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A Model for In-vivo Delivered Dose Estimation for Inhaled Bacillus anthracis Spores in Humans with Interspecies Extrapolation

Abstract

The quantitative yardstick for quantitative microbial risk assessment (QMRA) is the dose response assessment phase. In this phase of the QMRA paradigm a mathematical model is used to describe the relationship between host response (infection, disease, etc.) and pathogen dose. There are, however, key uncertainties which if addressed can expand our understanding of the dose response relationship and improve its accuracy. The dose response models most frequently used in this phase of QMRA are based on the average exposed dose (i.e., inhaled, ingested, etc.). However once inhaled, spores are considered infectious after being transported to a specific region of the lungs (alveoli), therefore, average exposed dose does not account for this required spore transport through the respiratory system. It is the aim of this manuscript to develop a model for the in vivo delivered dose to the alveolated region of the lungs that accounts for losses of spores through the respiratory system. A stochastic system is used to account for the physics in the respiratory system that account for the various sinks during respiration. This stochastic system is then integrated into the exponential and beta Poisson dose response models. The stochastic model is also then expanded to the respiratory systems of guinea pigs and rhesus macaques as these are common animal models. This work develops a framework for a new class of dose response models accounting for host physiology, making progress to understanding dose response heterogeneity among hosts.

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