Pharmacokinetics in Risk Assessment -- Copyright -- PREFACE -- Contents -- PART I INTRODUCTION: THE PROBLEM AND AN APPROACH -- Risk Assessment: Historical Perspectives -- References -- Tissue Dosimetry in Risk Assessment, or What's the Problem Here Anyway? -- INTRODUCTION -- A DOSE OF WHAT? -- ISN'T THIS VOLUME ABOUT PHARMACOKINETICS? -- GENOTOXIC CARCINOGENS -- PARENT CHEMICAL -- STABLE METABOLITES -- REACTIVE, NONISOLATABLE METABOLITES -- INTERCALATING AGENTS -- EPIGENETIC CARCINOGENS -- SUMMARY -- References -- PART II MATHEMATICAL MODELING -- Modeling: An Introduction -- References -- Physiologically Based Pharmacokinetic Modeling -- INTRODUCTION -- BIOLOGICAL BASIS OF PHYSIOLOGICAL PHARMACOKINETICS -- DEVELOPMENT OF MODELS -- CHOICE OF COMPARTMENTS -- BASIC MASS BALANCES -- Mass Balance: Blood Pool -- Mass Balance: Tissue Region i -- SIMPLIFICATIONS OF MASS BALANCES -- Examples -- DISCUSSION -- FUTURE RESEARCH NEEDS -- References -- PART III GENERALIZATIONS AND EXTRAPOLATIONS -- Allometry: Body Size Constraints in Animal Design -- INTRODUCTION -- SIZE, DESIGN, AND PHARMACOKINETICS -- Aerobic Energetics of Muscle In Vivo -- Conflict of Physiological and Chronological Time -- Species Extrapolations, Physiological Time, and Pharmacokinetics -- CONCLUSIONS -- SUMMARY -- References -- Prediction of In Vivo Parameters of Drug Metabolism and Distribution from In Vitro Studies -- IN VITRO PREDICTION OF IN VIVO DRUG METABOLISM -- IN VITRO PREDICTION OF IN VIVO DRUG BINDING AND DISTRIBUTION -- CONCLUSION -- References -- Dose, Species, and Route Extrapolation: General Aspects -- DIFFERENT PROBLEMS AND OBJECTIVES, DIFFERENT MODELS -- Different Mechanisms -- GENERAL PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS -- Simplification of Models -- Rates of Formation of Complexes -- Diffusional Barriers and Modified Fick's Law -- Simple PB-PK Models.

Basic Parameters fu and R -- Nonlinear Kinetics and Lost Concepts -- INTERFACE BETWEEN PB-PK MODELS AND CLEARANCES -- Organ Availabilities (F), Extraction Ratios (E), and Clearances (CL) -- Physiologically Based Linear Compartmental Pharmacokinetic Models -- Validity of the Assumption of Virtual Steady State -- Calculation of Other Compartmental Model Parameters -- Approximations of Terminal Half-Lives -- Approximate Time Required to Approach Steady State -- LINEAR PHARMACOKINETIC SYSTEMS -- Total Body Clearance -- Importance of the Unbound Concentration of Substances -- Classification of Organs -- Routes of Administration -- Non-First-Pass, Nonelimination Organs -- Range of Maximum and Minimum Unbound Concentrations in Nonelimination Organs and Repetitive Administration -- Non-First-Pass, Elimination Organs -- FIRST-PASS, NONELIMINATION ORGANS -- First-Pass, Elimination Organs -- ROUTE-TO-ROUTE EXTRAPOLATION -- Lungs and Skin Administration -- Oral Administration -- Biliary Excretion -- Location of Organs of Elimination -- Linear Steady-State Models for Metabolite Formation and Elimination -- Stable Metabolites -- Categories of Unstable Metabolites -- DOSE EXTRAPOLATIONS -- Unknown Biologically Active Forms -- Dose-Dependent Absorption of Insoluble Substances -- Fraction of the Dose Absorbed and Bioavailability -- Bioavailability and Gastrointestinal Absorption -- Bioavailability and Absorption Through Skin -- Dose Dependencies in Reversible Binding of Substances to Proteins and Other Macromolecules in Blood and Organs -- DOSE-DEPENDENT CHANGES IN METABOLISM OF SUBSTANCES AND THEIR METABOLITES -- Michaelis-Menten Kinetics -- Intraorgan Localization of Enzymes -- Fraction of the Dose Principle -- First Set of Simulations -- Enzyme 1 Km Equals Enzyme 2 Km -- Second Set of Simulations -- Concentration-Dependent Metabolite Elimination.

