Inhalation Anthrax: Dose Response and Risk Analysis

The notion that inhalation of a single Bacillus anthracis spore is fatal has become entrenched nearly to the point of urban legend, in part because of incomplete articulation of the scientific basis for microbial risk assessment, particularly dose-response assessment. Risk analysis (ie, risk assessment, risk communication, risk management) necessitates transparency: distinguishing scientific facts, hypotheses, judgments, biases in interpretations, and potential misinformation. The difficulty in achieving transparency for biothreat risk is magnified by misinformation and poor characterization of both dose-response relationships and the driving mechanisms that cause susceptibility or resistance to disease progression. Regrettably, this entrenchment unnecessarily restricts preparedness planning to a single response scenario: decontaminate until no spores are detectable in air, water, or on surfaces—essentially forcing a zero-tolerance policy inconsistent with the biology of anthrax. We present evidence about inhalation anthrax dose-response relationships, including reports from multiple studies documenting exposures insufficient to cause inhalation anthrax in laboratory animals and humans. The emphasis of the article is clarification about what is known from objective scientific evidence for doses of anthrax spores associated with survival and mortality. From this knowledge base, we discuss the need for future applications of more formal risk analysis processes to guide development of alternative non-zero criteria or standards based on science to inform preparedness planning and other risk management activities

Role of animal models in the study of drug-induced hypersensitivity reactions

Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very difficult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basis hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ∼0.25%, and large-breed dogs are difficult to use as an animal model. Two more practical models are penicillamine-induced auto-immunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquine-induced agranulocytosis/hepatotoxicity and halothane-induced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This finding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also significantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow