LAWRENCE A. KAPUSTKA, PhD, is an Emeritus Senior Ecologist and SETAC Fellow with experience as a professor, government research scientist, and environmental consultant. WAYNE G. LANDIS, PhD, is Research Professor Emeritus at Western Washington University, where he directed the Institute of Environmental Toxicology and Chemistry for over three decades. DAVID J. OSTRACH, PhD, is Chief Scientist at Ostrach Consulting, specializing in aquatic ecosystems, aquatic toxicology, and risk assessment. He founded the Pathobiology, Conservation and Population Biology Laboratory at UC Davis. CAMERON IRVINE is an Associate Environmental Scientist and Ecotoxicologist with Robertson-Bryan, Inc. He chairs the ASTM International E50.47 subcommittee developing international toxicity testing standards, has been an active SETAC member for over 25 years.

• List of Figures xiList of Tables xviiList of Contributors xixAbout the Editors xxiPrologue xxvAbbreviations xxxi1 Impetus for This Book 1David J. Ostrach, Lawrence A. Kapustka, and Cameron A. Irvine2 Foundations of Environmental Science 5Lawrence A. Kapustka3 Exposures and Effects 13Cameron A. Irvine, Mary A. Ottinger, and Lawrence A. KapustkaIntroduction 13Analytical Tools 14Toxicity Testing 17Predictive Toxicology 21Increasingly Sensitive Endpoints and Expanding Knowledge 23The Exposome and One Health 254 Sequence Effects 35Lawrence A. Kapustka5 Addressing the Challenges of Pharmaceutical Pollution 47Sam A. WelchIntroduction 47Drivers of Pharmaceutical Risk 48Demographic and Market Change 50Health and Management Change 51Climate Change 52Modeling the Risks of Pollutant Mixtures 52Modeling the Risks of Multiple Stressors 54Bayesian Networks for Environmental Risk Assessment 54BNs for ERA: A Norwegian Example 55Future Outlooks 59Conclusions 61Acknowledgments 616 The Role of Contaminants, in the Context of Multiple Stressors, in the Collapse of a Striped Bass Population 71David J. Ostrach and Cameron A. IrvineIntroduction 71Approach 71Contaminant Exposures 72Biochemical Activation 73EROD 74Immunointegrity 75Acetylcholinesterase Inhibition 75Metallothionein 77Vitellogenin 77Biochemical Effects Synthesis 79Egg-Ovaries 79Developmental and Histopathology Effects 80Otoliths – Habitat Use 82Conclusion 83Acknowledgments 837 Management of Environmental Systems Using Cumulative Risk Assessment – The Importance of Multiple Stressor Cumulative Ecological Risk Assessment for Long-Term Management of Environmental Systems Demonstrated Using the Upper San Francisco Estuary Case Study 91Wayne G. LandisIntroduction 91Basics of Using the RRM for Multiple Stressor Risk Assessment 91The Use of BNs for Calculation 92The Upper San Francisco Estuary Example – The Study Site 94The Development of the Conceptual Model 96Pesticide Data 98Water Quality Data 98Chinook, Delta Smelt Trawl Data 98Additional Chemical Screening and Geographic Distribution 100Building the Predicted Fish Mortality Pathway 100Options for the Conditional Probability Tables of the Predicted Fish Mortality Node 104Calculation of Risk to the Individual Species 106Discussion: Estimating Risk with Multiple Stressors/Cumulative Risk Assessment 1088 Integrating Emerging Science in Advancing Risk Assessment for Wildlife 115Mark S. Johnson and Thomas G. BeanIntroduction 115Considering Data Generated from New and Emerging Tools in Problem Formulation 117Improved Methods for Exposure Estimation 117Aspirational Ways to Improve Accuracy of Exposure Models 123What Has Been Incorporated Recently into Exposure Models? 