List of Figures .............................................. xiii
List of Tables ................................................. xv
The Editors .................................................. xvii
Contributors .................................................. xix
Preface ....................................................... xxi
Acknowledgments ............................................. xxiii
Chapter 1 "Omics" Approaches in the Context of
Environmental Toxicology ............................. 1
Jon C. Cook, Nancy D. Denslow, Taisen Iguchi,
Elwood A. Linney, Ann Miracle, Joseph R. Shaw,
Mark R. Viant, and Timothy R. Zacharewski
1.1 Introduction ............................................... 1
1.2 Overview of Omics Technologies ............................. 1
1.3 Discovery-Driven versus Hypothesis-Driven Research:
A Need for Balance ......................................... 4
1.4 Advantages, Challenges, and Solutions of Omics
Technologies ............................................... 6
1.4.1 Advantages of Genomics Approaches ................... 6
1.4.2 Challenges of Genomics Approaches ................... 8
1.4.3 Solutions Offered for Genomics Approaches ........... 9
1.4.4 Validation of Genomics .............................. 9
1.4.5 Potential of Genomics Approaches for
Ecotoxicology ...................................... 10
1.4.6 Transcriptomics .................................... 10
1.4.6.1 Emerging Transcriptomics Resources ........ 14
1.4.7 Proteomics ......................................... 14
1.4.8 Metabolomics - Molecular Phenotype and Metabolic
Trajectories ....................................... 16
1.4.9 Experimental Considerations for Metabolomics ....... 18
1.4.10 Annotation of Cellular Metabolome .................. 20
1.5 Pathway Mapping - The Future of Omics Technologies ........ 21
1.6 Example of Cross-Species Extrapolation Using
Transcriptomics ........................................... 21
1.7 Recommendations ........................................... 25
1.8 Future .................................................... 25
References ..................................................... 26
Chapter 2 Selection of Surrogate Animal Species for
Comparative Toxicogenomics .......................... 33
Nancy D. Denslow, John K. Colbourne, David Dix,
Jonathan H. Freedman, Caren C. Helbing, Sean
Kennedy, and Phillip L. Williams
2.1 Introduction .............................................. 33
2.2 Brief Review on Studies Using Comparative Genomics ........ 34
2.3 Selection Criteria for Surrogate Species .................. 36
2.3.1 Toxicologic Information ............................ 37
2.3.1.1 Weighting Selection Criteria Based on
Three Research Needs ...................... 39
2.3.1.2 Genome Information ........................ 40
2.4 Selection of Surrogate Species ............................ 40
2.5 Discussion ................................................ 46
2.5.1 Mammalian Models ................................... 47
2.5.1.1 Core Biological Studies and Human
Health .................................... 47
2.5.1.2 Ecotoxicology and Risk Assessment ......... 48
2.5.2 Aquatic Models for Human and Ecological Health ..... 49
2.5.2.1 Core Biology and Human Health Models ...... 49
2.5.2.2 Ecotoxicology and Risk Assessment ......... 50
2.5.3 Amphibian Models ................................... 52
2.5.3.1 Core Biology and Human Health Models ...... 52
2.5.3.2 Ecotoxicology and Risk Assessment ......... 53
2.5.4 Ciona .............................................. 55
2.5.5 Avian Models ....................................... 56
2.5.5.1 Core Biological Studies and Human
Health .................................... 57
2.5.5.2 Ecotoxicology and Risk Assessment ......... 58
2.5.6 Nematode Models .................................... 59
2.5.7 A Community-Based Approach for Promoting Daphnia
as a Model for Ecotoxicogenomics ................... 60
2.5.7.1 The Daphnia Genomics Consortium (DGC) ..... 61
2.5.7.2 Community Resources ....................... 62
2.5.7.3 The Daphnia Genome Project ................ 63
2.6 Conclusions ............................................... 64
References ..................................................... 65
Appendix A ..................................................... 70
Appendix В ..................................................... 71
Appendix С ..................................................... 73
Chapter 3 Species Differences in Response to Toxic
Substances: Shared Pathways of Toxicity - Value
and Limitations of Omics Technologies to Elucidate
Mechanism or Mode of Action ......................... 77
David Eaton, Evan Gallagher, Mike Hooper, Dan
Schlenk, Patricia Schmeider, and Claudia Thompson
3.1 What Omics Approaches Would Be of Greatest Value in
Predictive Toxicology That Utilizes Biologically
Relevant Effects in Organisms or the Environment? ......... 78
3.2 How Can Omics Be Utilized to Understand Mechanism and
Mode of Action? ........................................... 84
3.2.1 Discriminate between Defense/Adaptive Mechanisms
from Direct "Toxic Response" and Secondary
Downstream Events Responsible for Pathology ........ 85
3.2.2 Integrate Omics with "Traditional" or Alternative
Animal Models ...................................... 86
3.3 How Do We Integrate Responses across Gene Expression,
Proteomics, and Metabolomics and Apply This to Make
a Science-Based Statement about Health of an Organism? .... 87
3.4 How Does Development of Omics Technologies Affect the
Interspecies Extrapolation Process? ....................... 88
3.4.1 Effects Assessment in Field Studies ................ 89
3.4.2 Susceptibility Assessment .......................... 90
3.5 What Are Key Limitations and Considerations in Using
Omics Technologies to Inform Mechanisms of Cross-Species
Differences in Response to Xenobiotics? ................... 92
3.5.1 Time of Sample Collection .......................... 92
3.5.2 Duration of Exposure ............................... 93
