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

Abstract

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 LD(50) increases with aerosol size for aerosols at and above 4.5 mum. For both rhesus monkeys and guinea pigs there is about a 15-fold increase in LD(50) when aerosol size is increased from 1 mum to 12 mum. 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.

Modeling Inhalational Tularemia: Deliberate Release and Public Health Response

“…Figure 1A shows the data and exponential fit (r f = 0.070, p-value = 0.47 representing a good fit to the data) giving an ID 50 (ie, the dose at which there is a 50% probability of infection) of *10 organisms with approximately 7% of individuals inhaling 1 organism likely being infected. The commonly used 2-parameter beta-Poisson and log-probit models 20 did not provide sufficiently better fits to the data over the exponential model to justify the extra parameter. Primate data also support this high level of infectivity at low doses.…”

“…These authors also considered the Saslaw et al 16 results alone due to complications arising from pooling multiple data-sets. 20 Here, we similarly restrict our analysis to the Saslaw et al results, since this is the only data-set to include multiple low-dose responses, which are important for our subsequent hazard assessments. Unlike Jones et al, we used the 1-parameter exponential model to fit the data, because it is the simplest relationship that can be derived from basic biological considerations 20 such that:…”

Implications of Limits of Detection of Various Methods for Bacillus anthracis in Computing Risks to Human Health

“…A recent evaluation of dose-response data for B. anthracis spores through the inhalation exposure route found that the dose-response relationship could be modeled by the exponential equation (4) P͑d͒ ϭ 1 Ϫ e Ϫkd where P(d) is the probability of death (P) (when untreated) at dose d, and k is the probability that one organism will survive to initiate the response (4). In this study, a k value generated from a pooled guinea pig and rhesus monkey data set was used.…”

Quantification of the Relationship between Bacterial Kinetics and Host Response for Monkeys Exposed to Aerosolized Francisella tularensis

“…However, the authors did not provide a direct verification of the biological validity of the models with in vivo pathogen growth. This study aimed at such verification with data from monkey, which has been considered the animal model that most closely mimics inhalational diseases in humans and which was used in past dose-response studies for category A agents (3,17). Open literature was searched for survival doseresponse data and bacterial viable count data for monkeys infected by F. tularensis via the inhalation route.…”