126Future Options for Improving Exposure Assessment Models 127Novel Tools for Estimating Hazard (Toxicity) 131In vivo Alternative Tools (Adverse Outcome Pathways, Cell Lines, IVIVE) 131Methodological Improvements in Current Guidelines and Laboratory Model Development 134Development of Toxicological Benchmarks Using Evidence Integration Techniques 136Research and Data Needs 1379 Reflections from an Environmental Toxicologist Working in a Large Company 147alph G. Stahl Jr (Retired)Introduction 147Remediation and Restoration of Contaminated Land in the United States 148Remediation and Restoration of Contaminated Land Outside the United States 148What Is a "Site" 149DuPont Remediation Program 150Risk-Based Decision-Making 151Sites/Examples 151The United States – Superfund Site, Newport, Delaware 151The United States – RCRA-Corrective Action Site, Waynesboro, Virginia 153The United Kingdom – Contaminated Lands Program Site, Northern Ireland 155Discussion 157Acknowledgments 158Conflict of Interest Statement 159Disclaimer 159Data Availability 15910 Big Data – Artificial Intelligence and Machine Learning – Examples of the Application of Approaches Derived from Artificial Intelligence/Machine Learning to Analyze Large Datasets for Ecological Risk Assessment 163Wayne G. LandisIntroduction 163Section 1: Microcosm/Mesocosm Summary, the Effects of Jet Fuels, and Community Conditioning 165Section 2: Ecological Risk Assessment/Relative Risk Model and the Port Valdez Risk Assessment 170Section 3: Transition to BNs 175Section 4: Case Summary: Predicting Risk to Estuary Water Quality and Patterns of Benthic Environmental DNA in Queensland, Australia 176Section 5: Adaptive Management and Next Steps 179Cautions/Caveats 18011 New Tools and Approaches in Ecological Risk Assessment 185P. Bruce Duncan and Jeanmarie M. ZodrowIntroduction 185Despite the Goal to Advance Ecological Risk Assessment, Progress Can Be Very Slow 185Lessons from Development and Use of NAMs to Reduce Animal Testing 188Framework for Tool Development 192Actions to Advance the Use of New Tools and Approaches 195Q1. Why Are Uses in Decisions Not Easily Found? 195Q2. How Do You Unlock Obstacles to Advancement? 196Q2-Suggested Actions 197Q3. What Creates Compelling Arguments for Decision-Makers? 200Q3-Suggested Actions 201Q4. What Support for Tools Is Needed for Success? 203Q4-Suggested Actions 203Q5. Where Do We See Successes? 205Q5-Suggested Actions 205Summary and Conclusions 209Checklist of Actions 210References 213Appendix: Results of Author Survey 21712 Going Forward 221Lawrence A. KapustkaIntroduction 221References 224Index 227

LAWRENCE A. KAPUSTKA, PhD, is an Emeritus Senior Ecologist and SETAC Fellow with experience as a professor, government research scientist, and environmental consultant. WAYNE G. LANDIS, PhD, is Research Professor Emeritus at Western Washington University, where he directed the Institute of Environmental Toxicology and Chemistry for over three decades. DAVID J. OSTRACH, PhD, is Chief Scientist at Ostrach Consulting, specializing in aquatic ecosystems, aquatic toxicology, and risk assessment. He founded the Pathobiology, Conservation and Population Biology Laboratory at UC Davis. CAMERON IRVINE is an Associate Environmental Scientist and Ecotoxicologist with Robertson-Bryan, Inc. He chairs the ASTM International E50.47 subcommittee developing international toxicity testing standards, has been an active SETAC member for over 25 years.

