Toxicokinetics And Risk Assessment

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ISBN: 9780849337222 | 0849337224
Cover: Hardcover
Copyright: 10/10/2006

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Toxicokinetics in Risk Assessment discusses the noncancer risk assessment process and its reliance on uncertainty factors in order to facilitate the continued study and refinement of the scientific basis for health risk assessment. This text clearly demonstrates the application of physiologically-based pharmacokinetic (PBPK) modeling in human health risk assessment, as well as methods for data generation, extrapolation, and inclusion of laboratory results for chemical metabolism and computer-based predictions of biochemical constants to address estimates of variability between experimental animals and humans. This guide also includes recent examples of the use of toxicokinetic information to successfully replace default values for uncertainty factors with data-derived factors in risk assessments developed by the US Environmental Protection Agency.

Preface	p. iii
Acknowledgments	p. vii
Contributors	p. xvii
Overview of Approach to Noncancer Risk Assessment	p. 1
Introduction to the National Academy of Sciences Risk Assessment Paradigm	p. 2
Use of Uncertainty Factors in Risk Assessment	p. 6
Interindividual Variability	p. 9
Experimental Animal to Human Variability	p. 10
Subchronic to Chronic Extrapolation	p. 10
LOAEL to NOAEL Extrapolation	p. 11
Database Uncertainty	p. 11
Use of TK Data to Modify or Replace Uncertainty Factors	p. 13
Outstanding Issues, Research Areas, and Uncertainties	p. 21
Summary	p. 21
References	p. 22
Guidance for the Development of Chemical-Specific Adjustment Factors: Integration with Mode of Action Frameworks	p. 27
Introduction	p. 21
Development of Chemical-Specific/Compound-Related Adjustments Factors: The Construct	p. 29
Guidance for Development of CSAF	p. 36
Integrating Development of CSAF with MOA Frameworks-An Example	p. 39
Conclusions	p. 44
References	p. 44
Derivation and Modeling of Mechanistic Data for Use in Risk Assessment	p. 47
Introduction	p. 47
Evaluating Human Risk from Animal and Mechanistic Data	p. 48
Derivation of Pharmacokinetic and Pharmacodynamic Measures from Toxicology and Mechanistic Information	p. 50
The Necessity to Test Mechanistic Hypotheses	p. 56
Conclusion: Pharmacokinetic and Pharmacodynamic Modeling Is an Iterative Process	p. 61
References	p. 63
Empirically Observed Distributions of Pharmacokinetic and Pharmacodynamic Variability in Humans-Implications for the Derivation of Single-Point Component Uncertainty Factors Providing Equivalent Protection as Existing Reference Doses	p. 69
Introduction	p. 69
IPCS Assumptions of Single-Point Factors Representing Overall Interindividual Variability and PK/PD Components	p. 72
Description and Update of Previous Work to Construct a Straw Man Proposal for a Quantitative Distributional Goal for Defining Reference Doses Protection Objectives	p. 73
Expansion of the Estimated Pharmacokinetics Variability for Some Age-Related Differences	p. 79
Basic Inferences for the Split of Lognormal Variance in Interindividual Variability Log(GSD) Between PK and PD Portions of the Pathway from Oral Administration to Biological Responses	p. 80
Uncertainties in Current Estimates of PK and PD Variability for an Untested Chemical	p. 81
Effects of Perfect Knowledge of Overall and Component Interindividual Variability on Doses Needed to Achieve the Straw Man Protection Goal	p. 84
Lessons for the Derivation of Single-Point Factors to Represent Overall Interindividual Variability and PK/PD Components	p. 89
References	p. 92
Use of Classical Pharmacokinetic Evaluations in Drug Development and Safety Assessment	p. 95
Introduction	p. 95
Classical Pharmacokinetics and Toxicokinetics	p. 96
Tissue Drug Toxicokinetics	p. 102
Qualitative and Quantitative Assessment of Metabolites	p. 103
Drug-Drug Interactions	p. 105
Importance of Understanding Drug Metabolism in Discovery and Early Development	p. 113
References	p. 119
Considerations for Applying Physiologically Based Pharmacokinetic Models in Risk Assessment	p. 123
