Applications of Toxicogenomics in Safety Evaluation and Risk Assessment

This book provides a timely overview of toxicogenomics, with special emphasis on the practical applications of this technology to the risk assessment process. Introductory sections are followed by a series of chapters highlighting practical and systematic applications of toxicogenomics in informing the risk assessment process – including the areas of mutagenicity, carcinogenicity, endocrine toxicity, organ-specific toxicity, population monitoring, and ecotoxicology. The book concludes with approaches for the integration of this technology in safety evaluation studies, and an outlook on how toxicogenomics and complementary technologies can reframe the current risk assessment paradigm. PREFACE ix

CONTRIBUTORS xi

1 TOXICOLOGY, "OMICS" TECHNOLOGIES, AND TOXICOGENOMICS: A PRIMER 1
Darrell R. Boverhof and B. Bhaskar Gollapudi

2 INTRODUCTION TO HUMAN HEALTH RISK ASSESSMENT 13
Irene Baskerville-Abraham, Alison Willis, Bernard Gadagbui, and Lynne T. Haber

3 PRACTICAL CONSIDERATIONS FOR THE APPLICATION OF TOXICOGENOMICS TO RISK ASSESSMENT: EARLY EXPERIENCE, CURRENT DRIVERS, AND A PATH FORWARD 41
Darrell R. Boverhof, David R. Geter, B. Bhaskar Gollapudi, and Heli Hollnagel

4 APPROACHES AND PRACTICAL CONSIDERATIONS FOR THE ANALYSIS OF TOXICOGENOMICS DATA 65
Zhenqiang Su, Hong Fang, Weida Tong, Huixiao Hong, Roger Perkins, and Leming Shi

5 GENOMICS IN IDENTIFYING MUTAGENIC MODE OF ACTION IN CARCINOGENESIS 81
Jiri Aubrecht and Ebru Caba

6 APPLICATION OF GENOMICS FOR PREDICTING AND UNDERSTANDING THE MODE OF ACTION FOR NONGENOTOXIC CARCINOGENS 99
Mark R. Fielden

7 GENOMICS IN CHARACTERIZING ENDOCRINE TOXICITY 117
Jorge M. Naciff and George P. Daston

8 STUDYING ORGAN-SPECIFIC TOXICITY USING GENE-EXPRESSION PROFILING 147
M. Ann Mongan and Hisham K. Hamadeh

9 TOXICOGENOMIC STUDIES IN HUMAN POPULATIONS 177
Cliona M. McHale, Luoping Zhang, Alan E. Hubbard, and Martyn T. Smith

10 TOXICOGENOMICS APPLIED TO ECOLOGICAL RISK ASSESSMENT 207
Daniel L. Villeneuve, Dalma Martinovi´c, and Gerald T. Ankley

11 ANALYSIS OF TRANSCRIPTOMIC DOSE–RESPONSE DATA FOR TOXICOLOGY AND RISK ASSESSMENT 237
Russell S. Thomas, Longlong Yang, Harvey J. Clewell, and Melvin E. Andersen

12 TOXICOGENOMICS AS A TOOL FOR VALIDATING ANIMAL TO HUMAN EXTRAPOLATIONS IN CHEMICAL RISK ASSESSMENT: CONCEPTS, APPLICATIONS, AND CHALLENGES 251
Alan Dombkowski and J. Craig Rowlands

13 TOXICOGENOMICS AND ANIMAL ALTERNATIVES 267
Anne S. Kienhuis, Joost H. M. van Delft, and Jos C. S. Kleinjans

14 TOXICOGENOMICS AND THE REGULATORY FRAMEWORK 293
Kathryn Gallagher, Federico M. Goodsaid, David J. Dix, Susan Y. Euling, Melissa Kramer, Nancy E. McCarroll, Julian R. Preston, Philip G. Sayre, Banalata Sen, Douglas C. Wolf, and William H. Benson

15 STANDARDIZATION OF GENE-EXPRESSION INFORMATION FOR THE SAFETY EVALUATION: ACTIVITIES IN JAPAN 323
Ken-ichi Aisaki and Jun Kanno

16 APPLYING TRANSCRIPTIONAL PROFILING IN DRUG SAFETY EVALUATION 331
Lois D. Lehman-McKeeman and William R. Foster

17 REFRAMING THE RISK ASSESSMENT PARADIGM: TOWARD A SYSTEMS BIOLOGY APPROACH 349
Sarah N. Campion and Kim Boekelheide

INDEX 357

DARRELL R. BOVERHOF, PhD, is a Senior Toxicology Specialist at The Dow Chemical Company where he leads research programs on respiratory allergy and sensitization, nanotoxicology, and toxicogenomics. Dr. Boverhof has authored or coauthored numerous peer-reviewed publications, review articles, and book chapters in the area of toxicogenomics and serves on the editorial board of the journal Toxicological Sciences.

B. BHASKAR GOLLAPUDI, PhD, is the Scientific Director of Mammalian Toxicology at The Dow Chemical Company's Global Toxicology & Environmental Research Laboratory. Dr. Gollapudi has authored or co-authored more than 80 scientific publications. He is an Associate Editor of the journal Toxicological Sciences and is currently serving as an adjunct Associate Professor of Toxicology in the Department of Public Health at the University of Michigan.

Risk assessment and toxicogenomics — a practical review

The past decade has seen growing interest in the use of toxicogenomics for hazard evaluation and chemical safety assessment. This book addresses the need in the field for a comprehensive, up-to-date review of this emerging technology, providing toxicologists and regulatory scientists with practical considerations to take advantage of toxicogenomics when conducting risk assessment of industrial chemicals, pharmaceuticals, agrochemicals, and consumer products.

Written by leading scientists experienced in the application of toxicogenomics data, this book includes a complete introduction to toxicogenomics and the principles of risk assessment, examines the potential of the technology to improve risk assessment practices, and offers insight into promising future trends. The emphasis throughout is on practical risk assessment, highlighting applications of toxicogenomics in the risk assessment process across diverse and important areas.

Topics include:

• Applications in mutagenicity, carcinogenicity, endocrine toxicity, organ-specific toxicity, population monitoring, and ecotoxicology

• The use of toxicogenomics for enhancing mode-of-action and weight-of-evidence approaches

• The role of toxicogenomics in dose-response analysis, cross-species extrapolations, and animal alternatives

• The regulatory aspects of toxicogenomics, including chemical classification and prioritization for toxicity testing

• Strategic approaches for the integration of toxicogenomics in safetyevaluation studies