• List of Figures xiList of Tables xviiList of Contributors xixAbout the Editors xxiPrologue xxvAbbreviations xxxi1 Impetus for This Book 1David J. Ostrach, Lawrence A. Kapustka, and Cameron A. Irvine2 Foundations of Environmental Science 5Lawrence A. Kapustka3 Exposures and Effects 13Cameron A. Irvine, Mary A. Ottinger, and Lawrence A. KapustkaIntroduction 13Analytical Tools 14Toxicity Testing 17Predictive Toxicology 21Increasingly Sensitive Endpoints and Expanding Knowledge 23The Exposome and One Health 254 Sequence Effects 35Lawrence A. Kapustka5 Addressing the Challenges of Pharmaceutical Pollution 47Sam A. WelchIntroduction 47Drivers of Pharmaceutical Risk 48Demographic and Market Change 50Health and Management Change 51Climate Change 52Modeling the Risks of Pollutant Mixtures 52Modeling the Risks of Multiple Stressors 54Bayesian Networks for Environmental Risk Assessment 54BNs for ERA: A Norwegian Example 55Future Outlooks 59Conclusions 61Acknowledgments 616 The Role of Contaminants, in the Context of Multiple Stressors, in the Collapse of a Striped Bass Population 71David J. Ostrach and Cameron A. IrvineIntroduction 71Approach 71Contaminant Exposures 72Biochemical Activation 73EROD 74Immunointegrity 75Acetylcholinesterase Inhibition 75Metallothionein 77Vitellogenin 77Biochemical Effects Synthesis 79Egg-Ovaries 79Developmental and Histopathology Effects 80Otoliths – Habitat Use 82Conclusion 83Acknowledgments 837 Management of Environmental Systems Using Cumulative Risk Assessment – The Importance of Multiple Stressor Cumulative Ecological Risk Assessment for Long-Term Management of Environmental Systems Demonstrated Using the Upper San Francisco Estuary Case Study 91Wayne G. LandisIntroduction 91Basics of Using the RRM for Multiple Stressor Risk Assessment 91The Use of BNs for Calculation 92The Upper San Francisco Estuary Example – The Study Site 94The Development of the Conceptual Model 96Pesticide Data 98Water Quality Data 98Chinook, Delta Smelt Trawl Data 98Additional Chemical Screening and Geographic Distribution 100Building the Predicted Fish Mortality Pathway 100Options for the Conditional Probability Tables of the Predicted Fish Mortality Node 104Calculation of Risk to the Individual Species 106Discussion: Estimating Risk with Multiple Stressors/Cumulative Risk Assessment 1088 Integrating Emerging Science in Advancing Risk Assessment for Wildlife 115Mark S. Johnson and Thomas G. BeanIntroduction 115Considering Data Generated from New and Emerging Tools in Problem Formulation 117Improved Methods for Exposure Estimation 117Aspirational Ways to Improve Accuracy of Exposure Models 123What Has Been Incorporated Recently into Exposure Models? 126Future Options for Improving Exposure Assessment Models 127Novel Tools for Estimating Hazard (Toxicity) 131In vivo Alternative Tools (Adverse Outcome Pathways, Cell Lines, IVIVE) 131Methodological Improvements in Current Guidelines and Laboratory Model Development 134Development of Toxicological Benchmarks Using Evidence Integration Techniques 136Research and Data Needs 1379 Reflections from an Environmental Toxicologist Working in a Large Company 147alph G. Stahl Jr (Retired)Introduction 147Remediation and Restoration of Contaminated Land in the United States 148Remediation and Restoration of Contaminated Land Outside the United States 148What Is a "Site" 149DuPont Remediation Program 150Risk-Based Decision-Making 151Sites/Examples 151The United States – Superfund Site, Newport, Delaware 151The United States – RCRA-Corrective Action Site, Waynesboro, Virginia 153The United Kingdom – Contaminated Lands Program Site, Northern Ireland 155Discussion 157Acknowledgments 158Conflict of Interest Statement 159Disclaimer 159Data Availability 15910 Big Data – Artificial Intelligence and Machine Learning – Examples of the