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QUANTIFYING THE PHARMACOKINETICS AND PHARMACODYNAMICS FOR ENDOCRINE ACTIVE COMPOUNDS UNDERLYING LOW-DOSE EFFECTS
Impact/Purpose:
The objective of this research is to utilize computer simulation modeling to help elucidate how dose-response behaviors arise from the impact of exposure to compounds with endocrine activity on the underlying biological processes they affect. This project will further develop and apply methodology to quantitatively portray the uncertainty in model predictions, both to display the uncertainty in low-dose extrapolations and for comparing alternative model forms.
Description:
Major elements of the debate over endocrine disruption have revolved around dose-response behaviors for endocrine-mediated effects. Several modeling projects are underway or planned as part of this effort. Near-term efforts are based upon modeling existing scientific literature, while longer term activities will involve collection of pharmacokinetic data and modeling. Application of similar biological modeling techniques has proven useful to improving extrapolations across species, dosing regimens, and dose ranges using a variety of compounds. These methods are of major interest to risk assessors within EPA. This research will contact studies to extrapolate free serum concentrations from in vitro to in vivo and across life stages and species with varying serum binding proteins, determine development pharmacokinetics of selected compounds with endocrine disrupting activity, and analyze dose-response behaviors of biological regulatory processes using pharmacokinetic and pharmacodynamic modeling.