiate timely treatment. Awareness of the type and extent of an attack would also permit commanders to assess impact of the attack on meeting mission goals. These considerations make the development of fast, reliable BWA detectors that can alert personnel to possible BWA aerosol exposures a priority for the Department of Defense (DOD).

The development of detectors capable of providing the protections described above is a complex process. This report specifically addresses one step in that process, that of performance validation (test and evaluation) of candidate biological aerosol detection systems. Candidate detectors are subjected to biological aerosol test samples and their responses are evaluated to identify those that meet currently established requirements, such as minimum detectable concentration thresholds. The committee was asked to evaluate agent-containing particles per liter of air (ACPLA), the current standard unit of measure for biological aerosols.

1.1
REQUEST TO COMMITTEE

The DOD Joint Chemical and Biological Defense (CBD) Program’s current requirements for evaluating biological aerosol detectors are stated in Agent-Containing Particles per Liter of Air (ACPLA). ACPLA is not a measurement that can be made directly. It is inferred both from the measurement made by the referee instruments and by what is known about the test sample. For example, instruments may measure colony forming units (CFU) of bacteria, plaque forming units (PFU) of viruses, and nanograms or picograms of toxins in a given volume of air. The test protocol for evaluating detectors is often designed with a controlled release of a test agent or simulant that challenges the candidate detector. Referee systems are used to calibrate the source as well as the detection system being tested.1 However, these systems are not standardized across all tests and evaluations done for DOD and are often appropriately designed to be as simple as

1

For the purposes of this report, the term “detector” is used to describe equipment that is under evaluation or used in the field, “referee” corresponds to the description provided here, and “instrument” is used generically to describe the equipment and components in either detector or referee systems.



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1 Introduction Biological warfare agents (BWAs) possess properties that complicate defensive measures against them. First, the effective concentrations can be sufficiently low that an airborne attack need not be obvious or even directly sensible. Secondly, latencies or incubation periods between exposure and the onset of physiological reactions or symptoms are typically long (hours to days). By the time symptoms appear and clinical diagnosis is possible, the most effective treatment period may have passed. Simple awareness of an attack allows for the possibility of taking preventive action, such as donning protective equipment, to minimize exposure and initiate timely treatment. Awareness of the type and extent of an attack would also permit commanders to assess impact of the attack on meeting mission goals. These considerations make the development of fast, reliable BWA detectors that can alert personnel to possible BWA aerosol exposures a priority for the Department of Defense (DOD). The development of detectors capable of providing the protections described above is a complex process. This report specifically addresses one step in that process, that of performance validation (test and evaluation) of candidate biological aerosol detection systems. Candidate detectors are subjected to biological aerosol test samples and their responses are evaluated to identify those that meet currently established requirements, such as minimum detectable concentration thresholds. The committee was asked to evaluate agent-containing particles per liter of air (ACPLA), the current standard unit of measure for biological aerosols. 1.1 REQUEST TO COMMITTEE The DOD Joint Chemical and Biological Defense (CBD) Program’s current requirements for evaluating biological aerosol detectors are stated in Agent-Containing Particles per Liter of Air (ACPLA). ACPLA is not a measurement that can be made directly. It is inferred both from the measurement made by the referee instruments and by what is known about the test sample. For example, instruments may measure colony forming units (CFU) of bacteria, plaque forming units (PFU) of viruses, and nanograms or picograms of toxins in a given volume of air. The test protocol for evaluating detectors is often designed with a controlled release of a test agent or simulant that challenges the candidate detector. Referee systems are used to calibrate the source as well as the detection system being tested.1 However, these systems are not standardized across all tests and evaluations done for DOD and are often appropriately designed to be as simple as 1 For the purposes of this report, the term “detector” is used to describe equipment that is under evaluation or used in the field, “referee” corresponds to the description provided here, and “instrument” is used generically to describe the equipment and components in either detector or referee systems. 9

