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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models 4 Dosimetry Considerations DOSE METRICS The concept of a “dose metric” (measure of dose, also called an “indicator”) has recently been sharpened in relation to monitoring air pollutants (EPA 1996). A measurable physical/chemical property that has several characteristics, the dose metric principally corresponds to an agent’s ability to cause a biological effect of interest, such as the toxicity, infectivity, or efficacy of an agent. For chemical aerosols, the dose metric may be an aerosol mass fraction such as the inhalable mass fraction, the thoracic mass fraction, or the respirable mass (American Conference of Governmental Industrial Hygienists 2005). For infectious agents, the number of inhalable viable organisms, number of inhalable spores, or number of inhalable culturable units are potentially useful dose metrics. The size distribution of viable organisms also needs to be defined. In all cases, the dose metric needs to be directly measurable in a reproducible manner under a variety of laboratory and field conditions. Defining the Dose/Deposited Dose The concept of “dose” used in clinical medicine and routine toxicology is too simplistic to be of value in an aerosol-inhalation research setting, where dose refers to the amount of an agent (using the selected dose metric) that is presented to the specific tissue or tissues of interest (i.e., target tissues). Further, the dose is often normalized to some property of the target tissue, such as tissue mass or surface area, that relates to the potential for the presented dose to do harm. In inhalation toxicology, dose is often expressed in terms of exposure. Traditionally, an agent’s airborne concentration (C) times the exposure time (T)
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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models times the inhaled air volume per unit time ( ) has been used as a measure of the exposure dose (DE). That is, (1) However, this measure of dose is inadequate for several reasons. First, not all of an inhaled aerosol will actually deposit in the respiratory tract upon inhalation. Therefore the deposition fraction (FT) in the target region of the respiratory tract needs to be included. Second, the inhalability (I), which is the sampling efficiency of the entrances to the respiratory tract, also needs to be considered. This depends on the particle size of the aerosol. Third, the concentration must be defined in terms of a proper dose metric (CDM). Therefore, the deposition dose (DD) becomes (2) The FT and I are found by measurement under the experimental conditions, by reference to published values, or from dosimetry software (Brown and others 2005; ICRP 1995; Birchall and others 1991). The CDM, T, and can be directly measured during a study. However, is often either calculated or based on values reported in the literature. In practical applications, the protocol for an exposure system can be calibrated for a specific species such that strict adherence to the protocol will provide a reproducible dose. Great care is necessary, however, to control unwanted factors such as electrical charges on the aerosol and on surfaces (e.g., chambers, piping, and animals), as these factors can affect aerosol size distribution, airflow rates, and losses in the exposure system. Infectious Dose Dose is commonly reported as a median lethal dose (LD50) or median infectious dose (ID50). However, LD50 and ID50, which are indices of the potency of an agent for producing a response, are very procedure-specific. The potency of an agent can be affected by the method of delivery, the aerosol-particle-size distribution, the site of deposition in the respiratory tract, and the species under study. Therefore, defining an infectious dose for a given level of response presents a significant challenge, since the dose that causes the death (LD50) or infection (ID50) of 50 percent of the test group can be different in almost every experimental situation. This makes interpretation of a study or replication of an exposure difficult. Therefore, the Committee recommends that when a multiple of the LD50 or ID50 (e.g., 10 LD50) is used to report dose, then sufficient additional data, including indices of viability of the
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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models agent and characteristics of the exposure, particle-size, and generation of the aerosol should be acquired and reported. Acquiring data necessary to interpret or replicate the experiment requires careful attention to the biological material used and experimental conditions. Information about the viability of the agent should be acquired, for example obtaining a measurement of the number of viable organisms, the number of colony-forming unites, or the number of plaque-forming units. Specifics about the experimental design should also be noted or measured, including, details of the generation of the aerosol, particle-size, and exposure characteristics (see Tables 3-1 and 3-2).
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