toxicokinetics2.pptVIP

Toxicokinetics 2 Crispin Pierce, Ph.D. University of Washington crispo@u.washington.edu (206) 616-4390 Purposes of Toxicokinetics To quantify toxicant absorption, distribution, metabolism, and excretion (ADME). To provide an exposure framework for risk assessment. The Value of Modeling Understand biologic systems Drive data collection Interpolate Extrapolate Predict Reduce animal usage ? Models are an abstraction of reality. To establish dose-risk relationships, we can choose anything between a completely theoretical model, and massive testing of humans to toxic chemicals. What are the hallmarks of a model/testing paradigm that you would mandate? Four Modeling Approaches Hand-Waving Non-Compartmental Compartmental Physiologic Hand Waving The same dose/kg gives the same blood concentration. Use a 10-fold safety factor for test animal-human differences. Use a 10-fold safety factor for interindividual differences. Use a 1-10-fold modifying factor for additional uncertainties. ? For what kinds of substances, exposures, and test costs would the hand-waving approach be appropriate? Non-Compartmental Models Empiric observation of volume, clearance, and half-life. No structural model of where the toxicant goes. Compartmental Models Body is viewed as distinct compartments, which are interconnected by rate constants. Modeling is empiric, and compartments do not directly correspond to tissues. Complete flexibility in fitting model parameters to observed data. Use of minimum number of compartments that adequately describe the data. One Compartment Model One compartment model: xenobiotic distributes into a single, homogenous vessel (example: methanol). ? How would you define an adequate fit of your model to the data? Two Compartment Model Two compartment model: xenobiotic distributes into a central, and then a peripheral compartment. Rate of change of toxicant in central compartment = ka*Amount at absorption site - k12*Amount in Central Compartment + k21*Amount in Pe