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10 possible. Referee equipment may also include instruments to measure overall aerosol particle count, sample fluorescence, and other characteristics of the aerosol. Variation in both the methods of characterization and the units used to quantify the amount of airborne agent material has created a barrier to comparison and cross-correlation of quantitative test results. To address these issues, the DOD Joint CBD Program seeks a standard unit of measure that can be used for biological material independent of the state of the material (aerosol or aerosol resuspended or captured in liquid) and independent of agent type (i.e., bacteria, viruses, or toxins). The department asked the National Academies to conduct this study addressing the use of measurement in the testing of aerosol detector, whether ACPLA is the most appropriate measure and what alternatives exist. If one unit of measurement is not obtainable, the DOD seeks to establish a relationship for comparison of different units.2 1.2 DETERMINING A STANDARD UNIT OF MEASURE The charge was to determine whether it is possible to develop a single unit of measure for airborne biological agents that may include bacterial vegetative cells, bacterial spores, virions, and biological toxins. The ultimate purpose of this unit of measure is to aid in the evaluation of sensors that are designed to warn and provide a measure of protection against the risk of exposure. Modes of action and the nature of the health threat vary widely among the different possible agents, and may even vary with the mode of exposure to a particular agent. However, the different biological agents share a common feature, and that is the hazard they pose to exposed humans. This feature is also shared by pathogens associated with naturally-occurring epidemics such as SARS, avian influenza, or toxins associated with red tide. This report focuses on biological warfare agents, but the concepts presented are equally applicable to a broad range of airborne pathogens, biological toxins, and chemical agent aerosols. The potential harm of a BWA attack depends on such factors as the type of agent, activity or viability of the agent, quantity released, and method and circumstances of dispersal. As an illustration, the received dosage of a biological agent, such as anthrax, from which 50 percent of the exposed population dies (lethal dosage 50 percent, or LD50) can be obtained from multiple (e.g., internet) sources as a number between 5000-20,000 spores. What is not generally discussed in this type of reference is the dependence of the LD50 quantity on the specific strain of anthrax. For example, the Aum Shinrikyo cult conducted several unsuccessful biological warfare agent (BWA) attacks in Tokyo in the early 1990s. Only one of these attacks, in 1993, was even recognized at the time. The lack of harm and the failure to detect the attack were due in large part to the selection of a vaccine strain of B. anthracis as the agent. If the group had selected a virulent strain to distribute, the outcome could have been different. Thus, LD50 is a critical characteristic of a BWA, and one can quickly appreciate that in order to gauge the effectiveness of an attack, a detection system should not only measure the number of B. anthracis spores present but also provide a measure of both viability and virulence of the agent. If a unit of measure does not take biological activity of the agent into account, it will have little use as a measure of the hazard a released agent presents. Despite the many sources of potential variability in BWA attacks, it is useful to consider an idealized detector to help define appropriate units of detector performance. If consensus can be reached on an appropriate method of quantification for BWA aerosol sensors, the new method 2 See Appendix B for the full statement of task.

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11 can serve as a reference point to guide research and development, and to prioritize knowledge and data gaps. The actual measurement and characterization of biological aerosols will always be constrained by current scientific understanding and technological capability. It is necessary to develop a unit that can be implemented with current capabilities, but that will be robust enough to accommodate improvements in instrumentation and changes in the understanding of BWA aerosols. 1.2.1 Biological Warfare Agents This study seeks to address appropriate detector measures for traditional biological warfare agents (BWAs): bacteria (both vegetative cells and spore forms), viruses, and toxins. Each of these can be regarded as having an irreducible minimum unit: • Bacteria—a single cell or spore; • Viruses—a virion; and • Toxins—a single molecule. Although the three traditional classes of BWAs are our focus, some attention was given to making the overall framework relevant to broader classes of toxins, including chemically synthesized toxins, non-protein biological effectors, and pathogens that are not traditionally considered in BW including protozoa and fungi. The approach recommended in this report is sufficiently flexible to accommodate any future modification or expansion of the BW threat classes. At present, the definition of chemical versus biological agents is based primarily on the method of production. However, this distinction may be blurred somewhat as the capability to synthesize biological toxins expands. Therefore, the categories of biological toxins and chemical warfare agents can seem similar, from the perspective that exposure effects of certain BW toxins, such as botulinum, may be similar to some CW nerve agents, such as sarin. However, another important physical distinction exists: while CWAs include both molecular vapors (gasses) and particles, all BWAs are particulate materials (powders, aerosols). None of the BWAs, including biological toxin compounds, has a measurable vapor pressure at normal temperature and pressure, and therefore BWA exposure by an airborne attack necessarily involves the release or dispersion of suspended particles as aerosols. Consequently, a physical description of a BWA release would include some enumeration of the quantity of particles that contain these irreducible agent entities per unit volume of air. (The different types or classes of BWAs are described in more detail in Chapter 3.) Currently, Agent-containing Particles per Liter of Air (ACPLA) is the DOD standard for describing the concentration of BWA aerosols for all agent types. 1.2.2 Characteristics of an Ideal Unit of Measure What would an ideal detection system provide? To manage risk to troops or exposed populations, decision makers need a measure of the existing and future risk from an attack. During the attack, decision makers would need to know the identity of the hazardous biological