3.5.3 Dose-Response Considerations ....................... 93
3.5.4 Target Tissues ..................................... 93
3.5.5 Age, Gender ........................................ 94
3.5.6 Nutrition .......................................... 95
3.5.7 Conservation of Responses across Species ........... 95
3.5.8 Validation ......................................... 95
3.5.9 Kinetics, Identification of Rate-Limiting Steps .... 96
3.5.10 In Vitro versus In Vivo Studies: Correlations ...... 97
3.6 Conclusions ............................................... 97
3.7 Recommendations ........................................... 98
References .................................................... 100
Chapter 4 Bioinformatic Approaches and Computational Models
for Data Integration and Cross-Species
Extrapolation in the Postgenomic Era ................ 103
Kenneth S. Ramos, Renae L. Malek, John
Quakenbush, Ilya Shmulevich, Joshua Stuart, and
Michael Waters
4.1 Introduction ............................................. 103
4.2 Mechanistic versus Classification Studies ................ 106
4.3 Computational Methods for Orthologue Identification ...... 108
4.3.1 Available Orthology Resources ..................... 109
4.3.2 All-against-All Pair-Wise Sequence Analysis ....... 110
4.3.3 Reciprocity and Transitivity ...................... 110
4.3.4 Phylogenetically Based Approaches ................. 110
4.3.5 Future Directions ................................. 111
4.4 Interpreting Expression Data across Species .............. 112
4.4.1 Motivation ........................................ 112
4.4.2 Identification of Core Processes .................. 112
4.4.3 Using Core Processes to Interpret Gene
Expression Studies ................................ 114
4.5 Integrating Data across Domains .......................... 115
4.5.1 Analysis of Multiple Domains' Omics Data .......... 116
4.5.2 Development of a Knowledge-Based Science of
Toxicology ........................................ 117
4.5.3 Toxicogenomics Databases and Standards for
Exchange of Data .................................. 117
4.5.4 Systems Toxicology and Toxicogenomics Knowledge
Bases ............................................. 120
4.5.4.1 The Chemical Effects in Biological
Systems (CEBS) Knowledge Base ............ 121
4.5.5 Comparative Toxicogenomics ........................ 122
4.5.6 Optimizing Collection of Data and Development
of Knowledge ...................................... 122
4.6 Supervised and Unsupervised Analysis for
Toxicogenomics ........................................... 124
4.7 Networks ................................................. 126
4.7.1 What Class of Models Should We Choose? ............ 127
4.7.2 How Do We Represent Networks? ..................... 128
4.7.3 To What Extent Do Such Models Represent
Reality? .......................................... 129
4.7.4 Do We Have the "Right" Types of Data to Infer
These Models? ..................................... 130
4.7.5 Biological Systems Are Nonlinear Dynamical
Systems ........................................... 130
4.7.6 What Do We Hope to Learn from These Models? ....... 133
4.8 The Problem of Validation ................................ 134
4.9 Predictive Toxicology .................................... 136
4.10 Educating the Community .................................. 138
4.11 Recommendations for Advancing the Field .................. 141
4.12 Concluding Remarks ....................................... 141
References .................................................... 142
Chapter 5 The Extension of Molecular and Computational
Information to Risk Assessment and Regulatory
Decision Making .................................... 151
James S. Bus, Richard A. Canady, Tracy
K. Collier, J. William Owens, Syril D. Pettit,
Nathaniel L. Scholz, and Anita C. Street
5.1 Introduction ............................................. 151
5.1.1 Scope of the Chapter .............................. 152
5.2 Overview of Human and Ecological Risk Assessment ......... 154
5.2.1 Human Health Risk Assessment ...................... 155
5.2.2 Ecological Assessment ............................. 157
5.2.3 Differences in Statutory Requirements ............. 160
5.2.3.1 Human Health Risk Assessment ............. 160
5.2.3.2 Ecological Risk Assessment ............... 160
5.3 Potential of Omics to Improve Risk Assessment ............ 162
5.3.1 Reducing Uncertainty in Human Health Risk
Assessment ........................................ 162
5.3.1.1 Omics Approaches to Addressing
Cross-Species Uncertainties .............. 162
5.3.1.2 Screening ................................ 162
5.3.1.3 Impact of Genomics Technology on
Reducing Uncertainty in Chemical-
Specific Risk Assessments ................ 163
5.3.1.4 Use of Genomics Methods for Refining
Operational Principles of Risk
Assessment ............................... 164
5.3.2 Reducing Uncertainty in Ecological Risk
Assessment ........................................ 166
5.4 The Path Forward? ........................................ 168
5.4.1 Extrapolations and Inferences from Omics Data ..... 168
5.4.2 Groundtruthing and Validation ..................... 168
5.4.2.1 Conceptualizing Omics in the Regulatory
Risk Framework ........................... 168
5.4.2.2 Implementation Issues for Omics .......... 170
5.4.3 Institutional Limitations ......................... 172
5.4.3.1 Risk Assessment and Management
Infrastructure Limitations ............... 172
5.4.3.2 Phenotypic Anchoring and TSCA
Liability/Safe Harbor .................... 173
5.4.3.3 Data Standards across Regulatory
Agencies ................................. 174
5.4.3.4 Privacy Act .............................. 175
5.5 Conclusions and Recommendations .......................... 176
Acknowledgments ............................................... 178
References .................................................... 178
Index ......................................................... 181
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