Mechanistic Modeling of Emergency Events: Assessing the Impact of Hypothetical Releases of Anthrax

A modular system for source-to-dose-to-effect modeling analysis has been developed based on the modeling environment for total risk studies (MENTOR),^{( 1 )} and applied to study the impacts of hypothetical atmospheric releases of anthrax spores. The system, MENTOR-2E (MENTOR for Emergency Events), provides mechanistically consistent analysis of inhalation exposures for various release scenarios, while allowing consideration of specific susceptible subpopulations (such as the elderly) at the resolution of individual census tracts. The MENTOR-2E application presented here includes atmospheric dispersion modeling, statistically representative samples of individuals along with corresponding activity patterns, and population-based dosimetry modeling that accounts for activity and physiological variability. Two hypothetical release scenarios were simulated: a 100 g release of weaponized B. anthracis over a period of (a) one hour and (b) 10 hours, and the impact of these releases on population in the State of New Jersey was studied. Results were compared with those from simplified modeling of population dynamics (location, activities, etc.), and atmospheric dispersion of anthrax spores. The comparisons showed that in the two release scenarios simulated, each major approximation resulted in an overestimation of the number of probable infections by a factor of 5 to 10; these overestimations can have significant public health implications when preparing for and responding effectively to an actual release. This is in addition to uncertainties in dose-response modeling, which result in an additional factor of 5 to 10 variation in estimated casualties. The MENTOR-2E system has been developed in a modular fashion so that improvements in individual modules can be readily made without impacting the other modules, and provides a first step toward the development of models that can be used in supporting real-time decision making.     

Simulation Modeling of Anthrax Spore Dispersion in a Bioterrorism Incident

Recent events have increased awareness of the risk posed by terrorist attacks. Bacillus anthracis has resurfaced in the 21st century as a deadly agent of bioterrorism because of its potential for causing massive civilian casualties. This analysis presents the results of a computer simulation of the dispersion of anthrax spores in a typical 50-story, high-rise building after an intentional release during a bioterrorist incident. The model simulates aerosol dispersion in the case of intensive, small-scale convection, which equalizes the concentration of anthrax spores over the building volume. The model can be used to predict the time interval required for spore dispersion throughout a building after a terrorist attack in a high-rise building. The analysis reveals that an aerosol release of even a relatively small volume of anthrax spores during a terrorist incident has the potential to quickly distribute concentrations that are infectious throughout the building.     

Informed Consent and Investigational New Drug Abuses in the U.S. Military

Objective: The focal point of this investigation was to research the ethical issues surrounding the military's requests for informed consent waivers when using investigational drugs, and the recent debate surrounding the anthrax vaccine as an investigational new drug (IND). Design: The military's management of the informed consent process was examined using documents obtained through the Freedom of Information Act, Institutional Review Board (IRB) minutes, consent forms, legal pleadings, and protocols for specific investigational drugs. Results: In December 1990, prior to Operation Desert Storm, the Federal Drug Administration (FDA) granted the Department of Defense (DoD) an unprecedented waiver to the federally mandated informed-consent requirement for the use of investigational drugs. However, the waiver approval was conditional, and the FDA insisted on several safeguards. Partially in response to the subsequent Gulf War Syndrome debate, the FDA recently evaluated the military's use of investigational drugs during the Gulf War. The FDA cited the military for significant deviations from the originally approved protocols. Most notably, the military was found to be abusing the IRB process by convening a second IRB when the first IRB concluded that waiving informed consent was unethical. In addition, there was a gross lack of documentation and no monitoring of adverse reactions. The DoD's plan to use the current anthrax vaccine on all 2.4 million troops against inhalation anthrax has kindled an additional investigational drug controversy. The safety and efficacy of the use of the anthrax vaccine as a prophylactic against inhalation anthrax have been questioned by both military and medical organizations. There have never been any published studies of human efficacy or long-term effects for the anthrax vaccine. In addition, the military is not using the vaccine for its intended purpose, and it is also not adhering to prescribed dosing schedules. There is clear evidence to support the claim that, in fact, the military's use of the anthrax vaccine should be considered experimental. Conclusions: I argue that in medical situations, the military is obligated to treat its troops as autonomous persons entitled to basic rights and protections. The DoD is currently using an approved drug, the anthrax vaccine, for an unapproved purpose and in an unapproved manner. In doing so, the DoD is not only violating the FDA's regulations against such practices, it is also violating an executive order which only allows the president to authorize the use of INDs on service members without their consent.     

Risk‐Based Decision Making for Reoccupation of Contaminated Areas Following a Wide‐Area Anthrax Release

This article presents an analysis of postattack response strategies to mitigate the risks of reoccupying contaminated areas following a release of Bacillus anthracis spores (the bacterium responsible for causing anthrax) in an urban setting. The analysis is based on a hypothetical attack scenario in which individuals are exposed to B. anthracis spores during an initial aerosol release and then placed on prophylactic antibiotics that successfully protect them against the initial aerosol exposure. The risk from reoccupying buildings contaminated with spores due to their reaerosolization and inhalation is then evaluated. The response options considered include: decontamination of the buildings, vaccination of individuals reoccupying the buildings, extended evacuation of individuals from the contaminated buildings, and combinations of these options. The study uses a decision tree to estimate the costs and benefits of alternative response strategies across a range of exposure risks. Results for best estimates of model inputs suggest that the most cost‐effective response for high‐risk scenarios (individual chance of infection exceeding 11%) consists of evacuation and building decontamination. For infection risks between 4% and 11%, the preferred option is to evacuate for a short period, vaccinate, and then reoccupy once the vaccine has taken effect. For risks between 0.003% and 4%, the preferred option is to vaccinate only. For risks below 0.003%, none of the mitigation actions have positive expected monetary benefits. A sensitivity analysis indicates that for high‐infection‐likelihood scenarios, vaccination is recommended in the case where decontamination efficacy is less than 99.99%.     

Dose-Response Models for Inhalation of Bacillus anthracis Spores: Interspecies Comparisons

Because experiments with Bacillus anthracis are costly and dangerous, the scientific, public health, and engineering communities are served by thorough collation and analysis of experiments reported in the open literature. This study identifies available dose-response data from the open literature for inhalation exposure to B. anthracis and, via dose-response modeling, characterizes the response of nonhuman animal models to challenges. Two studies involving four data sets amenable to dose-response modeling were found in the literature: two data sets of response of guinea pigs to intranasal dosing with the Vollum and ATCC-6605 strains, one set of responses of rhesus monkeys to aerosol exposure to the Vollum strain, and one data set of guinea pig response to aerosol exposure to the Vollum strain. None of the data sets exhibited overdispersion and all but one were best fit by an exponential dose-response model. The beta-Poisson dose-response model provided the best fit to the remaining data set. As indicated in prior studies, the response to aerosol challenges is a strong function of aerosol diameter. For guinea pigs, the LD₅₀ increases with aerosol size for aerosols at and above 4.5 μm. For both rhesus monkeys and guinea pigs there is about a 15-fold increase in LD₅₀ when aerosol size is increased from 1 μm to 12 μm. Future experimental research and dose-response modeling should be performed to quantify differences in responses of subpopulations to B. anthracis and to generate data allowing development of interspecies correction factors.