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12 material and the concentration per unit volume of air. Later, it will be necessary to consider such additional risks as the propagation of the bioaerosol cloud, continuing exposure risks, and resuspension of settled material.3 Determining the actual exposure to a BWA that troops are likely to experience from an aerosol attack is difficult to assess for several reasons, many of which will be discussed further in subsequent sections of this report. Specific agent type or strains; method of dissemination; method of preparation, meteorological conditions, viability, and infectivity as a function of particle size all affect the exposure experienced by troops. Comprehensive assessment of the threat is substantially complex, with significantly greater information being required of the detection system than only the quantification and identification of a particular class of agent. The goal of this report is to address one small part of this picture by exploring the possibility of a standard unit of measure for accurate performance comparison of bioaerosol detection systems. The report argues that an ideal unit of measure would also set the foundation for using detection systems to measure health risk and facilitate informed judgments. The goal of this section is to illustrate why an ideal assessment of a BWA threat is inherently complex, and not all of the information needed to assess the risks is currently available. Any proposed unit of measure should not only be useful given current technological capabilities but also be capable of approaching this ideal goal as more information becomes available. This is not to suggest that definitive empirical information, for example, from non-human primate studies will be readily forthcoming due to the inherent challenges in such studies. In addition, limited opportunity exists for gathering information for agents of interest during naturally occurring disease outbreaks. Nevertheless, even imprecise measures of lethality would be helpful in setting priorities for how sensitive detectors need to be to different bioagents. At present, exposures to bacteria, virions, and toxins are expressed in units that reflect the numbers of agent-containing particles per unit volume (typically a liter) of air. For bacterial agents, this quantity has been called ACPLA. Informally, the term has been extended to virus or toxin exposures as well, but the information contained in the unit does not adequately reflect the biological effects of the different agents. ACPLA says nothing about the number of agents to which a person may be exposed (because it does not account for how much agent is contained in each particle), nor does it provide insights into the nature of the exposure (i.e., the difference between large particles that will deposit agent in the nose or throat when inhaled, and smaller particles that may convey agent into the lower airways). ACPLA also fails to account for the dramatic differences in the health hazard posed by different agents; the recipient of an ACPLA count must know what agent is detected and understand the health hazard posed by that agent in order to determine the proper course of action (e.g. antibiotics will not be effective treatment for viral or toxin agents). ACPLA is, therefore, not suitable for use as a single unit of measure for reporting bioaerosol data. Another possible unit, agent concentration in irreducible units (e.g., spores), suffers from similar issues as ACPLA. For example, assume a concentration of one anthrax spore per cm3, which is equivalent to 1000/liter, or 106/m3, and that a single spore has a volume of 1 µm3 (approximately true, on average). This means that an equivalent mass concentration would be achieved by one 10 µm particle per liter, or one 100 µm particle per m3. The larger agglomerate particle will settle out of the air faster and will likely not be as persistent, nor be transported as far as smaller particles, although turbulence and convection will allow particles to be transported 3 For more information about factors influencing a health risk assessment in a military context see Strategies to Protect the Health of Deployed U.S. Forces: Analytical Framework for Assessing Risks (NRC 2000).

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13 much farther than simple sedimentation models may suggest. While they are airborne, the larger particles are less likely to be inhaled. As the particle size increases the point of deposition moves from deep in the lungs to the bronchi to higher locations in the nasopharyngeal system, significantly changing both the infectivity and the lethality of the attack. At the point where the aerodynamic drag force on the particle for normal breathing intake velocities is small compared to its inertia, the particle has a low probability of being inhaled at all. An alternate representation of concentration of biological material in an aerosol is the number of colony-forming units (CFU) of bacteria or plaque-forming units (PFU) of virus or molecules or mass of toxins per unit volume of air. These measures better reflect the concentration of agent to which a person may be exposed and provide the ability to determine whether an agent is capable of producing an adverse biological outcome, but still lack the detail needed to fully assess risk. As will be discussed in greater detail in later chapters, important factors, such as particle size, are lost with these units. None of the above units of measure adequately achieves the goal of providing information about the potential health risk to exposed populations or troops, and an understanding of the possible health outcome could significantly affect a decision maker’s course of action. 1.3 THE HEALTH PROTECTION OBJECTIVE Exposure to biological agents can decrease personnel efficiency due to impaired health and the need to don restrictive protective equipment, whether individual or collective. Loss in efficiency may be suffered in the fighting force or in the support logistics and either can compromise mission objectives. A decision maker must weigh the perceived risks from exposure to biological agents versus the impacts of the intervention. An adversary can launch a hazardous BW attack in many ways. From the defensive point of view, the end goal is always the same: to reduce health risk while maintaining the troops’ ability to carry out their missions. Biological warfare agent (BWA) aerosol detectors play an integral role in the systems designed to defend troops. The role of biodetectors is at the community level (i.e., more of a public health tool than a predictor of individual disease) and should be viewed as supporting decision makers with a statistical estimation of health hazard. The probability of disease depends both on exposure and on host response, but the two factors are related because the nature of the exposure influences the host response. For example, the quantity of agent and the size distribution of the particles in which the agent is distributed are both critical physical characteristics influencing host response. Biodetection systems can help assess the probability of exposure and support approaches to reduce exposure. Knowledge of the population (e.g., vaccination history), in potentially exposed military personnel, can help estimate potential host response. Ideally, bioaerosol detection systems provide information that explicitly links environmental measurements to potential health hazards in time, space, and disease potential for a specific population. As is argued in the coming chapters, there is only one relevant shared element in the various BWAs: all have a measurable effect on human health. This direct link to health risk is the basis of the final, recommended measurement framework that: • establishes an absolute measure of performance;

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14 • allows comparisons across a variety of detectors and agents; • links health hazard to environmental measurement; • can be implemented with current technology, although worst-case assumptions will have to be employed for some parameters that cannot currently be measured or estimated; • supports and helps direct innovations in technology; and • anticipates emerging scientific discoveries.