De-Sheng Pei, PhD, Professor & Doctoral Supervisor, School of Public Health, Chongqing Medical University. He is currently engaged in research on animal disease models, germ-free fish models, toxicological effects of environmental pollutants, and molecular mechanisms of disease caused by environmental pollutants. His discoveries have been published in more than 180 research papers. Yiyun Liu, PhD, School of Public Health, Chongqing Medical University. In 2022, Dr. Liu graduated from the Research Center for Eco-Environmental Science (RCEES), Chinese Academy of Sciences.

• Foreword xiiiPreface xvAcknowledgments xviiList of Contributors xix1 Introduction to Combined Toxicology, Background, Key Terminologies, and Significance 1Yingjie Xia1.1 Introduction 11.2 Key Terminologies 51.3 Significance 72 Toxicokinetics of Chemical Mixture Exposure in the Environment 13Abdul Wahab Hussain, Mehvish Mumtaz, Asad Ullah Saeed, Maryam Mumtaz2.1 Unveiling Toxicokinetics 132.2 Toxicokinetics and Chemical Mixture Assessment 132.3 List of Toxic Chemicals/Pollutants Present in the Environment 152.4 Toxicokinetics of Selected Organohalide Compounds/Mixtures 162.5 Conclusions 243 Toxicodynamics of Chemical Mixtures Exposure in the Organism Body 29Chunjiao Lu, Ting Yang, Xin Meng, Xiaojun Yang3.1 Chemical Mixtures in Environment 293.2 Model Organism in Toxicology 323.3 Toxicodynamics of Chemical Mixtures 353.4 Conclusions 394 Principal Sources, Fate, and Mechanism of Chemical Mixtures in the Environment 47Bao-Fu Zhang, Yiyun Liu, De-Sheng Pei4.1 Introduction 474.2 MP Mixtures 474.3 Pesticide Mixtures 494.4 HM and Metalloid Metal Mixtures 504.5 Nanoparticle Mixtures 514.6 Persistent Organic Pollutants 514.7 Antibiotic Mixtures 524.8 Conclusions 535 Experimental Designs and Sampling Strategies for Combined Toxicity Studies Based on Concentrations 61Manoharan Saravanan, Karunanithi Vidhya5.1 Introduction 615.2 Need for Risk Assessment Studies 625.3 Risk Assessment of Mixture Toxicity 625.4 Experimental Designs and Methodologies for Mixture Toxicity 625.5 Concentration of Mixture Substances 645.6 Concentration-based Strategy 655.7 Ecotoxicity Tests: Acute (Short-term Exposure) and Chronic Test (Long-term Exposure) 665.8 Sampling of Biomarkers 715.9 Animal Models for Combined Toxicity 725.10 Conclusions 766 Migration and Transformation of Chemical Pollutants as Mixtures 83Xiang Ge, Yingxin Yu6.1 Introduction 836.2 Volatile Organic Compounds 846.3 Polybrominated Diphenyl Ethers 856.4 Tetrabromobisphenol A and Its Derivatives 876.5 Per- and Polyfluoroalkyl Substances 886.6 Organophosphorus Flame Retardants 896.7 Phthalic Acid Esters 906.8 Polycyclic Aromatic Hydrocarbons 916.9 Alkylphenols 926.10 Methylsiloxanes 937 Analytical Techniques Used to Detect Chemical Mixtures in the Environment 103Thodhal Yoganandham Suman7.1 Introduction 1037.2 Navigating the Complexities of Mixture Toxicity: A Persistent Challenge in Environmental Health 1047.3 Advancing Environmental Monitoring: Toward a Holistic Understanding of Chemical Mixtures 1047.4 Sample Preparation: Enhancing Specificity and Efficiency in Mixture Analysis 1067.5 Expanding the Analytical Toolbox: Emerging Extraction Techniques for Complex Environmental Matrices 1077.6 Analytical Techniques for Characterizing Organic Pollutants: Advancing Beyond Traditional Approaches 1087.7 Outlook: Toward Holistic Environmental Monitoring with Advanced Analytical Tools 1118 Common Toxicological Experimental Models 115Xuan Ma, Dejun Huang8.1 Male Reproductive Function 1158.2 