Pharmacokinetics, the study of the movement of chemicals within the body, is a vital tool in assessing the risk of exposure to environmental chemicals. This book—a collection of papers authored by experts in academia, industry, and government—reviews the progress of the risk-assessment process and discusses the role of pharmacokinetic principles in evaluating risk. In addition, the authors discuss software packages used to analyze data and to build models simulating biological phenomena. A summary chapter provides a view of trends in pharmacokinetic modeling and notes some prospective fields of study.
- Pharmacokinetics in Risk Assessment
- Copyright
- PREFACE
- Contents
- PART I INTRODUCTION: THE PROBLEM AND AN APPROACH
- Risk Assessment: Historical Perspectives
- 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
- 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
- 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
- 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
- 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
- LOWER RESPIRATORY TRACT MATHEMATICAL DOSIMETRY MODELING
- Model Conceptualization
- Examples of O3 Dosimetry Modeling Results
- CRITICAL TOXICITY REFERENCE SYSTEM
- SUMMARY
- ACKNOWLEDGMENTS
- References
- Role of Pharmacokinetic Modeling in Risk Assessment: Perchloroethylene as an Example
- INTRODUCTION
- METABOLIC DATA PERTINENT TO THE CONDITIONS OF PCE CARCINOGEN BIOASSAYS
- Oral Studies
- Inhalation Studies
- USE OF PB-PK MODEL TO ESTIMATE METABOLIZED DOSE FOR NCI (GAVAGE) AND NTP (INHALATION) BIOASSAY MICE
- CALCULATION OF THE DOSE-RESPONSE RELATIONSHIP
- COMPARISON OF RISK ESTIMATES FOR DRINKING WATER AND INHALATION EXPOSURE, WITH AND WITHOUT THE USE OF PB-PK MODELING
- DISCUSSION
- SUMMARY
- FUTURE DIRECTIONS
- ACKNOWLEDGMENT
- References
- APPENDIX: CONSTRUCTION OF PB-PK MODELS
- Description of the PB-PK Model for Inhaled PCE
- Parameters Used in the Model
- Physiological Parameters
- Partition Coefficients
- Metabolism Rate Constants, Vm and Km
- Development of Multispecies, Multiroute Pharmacokinetic Models for Methylene Chloride and 1,1,1-Trichloroethan (Methyl…
- INTRODUCTION
- ROLE OF METABOLISM (MECL2)
- Bioassay Results
- Electrophilic Intermediates
- Metabolic Pathways
- Future Research
- EXTRAPOLATION BETWEEN SPECIES (MC)
- Rats
- Mice
- Human Data
- Was the Simulation Successful?
- MODELING DRINKING WATER EXPOSURES (MC, PERC)
- MODELING INTRAVENOUS INJECTION EXPOSURES (MC)
- PHARMACOKINETIC STUDIES IN OLD ANIMALS
- References
- Methotrexate: Pharmacokinetics and Assessment of Toxicity
- INTRODUCTION
- MTX PHARMACOKINETICS
- MECHANISM OF TOXICITY
- A METHOTREXATE PHARMACOKINETIC MODEL
- DOSE SCALING
- DOSE SCHEDULING
- SUMMARY
- References
- PART VII SUMMARY: PROSPECTIVES AND FUTURE DIRECTIONS
- Prospective Predictions and Validations in Anticancer Therapy
- INTRODUCTION
- DRUG DEVELOPMENT
- COMPARISON OF HUMAN AND MURINE TOXICITY
- FACTORS OTHER THAN C × T
- SUMMARY OF DATA
- CONCLUSIONS
- ACKNOWLEDGMENTS
- References
- The Application of Pharmacokinetic Data in Carcinogenic Risk Assessment
- INTRODUCTION
- CARCINOGENIC RISK ASSESSMENT
- Models of Carcinogenesis
- Risks at Low Doses
- PHARMACOKINETIC MODELS
- Mathematical Pharmacokinetic Models
- Physiologically Based Pharmacokinetic Models
- ADMINISTERED AND DELIVERED DOSES
- Curvilinear Dose Response
- Time-Dependent Exposure
- Risks with Time-Dependent Exposure Patterns
- APPLICATIONS
- Formaldehyde
- Vinyl Chloride
- Methylene Chloride and Perchloroethylene
- SUMMARY AND CONCLUSIONS
- ACKNOWLEDGMENTS
- References
- Appendix: The Multistage Model and Time-Dependent Dosing
- PART VIII PERSPECTIVES
- Perspectives
- INDEX
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