Dose-Dependent Cofactor Depletion -- Suicide Inhibitors -- SPECIES-TO-SPECIES EXTRAPOLATIONS -- Extrapolations in the Absorption of Substances -- Extrapolations of Interorgan Distribution of Substances -- Valid and Invalid Extrapolations of Allometric Methods -- Relevance and Irrelevance of Distributional Rate Constants -- SPECIES DIFFERENCES IN THE ELIMINATION OF FOREIGN COMPOUNDS -- Elimination by Excretion into Urine, Air, and Bile -- Elimination by Metabolism -- Individuals and Strain Differences in Metabolism of Foreign Compounds -- Isozymes with Different Km Values -- Sex Differences -- Inducers -- Interorgan Differences in Metabolism -- Interstrain Differences -- Polymorphisms in Animals -- Polymorphisms and Environmental Differences in Humans -- Interspecies Differences in the Metabolism of Foreign Compounds -- GENERAL COMMENTS -- References -- Dose, Species, and Route Extrapolation Using Physiologically Based Pharmacokinetic Models -- INTRODUCTION -- Dose -- Species -- Route -- Exposure Scenario -- Pharmacokinetically Based Extrapolations -- PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING -- DOSE-ROUTE EXTRAPOLATION -- EXPOSURE SCENARIO EXTRAPOLATION -- SPECIES EXTRAPOLATION -- DOSE EXTRAPOLATION -- SUICIDE ENZYME INHIBITION -- GLUTATHIONE DEPLETION -- CONCLUSION -- References -- PART IV UNCERTAINTIES: INTEGRATION WITH RISK ASSESSMENT AND RESOURCES -- Dealing with Uncertainty in Pharmacokinetic Models Using SIMUSOLV -- INTRODUCTION -- MODEL BUILDING -- UNCERTAINTIES AND ERROR ANALYSIS IN MODEL BUILDING -- Experimental Error -- APPLICATIONS -- Problem 1 -- Problem 2 -- Problem 3 -- CONCLUSION -- References -- APPENDIX -- Interspecies and Dose-Route Extrapolations -- INTRODUCTION -- DESCRIPTION OF THE MODEL -- INTERSPECIES EXTRAPOLATION -- Rat Inhalation -- Rat Ingestion -- Human Inhalation -- DOSE-ROUTE EXTRAPOLATION -- DISCUSSION.