Female Reproductive Function 1209 Combined Molecular Toxicity Mechanism of Heavy Metals Mixtures 125Kusheng Wu, Yuequn Chen, Wenlong Huang9.1 Introduction: Heavy Metal Exposures Are Everywhere 1259.2 Combined Molecular Toxicity of Heavy Metal Mixtures in the Cardiovascular System 1259.3 Combined Molecular Toxicity of Heavy Metal Mixtures in the Nervous System 1299.4 Combined Molecular Toxicity of Heavy Metal Mixtures in the Male Reproductive System 1339.5 Combined Molecular Toxicity of Heavy Metal Mixtures in the Female Reproductive System 1359.6 Combined Molecular Toxicity of Heavy Metal Mixtures in the Liver 1389.7 Combined Molecular Toxicity of Heavy Metal Mixtures in the Immune System 1399.8 Combined Toxicity of Heavy Metals Mixture in the Regulation of Immune Mediators 1459.9 Combined Toxicity of Heavy Metals Mixture in the Immune Response to the Immunogen 1469.10 Combined Molecular Toxicity of Heavy Metal Mixtures in the Tumorigenesis 1479.11 Combined Molecular Toxicity of Heavy Metal Mixtures in the Orofacial Clefts 1499.12 Combined Molecular Toxicity of Heavy Metal Mixtures in the Olfactory System 15210 Combined Molecular Toxicity Mechanism of Pesticide Mixtures 173Ali Omar Jimale, Yiyun Liu, De-Sheng Pei10.1 Introduction 17310.2 Epidemiology of Pesticide Pollution 17410.3 Diseases Caused by Pesticides 17410.4 The Combined Molecular Toxicity Mechanisms of Pesticide Mixtures 17510.5 Summary 17811 Combined Molecular Toxicity Mechanism of Persistent Organic Pollutant Mixtures 183Ruijia Zhang, Tiangang Luan11.1 Introduction 18311.2 Design of the Components of POP Mixtures and Their Concentrations 18411.3 Developmental Toxicity of POP Mixtures 18911.4 Endocrine Effects of POP Mixtures 18911.5 Molecular Toxicity Mechanisms of POPs 19111.6 Conclusions 19212 Combined Molecular Toxicity Mechanism of Emerging Pollutant Mixtures 195Xiangsheng Hong12.1 Introduction 19512.2 ADIs or Reactions of Pharmaceutical Mixtures 19712.3 Mechanistic Toxicology of PPCP Mixtures 19812.4 Conclusions and Recommendations for Future Studies 20113 Combined Molecular Toxicity Mechanism of Phthalate Mixtures 209Yiyun Liu, De-Sheng Pei13.1 Human Exposure of Phthalates 20913.2 PAEs and Diseases 21113.3 The Toxic Molecular Mechanisms of PAEs Mixture 21513.4 Conclusion 22414 Combined Molecular Toxicity Mechanism of Microplastics Mixtures 239Ya Liu, Yin Liu14.1 Introduction 23914.2 Heavy Metals 23914.3 Persistent Organic Pollutants 24114.4 Pathogens 24314.5 Engineered Nanomaterials 24414.6 Other Contaminants 24514.7 Conclusion and Prospect 24515 Combined Molecular Toxicity Mechanism of Flame Retardant Mixtures 249Xinyan Li, Tiangang Luan15.1 Introduction 24915.2 Synergistic Effects of OFR Co-exposure on Oxidative Stress and DNA Damage 25015.3 Synergistic Effects of OFR Co-exposure on Endocrine Disruption and Reproduction Toxicity 25715.4 Synergistic Effects of OFR Co-exposure on Neurotoxicity 25915.5 Synergistic Effects of OFR Co-exposure on Immunotoxicity 26215.6 Synergistic Effects of OFR Co-exposure on Growth, Development, and Organ 26215.7 Antagonism Effects of OFR Co-exposure on Growth, Development, and Organ 26615.8 Summary and Perspectives 26716 Adverse Outcome Pathways (AOPs) of Combined Pollutant Mixtures and Their Toxicogenetic Endpoints 275Hossam El Din H. Abdelhafez, Mohamed Bedair M. Ahmed, Magdy Moheb El-Dein Saad16.1 Introduction 27516.2 Originated AOP and Approaches of Research in Public Databases 27716.3 AOP Development Program 27816.4 Pollutants 28216.5 Challenges and Future Perspectives 28816.6 