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PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT
Citation:
Barton, H A. PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Presented at Environmental Mutagen Society, Miami Beach, FL, May 12, 2003.
Description:
PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking information beginning with exposure and extending through pharmacokinetics and pharmacodynamics to the final adverse health outcome. Regulatory agencies largely have relied on standard default methods using limited chemical-specific data. Increasingly, quantitative data on chemical pharmacokinetics (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamics (e.g. DNA adduct formation, cell turnover) can be incorporated through biologically-based modeling of biological systems. Systems biology, the mathematical modeling of biological systems to describe their function, is increasing in response to the acquisition of genomics data. This will speed the development of pharmacodynamic models that can describe aspects of the modes of action by which chemicals perturb the system to create effects and provide insights into the observable dose-response for toxic effects. Examples will be given of PBPK models for DNA damaging agents and how these models link different measures of dose to observed responses. Most commonly PBPK models for volatile organics and soluble compounds have provided measures of the amount metabolized to reactive intermediates or concentrations in blood or tissues. Some PBPK/PD models have extended to describe depletion of glutathione, enzyme induction, adduct formation, and receptor binding. PBPK models also have been linked with clonal growth models. Now, measures of tissue dose must be linked with genomic response data and observable adverse effects for both in vitro and in vivo systems. (This abstract dose not represents Agency policy.)