References -- Carcinogen-DNA Adducts as a Measure of Biological Dose for Risk Analysis of Carcinogenic Data -- EVIDENCE FOR USE OF DNA ADDUCTS AS A MEASURE OF BIOLOGICAL DOSE -- FACTORS TO CONSIDER IN CONSTRUCTING A MEASURE OF BIOLOGICAL DOSE FROM CARCINOGEN-DNA ADDUCT LEVELS -- DETERMINATION OF CARCINOGEN-DNA ADDUCT ACCUMULATION -- DOSE-RESPONSE RELATIONSHIPS -- References -- Resources Available for Simulation in Toxicology: Specialized Computers, Generalized Software, and Communication... -- INTRODUCTION -- GENERAL APPROACHES TO SIMULATION -- COMPUTER LANGUAGES USED IN PHARMACOKINETIC MODELS -- SIMULATION LANGUAGES -- EQUIPMENT NEEDS FOR PHARMACOKINETIC MODELING -- CONVENTIONAL APPROACHES TO MODELING -- AN EXAMPLE OF A MODULAR PROGRAM -- AN EXAMPLE SCOP PROGRAM -- SHARING RESOURCES -- THE TOXIN CONCEPT -- FUTURE TRENDS -- CONCLUSIONS -- ACKNOWLEDGMENTS -- References -- PART V POSTER SESSION -- Introduction -- Route-to-Route Extrapolation of Dichloromethane Exposure Using a Physiological Pharmacokinetic Model -- BACKGROUND -- RESULTS AND DISCUSSION -- CONCLUSIONS -- References -- APPENDIX -- Liver -- Gut -- Lung -- Alveolar Space -- Carcass -- Kidney -- Arterial Blood -- Venous Blood -- 14CO Balance -- 14CO2 Balance -- DCM Balance -- Sensitivity Analysis in Pharmacokinetic Modeling -- INTRODUCTION -- RESULTS -- CONCLUSIONS -- References -- Mutation Accumulation: A Biologically Based Mathematical Model of Chronic Cytotoxicant Exposure -- INTRODUCTION -- METHODS -- Computer Hardware and Software -- Modeling of Cytotoxicity -- Modeling the Relationship of Cell Birth to Mutation Accumulation -- Generic Nature of Cytotoxicity Model -- RESULTS -- DISCUSSION -- Limitations of the Model-What Is Modeled and What Is Not -- Model Validation -- ACKNOWLEDGMENTS -- References.

Physiologically Based Pharmacokinetic Model for Ethylene Dichloride and Its Application in Risk Assessment -- INTRODUCTION -- METHODS -- PB-PK Model Development -- Partition Coefficient -- Metabolism Rate Constant -- Physiological Parameters -- RESULTS -- Dose Surrogates -- PB-PK Model and Risk Assessment -- PB-PK Model and Virtually Safe Doses -- PB-PK Model and Route-of-Exposure Differences -- DISCUSSION -- References -- Mathematical Modeling of Ozone Absorption in the Lower Respiratory Tract -- INTRODUCTION -- METHODS -- RESULTS AND DISCUSSION -- Effect of Anatomical Model on the Distribution of Simulated Absorbed O3 in the LRT -- Effect of Exercise on Predicted Uptake and Distribution of Absorbed O3 in the LRT of Man -- SUMMARY -- References -- Development of a Physiologically Based Pharmacokinetic Model for Multiday Inhalation of Carbon Tetrachloride -- INTRODUCTION -- METHODS -- Data Base -- Elimination -- Humans -- Physiological Modeling -- Metabolites -- Model Parameters -- Partition Coefficients -- Biochemical Constants -- Validation -- RESULTS -- Validity of the PB-PK Model -- Elimination Via 14CO2 and Urine -- DISCUSSION -- References -- The Delivered/Administered Dose Relationship and Its Impact on Formaldehyde Risk Estimates -- LIMITATIONS OF CONVENTIONAL LOW-DOSE RISK EXTRAPOLATION -- EVIDENCE THAT LINEAR PROPORTIONALITY DOES NOT HOLD FOR FORMALDEHYDE -- COMPARISON OF RISK ESTIMATES: ADMINISTERED VERSUS DELIVERED DOSE -- QUESTIONS STILL TO BE RESOLVED -- References -- Pharmacokinetic Simulation as an Adjunct to Experimental Data in Risk Assessment: Predicting Exposure of the Bladder… -- INTRODUCTION -- METHODS -- RESULTS AND DISCUSSION -- CONCLUSIONS -- ACKNOWLEDGMENTS -- References -- PART VI APPLICATIONS OF MATHEMATICAL MODELING -- Hazard Assessment Using an Integrated Physiologically Based Dosimetry Modeling Approach: Ozone.

INTRODUCTION.