Conclusion 28817 Mathematical Model for Combined Toxicity Prediction 293Fasiha Javaid, De-Sheng Pei17.1 Significance of Predicting Combined Toxicity 29317.2 Fundamental Concepts of Combined Toxicity 29417.3 Relevance of Combined Toxicity in Environmental Hazard Evaluation 30117.4 Mathematical Models for Combined Toxicity Prediction 30217.5 Evaluation of Model and Selection Criteria 33517.6 Future Directions and Research Needs 33517.7 Conclusion 33618 Novel Quantitative Structure–Activity Relationship Tox21 Techniques for Combined Toxicity Prediction 343Na li18.1 Introduction 34318.2 Computational Approaches and the Policy 34318.3 The Methods for QSAR Models 34418.4 Tox21 and ToxCast 34418.5 The Cases of QSAR Studies for Prediction of the Toxicity of Chemical Mixtures 34618.6 Future Avenues of Chemical Mixture Toxicity Prediction Research 34919 Challenges and Prospects in the Application of Experimental, Analytical, and Predictive Models in Combined Toxicity Assessment 351Naima Hamid, Qiang Yue, Jun Wang, Muhammad Junaid19.1 Introduction 35119.2 Experimental Models 35219.3 Analytical Methods 35519.4 Mathematical Models 35619.5 Challenges and Future Prospects Associated with Combined Toxicity Assessment 35719.6 Conclusion 35920 Future Research Perspectives of Combined Toxicology 365Tariq Mehmood, Anam Ashraf, Kousar Parveen, Muhammad Azher Hassan, Muhammad Fahad Sardar, Muhammad Faheem, Licheng Peng, Shakeel Ahmad, Tauseef Ahmad, Predrag Ilić20.1 Introduction 36520.2 General Terms of TA 36620.3 Exposure to Combined Chemicals or Mixtures 36720.4 Risk Exposure Assessment 36920.5 Limitations in Current Knowledge of Combined Chemical Exposure 37220.6 Data Limitations 37220.7 Improvements and Future Perspectives 37421 Combined Toxicity of Chemicals: Final Thoughts and Concluding Remarks 381De-Sheng Pei, Marriya Sultan, YiYun Liu21.1 Summary of Key Findings of This Book 38121.2 Final Thoughts 38121.3 Concluding Remarks 382Index 385

De-Sheng Pei, PhD, Professor & Doctoral Supervisor, School of Public Health, Chongqing Medical University. He is currently engaged in research on animal disease models, germ-free fish models, toxicological effects of environmental pollutants, and molecular mechanisms of disease caused by environmental pollutants. His discoveries have been published in more than 180 research papers. Yiyun Liu, PhD, School of Public Health, Chongqing Medical University. In 2022, Dr. Liu graduated from the Research Center for Eco-Environmental Science (RCEES), Chinese Academy of Sciences.

• Foreword xiiiPreface xvAcknowledgments xviiList of Contributors xix1 Introduction to Combined Toxicology, Background, Key Terminologies, and Significance 1Yingjie Xia1.1 Introduction 11.2 Key Terminologies 51.3 Significance 72 Toxicokinetics of Chemical Mixture Exposure in the Environment 13Abdul Wahab Hussain, Mehvish Mumtaz, Asad Ullah Saeed, Maryam Mumtaz2.1 Unveiling Toxicokinetics 132.2 Toxicokinetics and Chemical Mixture Assessment 132.3 List of Toxic Chemicals/Pollutants Present in the Environment 152.4 Toxicokinetics of Selected Organohalide Compounds/Mixtures 162.5 Conclusions 243 Toxicodynamics of Chemical Mixtures Exposure in the Organism Body 29Chunjiao Lu, Ting Yang, Xin Meng, Xiaojun Yang3.1 Chemical Mixtures in Environment 293.2 Model Organism in Toxicology 323.3 Toxicodynamics of Chemical Mixtures 353.4 Conclusions 394 Principal Sources, Fate, and Mechanism of Chemical Mixtures in the Environment 47Bao-Fu Zhang, Yiyun Liu, De-Sheng Pei4.1 Introduction 474.2 MP Mixtures 474.3 Pesticide