Biological Concepts and Techniques in Toxicology DDK4995_FM.inddK4995_FM.indd 1 11/5/06/5/06 22:01:50:01:50 PPMM PProcessrocess CCyanyanPProcessrocess MMagentaagentaPProcessrocess YYellowellowPProcessrocess BBlacklack Biological Concepts and Techniques in Toxicology An Integrated Approach edited by Jim E. Riviere North Carolina State University Raleigh, North Carolina, U.S.A. DDK4995_FM.inddK4995_FM.indd 2 11/5/06/5/06 22:01:50:01:50 PPMM PProcessrocess CCyanyanPProcessrocess MMagentaagentaPProcessrocess YYellowellowPProcessrocess BBlacklack DK4995_Discl.fm Page 1 Wednesday, November 30, 2005 10:12 AM Published in 2006 by Taylor & Francis Group 270 Madison Avenue New York, NY 10016 © 2006 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10987654321 International Standard Book Number-10: 0-8247-2979-X (Hardcover) International Standard Book Number-13: 978-0-8247-2979-0 (Hardcover) Library of Congress Card Number 2005056861 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Biological concepts and techniques in toxicology : an integrated approach / edited by Jim E. Riviere. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-8247-2979-0 (hardcover : alk. paper) ISBN-10: 0-8247-2979-X (hardcover: alk. paper) 1. Toxicology. 2. Molecular toxicology. 3. Drugs--Toxicology. I. Riviere, J. Edmond (Jim Edmond) [DNLM: 1. Toxicology--methods. 2. Drug Toxicity. QV 600 B6146 2006] RA1191.B52 2006 615.9--dc22 2005056861 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group is the Academic Division of Informa plc. Preface Toxicology is a rapidly developing discipline whose advances are often based on uti- lizing concepts and techniques developed from basic biomedical research. Earlier revolutions in molecular biology and mathematical modeling have led to routine use of in vitro models and toxicokinetics developed from these disciplines. In order for toxicology to remain current and continue making significant advances, it is important that the latest developments be presented in a context focused on how they can be applied to different fields of investigation. How do concepts and new paradigms migrate into routine practice? Several recent toxicology issues have engendered attention and are deserving of a review that illustrates how new techni- ques have been applied to actual problems of toxicological interest. How did these migrate from the basic science laboratory to routine toxicology test protocols? How will today’s revolution in the ‘‘-omics’’ affect the practice of toxicology in the next decade? This book is meant to provide a timely introduction to these tech- niques focused on how the latest science can be applied to existing problems in tox- icology. It is also meant to overview some recent areas where progress has been made and a story can begin to be told. The initial chapters review new approaches or concepts that will have a major impact on the practice of toxicology in the coming decade. These include the ‘‘omics’’ which together comprise systems biology as well as mathematical approaches designed to link chemical structure to activity. This section ends with a cogent pre- sentation of hormesis, a concept that has begun to alter the way toxicologists and others interpret dose–response relationships, the cornerstone to the practice of clas- sical toxicology. The four chapters comprising the next section of the book deal with how biological data and test systems are integrated into the actual practice of toxicology. What is the validation process that allows a novel idea to become a stan- dard test? The final section of chapters reviews applications of toxicology to specific and more focused topics that represent current issues facing society today, including discussions of genetically modified food, nanomaterials, and pharmaceutics. Specific disciplines, including inhalational and forensic toxicology are discussed, as are current military issues that continue to draw attention. iii iv Preface The goal of this book is not to reproduce comprehensive toxicology texts cov- ering basic mechanisms of toxicity or target organ toxicology; nor is it a methods text overviewing the nuts and bolts of new techniques. The goal is to highlight new methods and concepts that may have a major impact on toxicology and present how such concepts and techniques migrate into the mainstream of toxicology. Jim E. Riviere Raleigh, North Carolina Contents Preface . iii Contributors . xi 1. Introduction and Overview . ........................ 