Introduction	p. 123
Pharmacokinetic Data Required for Risk Assessments	p. 125
Choosing PBPK Models Appropriate for Use in Risk Assessment	p. 126
Evaluation of Dose Metrics for PBPK Model-Based Assessments	p. 128
Generic Examples of the Use of PBPK Models in Risk Assessment	p. 130
Perspectives and Concluding Remarks	p. 135
References	p. 137
Considerations of Design and Data When Developing Physiologically Based Pharmacokinetic Models	p. 141
Introduction	p. 141
Physiological Parameters	p. 146
Chemical-Specific Parameters	p. 149
Metabolism: Gas Uptake and In Vitro Methods	p. 152
Model Development and Validation	p. 155
Advanced PBPK Models	p. 161
PBPK/PD	p. 162
Conclusions: Application to Risk Assessment	p. 163
References	p. 164
In Silico Predictions of Partition Coefficients for Physiologically Based Pharmacokinetic Models	p. 167
Introduction	p. 167
In Silico Approaches for Estimating PCs	p. 168
Mechanistic In Silico Approaches for Predicting Interindividual Differences in PCs	p. 169
Interindividual Differences in PCs, Tissue Dose, and Risk Assessment	p. 178
References	p. 181
In Vitro to In Vivo Extrapolation of Metabolic Rate Constants for Physiologically Based Pharmacokinetic Models	p. 185
Introduction	p. 185
The Structure and Function of Enzymes	p. 186
Fundamentals of Enzyme Kinetics	p. 187
Enzymes Involved in Biotransformation	p. 194
In Vitro Systems to Study Biotransformation	p. 199
Design of In Vitro Experiments to Predict Biotransformation Kinetics	p. 200
Extrapolation of Kinetic Parameters to Whole Organisms	p. 201
References	p. 206
Use of Physiologically Based Pharmacokinetic Modeling to Evaluate Implications of Human Variability	p. 211
Introduction	p. 211
Determinants of Impact	p. 212
Pharmacokinetic Variability Between Individuals of Different Ages	p. 213
Pharmacokinetic Variability Among Individuals at the Same Age	p. 217
Pharmacokinetic Variability Resulting from Differences Between Subpopulations	p. 218
Conclusions	p. 225
References	p. 227
Developmental Aspects of Children's Pharmacokinetics	p. 231
Children's Pharmacokinetics: Overview	p. 231
Absorption, Distribution, Metabolism, and Excretion in Children	p. 233
Development of Phase II Conjugation Systems	p. 238
Development of Renal Elimination	p. 239
Variability in Pediatric Pharmacokinetic Data	p. 240
Development of Children's PBPK Models	p. 240
Summary	p. 244
References	p. 245
Sensitive Populations and Risk Assessment	p. 251
Introduction	p. 251
General Principles	p. 251
Uncertainty Factors that Account for Sensitivity	p. 254
Mechanistic Information and Sensitive Populations	p. 259
Summary	p. 264
References	p. 264
Statistical Issues in Physiologically Based Pharmacokinetic Modeling	p. 269
Introduction	p. 269
Sensitivity, Identifiability, and the Role of Statistics	p. 270
Case Studies	p. 274
Conclusions	p. 281
References	p. 281
Drug Development and the Use of Pharmacokinetics/Toxicokinetics in Selecting the First Dose of Systemically Administered Drugs in Humans-A Nonclinical Perspective	p. 285
The Overall Drug Development/Approval Process	p. 285
Selection of the First Dose in Humans	p. 290
Pharmacology and Toxicology Data	p. 291
Within Species Evaluations	p. 292
Cross Species Comparisons	p. 293
Use of PK in Picking the First Dose in Humans and Uncertainties	p. 296
Use of PK in Picking the Maximum Dose to Be Used in Human Volunteers	p. 298
Conclusions	p. 298
References	p. 299
Pharmacokinetic/Physiologically Based Pharmacokinetic Models in Integrated Risk Information System Assessments	p. 301
Introduction-Increasing Use of PK/PBPK Models in IRIS	p. 302
The Use of PK and PBPK Models in the IRIS Program	p. 302
Evaluation of PBPK Models Used in IRIS Assessments	p. 308
Specific Examples of Use of PK/PBPK Models in IRIS System	p. 310
PBPK Models or PK Data Used in the Derivation of Reference Values	p. 314
Vinyl Chloride	p. 319
Dichloromethane	p. 323
Xylene	p. 328
Boron and Compounds	p. 332
The IEUBK Model	p. 335
References	p. 341
Index	p. 349
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Toxicokinetics And Risk Assessment

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