Mixtures 494.4 HM and Metalloid Metal Mixtures 504.5 Nanoparticle Mixtures 514.6 Persistent Organic Pollutants 514.7 Antibiotic Mixtures 524.8 Conclusions 535 Experimental Designs and Sampling Strategies for Combined Toxicity Studies Based on Concentrations 61Manoharan Saravanan, Karunanithi Vidhya5.1 Introduction 615.2 Need for Risk Assessment Studies 625.3 Risk Assessment of Mixture Toxicity 625.4 Experimental Designs and Methodologies for Mixture Toxicity 625.5 Concentration of Mixture Substances 645.6 Concentration-based Strategy 655.7 Ecotoxicity Tests: Acute (Short-term Exposure) and Chronic Test (Long-term Exposure) 665.8 Sampling of Biomarkers 715.9 Animal Models for Combined Toxicity 725.10 Conclusions 766 Migration and Transformation of Chemical Pollutants as Mixtures 83Xiang Ge, Yingxin Yu6.1 Introduction 836.2 Volatile Organic Compounds 846.3 Polybrominated Diphenyl Ethers 856.4 Tetrabromobisphenol A and Its Derivatives 876.5 Per- and Polyfluoroalkyl Substances 886.6 Organophosphorus Flame Retardants 896.7 Phthalic Acid Esters 906.8 Polycyclic Aromatic Hydrocarbons 916.9 Alkylphenols 926.10 Methylsiloxanes 937 Analytical Techniques Used to Detect Chemical Mixtures in the Environment 103Thodhal Yoganandham Suman7.1 Introduction 1037.2 Navigating the Complexities of Mixture Toxicity: A Persistent Challenge in Environmental Health 1047.3 Advancing Environmental Monitoring: Toward a Holistic Understanding of Chemical Mixtures 1047.4 Sample Preparation: Enhancing Specificity and Efficiency in Mixture Analysis 1067.5 Expanding the Analytical Toolbox: Emerging Extraction Techniques for Complex Environmental Matrices 1077.6 Analytical Techniques for Characterizing Organic Pollutants: Advancing Beyond Traditional Approaches 1087.7 Outlook: Toward Holistic Environmental Monitoring with Advanced Analytical Tools 1118 Common Toxicological Experimental Models 115Xuan Ma, Dejun Huang8.1 Male Reproductive Function 1158.2 Female Reproductive Function 1209 Combined Molecular Toxicity Mechanism of Heavy Metals Mixtures 125Kusheng Wu, Yuequn Chen, Wenlong Huang9.1 Introduction: Heavy Metal Exposures Are Everywhere 1259.2 Combined Molecular Toxicity of Heavy Metal Mixtures in the Cardiovascular System 1259.3 Combined Molecular Toxicity of Heavy Metal Mixtures in the Nervous System 1299.4 Combined Molecular Toxicity of Heavy Metal Mixtures in the Male Reproductive System 1339.5 Combined Molecular Toxicity of Heavy Metal Mixtures in the Female Reproductive System 1359.6 Combined Molecular Toxicity of Heavy Metal Mixtures in the Liver 1389.7 Combined Molecular Toxicity of Heavy Metal Mixtures in the Immune System 1399.8 Combined Toxicity of Heavy Metals Mixture in the Regulation of Immune Mediators 1459.9 Combined Toxicity of Heavy Metals Mixture in the Immune Response to the Immunogen 1469.10 Combined Molecular Toxicity of Heavy Metal Mixtures in the Tumorigenesis 1479.11 Combined Molecular Toxicity of Heavy Metal Mixtures in the Orofacial Clefts 1499.12 Combined Molecular Toxicity of Heavy Metal Mixtures in the Olfactory System 15210 Combined Molecular Toxicity Mechanism of Pesticide Mixtures 173Ali Omar Jimale, Yiyun Liu, De-Sheng Pei10.1 Introduction 17310.2 Epidemiology of Pesticide Pollution 17410.3 Diseases Caused by Pesticides 17410.4 The Combined Molecular Toxicity Mechanisms of Pesticide Mixtures 17510.5 Summary 17811 Combined Molecular Toxicity Mechanism of Persistent Organic Pollutant Mixtures 183Ruijia Zhang, Tiangang Luan11.1 Introduction 18311.2 Design of the Components of POP