Y-011. Integration of Benchmark Dose and Physiologically-Based BioKinetic (PBBK) Modeling to Derive Heath Hazard Predictors for Biothreat Agents

G. Diamond, M. Odin, S. Massulik, M. Lumpkin, M. E. Coleman, P. McGinnis;
Syracuse Res. Corp., Syracuse, NY.

Tools and methodology to quantitatively predict human responses to environmental exposures to biothreat agents are lacking. As a result, derivation of science-based values for detection and response to biothreat agents in the environment, food, and drinking water has been problematic. A novel application is presented that incorporates Benchmark Dose and Physiologically-Based BioKinetic (PBBK) modeling for interspecies extrapolation (Figure 1). A case study was developed for deriving values (Health Hazard Predictors) for inhalation anthrax risk based on a synthesis of experimental inhalation studies in animals and physiologic data on respiratory deposition and clearance of spores in multiple host species. Dose-response assessment of the animal inhalation data was performed using Benchmark Dose methodology. Extrapolation to humans was accomplished using a PBBK model for deposition and clearance of spores as 1 micron particles based on the human ICRP model and its adaptation to animal respiratory tracts and lymphatic systems. The approach involved using the PBBK model to estimate internal doses resulting from external exposures equivalent to lower bounds on benchmark doses derived from animal studies. The resulting internal doses in animals were then translated into equivalent internal doses and external exposures in humans using the human PBBK model. The PBBK model was also exercised using selected human external exposures as inputs to estimate internal doses and equivalent doses in animals. Further development and verification of such mechanistic models are underway in multiple species to enhance the scientific basis for estimating adverse effect levels for the protection of individuals visiting or working in sites contaminated with biothreat agents.
Figure 1. Interspecies Extrapolation for Inhalation Anthrax