Supporting Agencies
Project III:
Dose Response Assessment
Investigators:
- Charles N. Haas, Drexel University (haas@drexel.edu)
- Carole Bolin, Michigan State University (bolinc@dcpah.msu.edu)
Institutions:
- Drexel University, Philadelphia, PA
- Michigan State University, East Lansing, MI
Project Summary:
The objectives of the proposed work are to:
- To determine the applicability of exponential, beta-Poisson and other previously used dose-response models to the Category A bioterrorist agents via the oral, inhalation and dermal routes.
- To assess the validity of animal to human extrapolation of dose-response.
- To assess the influence of modifying factors (e.g., host age) on dose-response.
- To develop a new class of physiologically-based dose-response functions and to test their applicability on bioterrorist agents.
- To conduct animal studies which will help inform the development of the above dose-response models.
We will review the archival literature and the "gray" literature for data sources to inform dose-response models, and subject that data to a systematic quality screen. We will fit candidate dose-response models to each data set, test strain and host differences, and assess the impact of other variables (such as host age). We will test the dose-response fits to available data on outbreak or endemic cases (where such information is available). We will use information on the in vivo fate, transport, and dynamics, of pathogens in humans and non-human hosts to develop models that start with the ingested/inhaled/dermal dose, predict the dose at the point of colonization and the extent of reproduction, and use these predictions in a dose-response relationship for outcome. It is our hypothesis that such models may be useful in assessing factors associated with different host-sensitivities, effect of concomitant exposures to other materials, and interspecies extrapolations. We will conduct animal studies to assess the infectivity of certain select pathogens where there appear to be significant data gaps. These studies will inform the development of both "classical" and physiologically based dose-response models.
Expected Results or Benefits:
This project will produce a reference set of critically reviewed dose-response relationships for Category A agents. By compiling dose-response relationships in various hosts and for various strains, in conjunction with information from other projects in CAMRA, we will be able to ascertain the inter-(microbe)species heterogeneity in infectivity, and determine whether there are discernable genetic markers which may be correlated to such differences. This may facilitate an assessment of the potential for further alterations in a strain to change potency