Application of Approaches Derived from Artificial Intelligence/Machine Learning to Analyze Large Datasets for Ecological Risk Assessment 163Wayne G. LandisIntroduction 163Section 1: Microcosm/Mesocosm Summary, the Effects of Jet Fuels, and Community Conditioning 165Section 2: Ecological Risk Assessment/Relative Risk Model and the Port Valdez Risk Assessment 170Section 3: Transition to BNs 175Section 4: Case Summary: Predicting Risk to Estuary Water Quality and Patterns of Benthic Environmental DNA in Queensland, Australia 176Section 5: Adaptive Management and Next Steps 179Cautions/Caveats 18011 New Tools and Approaches in Ecological Risk Assessment 185P. Bruce Duncan and Jeanmarie M. ZodrowIntroduction 185Despite the Goal to Advance Ecological Risk Assessment, Progress Can Be Very Slow 185Lessons from Development and Use of NAMs to Reduce Animal Testing 188Framework for Tool Development 192Actions to Advance the Use of New Tools and Approaches 195Q1. Why Are Uses in Decisions Not Easily Found? 195Q2. How Do You Unlock Obstacles to Advancement? 196Q2-Suggested Actions 197Q3. What Creates Compelling Arguments for Decision-Makers? 200Q3-Suggested Actions 201Q4. What Support for Tools Is Needed for Success? 203Q4-Suggested Actions 203Q5. Where Do We See Successes? 205Q5-Suggested Actions 205Summary and Conclusions 209Checklist of Actions 210References 213Appendix: Results of Author Survey 21712 Going Forward 221Lawrence A. KapustkaIntroduction 221References 224Index 227

LAWRENCE A. KAPUSTKA, PhD, is an Emeritus Senior Ecologist and SETAC Fellow with experience as a professor, government research scientist, and environmental consultant. WAYNE G. LANDIS, PhD, is Research Professor Emeritus at Western Washington University, where he directed the Institute of Environmental Toxicology and Chemistry for over three decades. DAVID J. OSTRACH, PhD, is Chief Scientist at Ostrach Consulting, specializing in aquatic ecosystems, aquatic toxicology, and risk assessment. He founded the Pathobiology, Conservation and Population Biology Laboratory at UC Davis. CAMERON IRVINE is an Associate Environmental Scientist and Ecotoxicologist with Robertson-Bryan, Inc. He chairs the ASTM International E50.47 subcommittee developing international toxicity testing standards, has been an active SETAC member for over 25 years.

• List of Figures xiList of Tables xviiList of Contributors xixAbout the Editors xxiPrologue xxvAbbreviations xxxi1 Impetus for This Book 1David J. Ostrach, Lawrence A. Kapustka, and Cameron A. Irvine2 Foundations of Environmental Science 5Lawrence A. Kapustka3 Exposures and Effects 13Cameron A. Irvine, Mary A. Ottinger, and Lawrence A. KapustkaIntroduction 13Analytical Tools 14Toxicity Testing 17Predictive Toxicology 21Increasingly Sensitive Endpoints and Expanding Knowledge 23The Exposome and One Health 254 Sequence Effects 35Lawrence A. Kapustka5 Addressing the Challenges of Pharmaceutical Pollution 47Sam A. WelchIntroduction 47Drivers of Pharmaceutical Risk 48Demographic and Market Change 50Health and Management Change 51Climate Change 52Modeling the Risks of Pollutant Mixtures 52Modeling the Risks of Multiple Stressors 54Bayesian Networks for Environmental Risk Assessment 54BNs for ERA: A Norwegian Example 55Future Outlooks 59Conclusions 61Acknowledgments 616 The Role of Contaminants, in the Context of Multiple Stressors, in the Collapse of a Striped Bass Population 71David J. Ostrach and Cameron A. IrvineIntroduction 71Approach 71Contaminant Exposures 72Biochemical Activation 73EROD 74Immunointegrity 75Acetylcholinesterase Inhibition 75Metallothionein 77Vitellogenin 77Biochemical Effects Synthesis 79Egg-Ovaries 79Developmental and Histopathology Effects 80Otoliths – Habitat Use 82Conclusion 83Acknowledgments 837 Management of Environmental Systems Using Cumulative