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Plumbing 101 or How a good boy went bad

Plumbing 101 or How a good boy went bad. Mel Andersen McKim Conference QSAR and Aquatic Toxicology & Risk Assessment June 27-29, 2006. You and me, fish, and rats are:. Collections of organs organized in parallel or series with a continuous blood flow

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Plumbing 101 or How a good boy went bad

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  1. Plumbing 101orHow a good boy went bad Mel Andersen McKim Conference QSAR and Aquatic Toxicology & Risk Assessment June 27-29, 2006

  2. You and me, fish, and rats are: • Collections of organs organized in parallel or series with a continuous blood flow • There are differences in the function of organs, their arrangement with respect to the circulation and each other, and biological content. • Differences correlate with the evolutionary pressures and environments in which the organisms first developed and now live.

  3. PhD - 1971 After such a promising start: Joined the mammalian toxicology world with an interest in pharmacokinetics and pharmacodynamics of toxic compounds in rats and mice and extrapolation from rodents to human populations. An Almost Post-Doc – 1972-1974

  4. The Plumbing and Delivery System (Tissue Dose, not simply Applied Dose) Qp Ci Cx Qc Qc Ca Lung QL Cvl Liver Qf Cvf Fat Qr Cvr Rapidly perfused (brain, kidney, etc.) Slowly perfused (muscle, bone, etc.) Qs Cvs

  5. Describing the Individual Pieces Quantitatively Dead Space Expired Air Inspired Air Lung Ventilation PulmonaryBlood Body Tissue Capillary Blood From: Hagaard (1924)

  6. Countercurrent Exchange Terms: Qc = cardiac output Qp = alveolar ventilation Cinh = inhaled concentration Cexh = exhaled concentration Cart = arterial concentration Cven = venous concentration Pb =blood/air partition coeffecient QpCexh QpCinh Cexh Cart QcCven QcCart Problem: Estimate amount taken up in first few breaths. Uptake = Qc Cart = Pb Qc Qp Cinh /(Pb Qc + Qp)

  7. Linking the Units in Parallel Lung Fat Body Muscle Kety (1951)

  8. mass-balance equation: dAt =Vt dCt = QtCart - QtCvt dt dt Describing a Single Tissue Terms Qt = tissue blood flow Cvt = venous blood concentration QtCart QtCvt Pt = tissue blood partition coefficient Vt; At; Pt Vt = volume of tissue Tissue At = amount of chemical in tissue Cvt = Ct/Pt (venous equilibration assumption)

  9. Blood Flow Characteristics in Animals & Digital Computation LUNG Right heart Left heart Upper body Liver Spleen Small intestine Large intestine Kidney Trunk Lower extremity Bischoff and Brown (1961)

  10. Qalv Qalv Alveolar Space Calv (Cart/Pb) Cinh Qc Qc Lung Blood Cven Cart Qt Fat Tissue Group Cvt Cart Qm Muscle Tissue Group Cart Cvm Qr Richly Perfused Tissue Group Cart Cvr Liver Metabolizing Tissue Group Ql ( ) Cvl Cart Vmax Metabolites Km An application in toxicology.... Ramsey and Andersen (1984)

  11. 100 Conc = 1200 ppm Conc = 600 ppm 10 1 Venous Concentration – mg/lier blood 0.1 Conc = 80 ppm 0.01 0.001 0 5 10 15 20 25 TIME - hours Extrapolations – Across Doses

  12. Qalv Qalv Alveolar Space Calv (Cart/Pb) Cinh Qc Qc Lung Blood Cven Cart IV Oral Qt Fat Tissue Group Cvt Cart Qm Muscle Tissue Group Cart Cvm Qr Richly Perfused Tissue Group Cart Cvr Cvl Liver Metabolizing Tissue Group Ql ( ) Cart Vmax Metabolites Km What do we need to add/change in the models to incorporate another dose route – iv or oral?

  13. Styrene - Dose Route Extrapolation 10 100 IV Oral 10 1.0 Styrene Concentration (mg/l) Styrene Concentration (mg/l) 1.0 0.1 0.1 0.01 0.01 3.0 2.4 3.6 1.2 2.8 0 0.6 1.8 2.0 1.6 2.4 0.8 0 0.4 1.2 Hours Hours

  14. Qalv Qalv Alveolar Space Calv (Cart/Pb) Cinh Qc Qc Lung Blood Cven Cart Qt Fat Tissue Group Cvt Cart Qm Muscle Tissue Group Cart Cvm Qr Richly Perfused Tissue Group Cart Cvr Cvl Liver Metabolizing Tissue Group Ql ( ) Cart Vmax Metabolites Km What do we need to add/change in the models to describe another animal species? • Sizes • Flows • Metabolic Constants

  15. 0.1 10 1.0 80 ppm 0.01 0.1 Blood Styrene Concentration (mg/l) Styrene Concentration (mg/l) 0.01 376 0.001 0.001 Exhaled Air 216 51 0.0001 0.00001 0.0001 40 16 32 48 0 24 8 3.0 7.5 9.0 1.5 4.5 6.0 0 Hours Hours Styrene - Interspecies Extrapolation Rat - Human

  16. Getting Constants for Modeling Metabolism and Closed Chamber Gas Chromatograph 5 mL Gas Sampling Loop Stainless Steel Bellows Pump Particulate Filter O2 Monitor CO2 Scrubber INTEGRATOR Pressure Gauge Injection Port ~ 2.0 L/min ~ 100 mL/min Ice Filled Pan for H2O Condensation Desiccator Jar Chamber

  17. CH2FCl CH2Cl2 PPM PPM Time (hours) Time (hours) Dihalomethane: Closed Chamber Gas Uptake Studies Rapid estimation of Vmax, Km for a data base to support SAR/QSAR

  18. Then along came Jim:

  19. Jim shows up in Dayton:

  20. Physiologically Based Pharmacokinetic (PBPK) Modeling Air/Water Metabolic Constants Tissue Solubility Tissue Volumes Blood and Air Flows Experimental System Lung/Gill Body Tissue Concentration X Fat X X X X X X Liver X Model Equations Time Define Realistic Model Make Predictions Collect Needed Data Refine Model Structure

  21. PBPK Modeling – Getting the right data • Establish role of partition coefficients and provide emphasis on establishing appropriate metabolic parameters in vitro • Generate data bases suitable for SAR and QSAR modeling of PCs, Vmax, Km • Organizing physiological and anatomical information to support modeling needs and show value of approach broadly across animal species – mammals, fish, birds, etc.- for estimating tissue dose (as concentration of parent, metabolites, area under curves, etc.)

  22. Thank you • Some collaborators Jim McKim John Nichols Mike Gargas Harvey Clewell John Ramsey

  23. Compartments in Physiological Model for Methotrexate Plasma QL - QG QG Liver G.I. Tract Gut absorption Feces C1 C2 C3 C4 T T T r3 r1 r2 Gut Lumen QK Kidney QM Muscle Bischoff et al. (1971)

  24. A2 k21 k12 Tissue Concentration Tissue Concentration X X A1 X X X X KO kout X X X X X X X X X X time time Select Model Fit Model to Data Collect Data Ct = A e –kaxt + B e-kbxt Compartmental PK Modeling

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