1 Jim E. Riviere PART I. NEW CONCEPTS AND APPROACHES 2. Toxicogenomics: Gene Expression Analysis and Computational Tools .................................. 5 Rupesh P. Amin, Hisham K. Hamadeh, J. Todd Auman, Lee Bennett, Cynthia A. Afshari, Pierre R. Bushel, Richard S. Paules, and J. Christopher Corton Introduction . 5 Microarray-Based Gene Expression Profiling . 6 Selection of Differentially Expressed Genes . 9 Finding Expression Patterns . 11 Data Management . 13 Biological Databases Useful for Toxicogenomics . 14 Examples from an In Vivo Toxicogenomics Study . 14 Future Prospects for Toxicogenomics . 19 References . 21 3. Proteomics ........................................ 25 Frank A. Witzmann Introduction . 25 Differential Expression Proteomic Technologies . 27 A 2-D Gel-Based Toxicoproteomic Analysis of Jet Fuel Exposure . 39 Conclusion . 41 References . 42 v vi Contents 4. The Potential of Metabonomics in Toxicology . ......... 47 Julian L. Griffin Introduction . 47 Metabonomics and Genomics . 49 Metabonomics and Disease . 51 Metabonomics and Transcriptomics . 51 MS and Metabonomics . 55 Metabonomics and Systems Biology . 56 Future Developments . 56 Conclusions . 58 References . 59 5. Quantitative Structure–Toxicity Relationships Using Chemodescriptors and Biodescriptors . ................ 61 Subhash C. Basak, Denise Mills, and Brian D. Gute Introduction . 61 The Molecular Structure Conundrum . 62 The HiQSAR Approach . 63 Statistical Methods . 69 Applications in Toxicokinetics and Toxicodynamics . 70 Cell Level Toxicity Estimation . 71 Molecular Similarity and Predictive Toxicology . 75 Discussion . 76 References . 79 6.Hormesis:AKeyConceptinToxicology .................... 83 Edward J. Calabrese What Does This Mean Today? .... 90 References . 90 PART II. INTEGRATION INTO PRACTICE 7. Chemical Risk Assessment . ....................... 93 Ronald E. Baynes and Jennifer L. Buur Introduction . 93 Hazard Identification . 94 WOE . 96 Dose–Response Assessment . 98 Quantifying Risk for Noncarcinogenic Effects: Hazard Quotient . 103 Chemical Mixtures . 104 Dermal RA . 107 PBPK Modeling . 108 Conclusion . 114 References . 114 Contents vii 8. Toxicokinetics: Fundamentals and Applications in Drug Development and Safety Assessment . ............... 117 Rakesh Dixit Introduction . 117 Pharmacokinetics and Toxicokinetics . 117 Conclusions . 156 References . 157 9. Validation of In Vitro Methods for Toxicology Studies ........ 161 William S. Stokes Introduction . 161 The Concept of Test Method Validation . 162 Evolution Process for Test Methods . 162 Validation and Regulatory Acceptance Criteria . 164 The Validation Process . 165 ICCVAM Role in Validation and Regulatory Acceptance . 170 Summary . 173 References . 174 10. Chemical Mixtures Risk Assessment and Technological Advances . ...................... 177 M. M. Mumtaz, B. A. Fowler, C. T. De Rosa, P. Ruiz, M. Whittaker and J. Dennison Disease Conditions Caused by Chemical Mixtures . 177 Assessment Approaches . 184 New Developments . 192 Research Advancements in Joint Toxicity of Metals . 195 Perspectives and Future Needs . 197 References . 199 PART III. EXAMPLES APPLIED TO PROBLEMS 11. Risk-Based Approach to Foods Derived from Genetically Engineered Animals . ................................ 205 Larisa Rudenko, Kevin J. Greenlees, and John C. Matheson III Introduction: The Need to Move Beyond Traditional Dose-Exaggeration Studies . 205 Underlying Risk Basis and Paradigm Setting . 208 Toward a Risk-Based Approach . 209 Hazard Analysis for GE Animals Traditionally Consumed for Food . 210 Looking Forward