Risk Assessment – The Importance of Multiple Stressor Cumulative Ecological Risk Assessment for Long-Term Management of Environmental Systems Demonstrated Using the Upper San Francisco Estuary Case Study 91Wayne G. LandisIntroduction 91Basics of Using the RRM for Multiple Stressor Risk Assessment 91The Use of BNs for Calculation 92The Upper San Francisco Estuary Example – The Study Site 94The Development of the Conceptual Model 96Pesticide Data 98Water Quality Data 98Chinook, Delta Smelt Trawl Data 98Additional Chemical Screening and Geographic Distribution 100Building the Predicted Fish Mortality Pathway 100Options for the Conditional Probability Tables of the Predicted Fish Mortality Node 104Calculation of Risk to the Individual Species 106Discussion: Estimating Risk with Multiple Stressors/Cumulative Risk Assessment 1088 Integrating Emerging Science in Advancing Risk Assessment for Wildlife 115Mark S. Johnson and Thomas G. BeanIntroduction 115Considering Data Generated from New and Emerging Tools in Problem Formulation 117Improved Methods for Exposure Estimation 117Aspirational Ways to Improve Accuracy of Exposure Models 123What Has Been Incorporated Recently into Exposure Models? 126Future Options for Improving Exposure Assessment Models 127Novel Tools for Estimating Hazard (Toxicity) 131In vivo Alternative Tools (Adverse Outcome Pathways, Cell Lines, IVIVE) 131Methodological Improvements in Current Guidelines and Laboratory Model Development 134Development of Toxicological Benchmarks Using Evidence Integration Techniques 136Research and Data Needs 1379 Reflections from an Environmental Toxicologist Working in a Large Company 147alph G. Stahl Jr (Retired)Introduction 147Remediation and Restoration of Contaminated Land in the United States 148Remediation and Restoration of Contaminated Land Outside the United States 148What Is a "Site" 149DuPont Remediation Program 150Risk-Based Decision-Making 151Sites/Examples 151The United States – Superfund Site, Newport, Delaware 151The United States – RCRA-Corrective Action Site, Waynesboro, Virginia 153The United Kingdom – Contaminated Lands Program Site, Northern Ireland 155Discussion 157Acknowledgments 158Conflict of Interest Statement 159Disclaimer 159Data Availability 15910 Big Data – Artificial Intelligence and Machine Learning – Examples of the Application of Approaches Derived from Artificial Intelligence/Machine Learning to Analyze Large Datasets for Ecological Risk Assessment 163Wayne G. LandisIntroduction 163Section 1: Microcosm/Mesocosm Summary, the Effects of Jet Fuels, and Community Conditioning 165Section 2: Ecological Risk Assessment/Relative Risk Model and the Port Valdez Risk Assessment 170Section 3: Transition to BNs 175Section 4: Case Summary: Predicting Risk to Estuary Water Quality and Patterns of Benthic Environmental DNA in Queensland, Australia 176Section 5: Adaptive Management and Next Steps 179Cautions/Caveats 18011 New Tools and Approaches in Ecological Risk Assessment 185P. Bruce Duncan and Jeanmarie M. ZodrowIntroduction 185Despite the Goal to Advance Ecological Risk Assessment, Progress Can Be Very Slow 185Lessons from Development and Use of NAMs to Reduce Animal Testing 188Framework for Tool Development 192Actions to Advance the Use of New Tools and Approaches 195Q1. Why Are Uses in Decisions Not Easily Found? 195Q2. How Do You Unlock Obstacles to Advancement? 196Q2-Suggested Actions 197Q3. What Creates Compelling Arguments for Decision-Makers? 200Q3-Suggested Actions 201Q4. What Support for Tools Is Needed for Success? 203Q4-Suggested Actions 203Q5. Where Do We See Successes? 205Q5-Suggested Actions 205Summary and Conclusions 209Checklist of Actions 210References 213Appendix: Results of Author Survey 21712 Going Forward 221Lawrence A. KapustkaIntroduction 221References 224Index 227