Mixtures and Their Concentrations 18411.3 Developmental Toxicity of POP Mixtures 18911.4 Endocrine Effects of POP Mixtures 18911.5 Molecular Toxicity Mechanisms of POPs 19111.6 Conclusions 19212 Combined Molecular Toxicity Mechanism of Emerging Pollutant Mixtures 195Xiangsheng Hong12.1 Introduction 19512.2 ADIs or Reactions of Pharmaceutical Mixtures 19712.3 Mechanistic Toxicology of PPCP Mixtures 19812.4 Conclusions and Recommendations for Future Studies 20113 Combined Molecular Toxicity Mechanism of Phthalate Mixtures 209Yiyun Liu, De-Sheng Pei13.1 Human Exposure of Phthalates 20913.2 PAEs and Diseases 21113.3 The Toxic Molecular Mechanisms of PAEs Mixture 21513.4 Conclusion 22414 Combined Molecular Toxicity Mechanism of Microplastics Mixtures 239Ya Liu, Yin Liu14.1 Introduction 23914.2 Heavy Metals 23914.3 Persistent Organic Pollutants 24114.4 Pathogens 24314.5 Engineered Nanomaterials 24414.6 Other Contaminants 24514.7 Conclusion and Prospect 24515 Combined Molecular Toxicity Mechanism of Flame Retardant Mixtures 249Xinyan Li, Tiangang Luan15.1 Introduction 24915.2 Synergistic Effects of OFR Co-exposure on Oxidative Stress and DNA Damage 25015.3 Synergistic Effects of OFR Co-exposure on Endocrine Disruption and Reproduction Toxicity 25715.4 Synergistic Effects of OFR Co-exposure on Neurotoxicity 25915.5 Synergistic Effects of OFR Co-exposure on Immunotoxicity 26215.6 Synergistic Effects of OFR Co-exposure on Growth, Development, and Organ 26215.7 Antagonism Effects of OFR Co-exposure on Growth, Development, and Organ 26615.8 Summary and Perspectives 26716 Adverse Outcome Pathways (AOPs) of Combined Pollutant Mixtures and Their Toxicogenetic Endpoints 275Hossam El Din H. Abdelhafez, Mohamed Bedair M. Ahmed, Magdy Moheb El-Dein Saad16.1 Introduction 27516.2 Originated AOP and Approaches of Research in Public Databases 27716.3 AOP Development Program 27816.4 Pollutants 28216.5 Challenges and Future Perspectives 28816.6 Conclusion 28817 Mathematical Model for Combined Toxicity Prediction 293Fasiha Javaid, De-Sheng Pei17.1 Significance of Predicting Combined Toxicity 29317.2 Fundamental Concepts of Combined Toxicity 29417.3 Relevance of Combined Toxicity in Environmental Hazard Evaluation 30117.4 Mathematical Models for Combined Toxicity Prediction 30217.5 Evaluation of Model and Selection Criteria 33517.6 Future Directions and Research Needs 33517.7 Conclusion 33618 Novel Quantitative Structure–Activity Relationship Tox21 Techniques for Combined Toxicity Prediction 343Na li18.1 Introduction 34318.2 Computational Approaches and the Policy 34318.3 The Methods for QSAR Models 34418.4 Tox21 and ToxCast 34418.5 The Cases of QSAR Studies for Prediction of the Toxicity of Chemical Mixtures 34618.6 Future Avenues of Chemical Mixture Toxicity Prediction Research 34919 Challenges and Prospects in the Application of Experimental, Analytical, and Predictive Models in Combined Toxicity Assessment 351Naima Hamid, Qiang Yue, Jun Wang, Muhammad Junaid19.1 Introduction 35119.2 Experimental Models 35219.3 Analytical Methods 35519.4 Mathematical Models 35619.5 Challenges and Future Prospects Associated with Combined Toxicity Assessment 35719.6 Conclusion 35920 Future Research Perspectives of Combined Toxicology 365Tariq Mehmood, Anam Ashraf, Kousar Parveen, Muhammad Azher Hassan, Muhammad Fahad Sardar, Muhammad Faheem, Licheng Peng, Shakeel Ahmad, Tauseef Ahmad, Predrag Ilić20.1 Introduction 36520.2 General Terms of TA 36620.3 Exposure to Combined Chemicals or Mixtures 36720.4 Risk Exposure Assessment 36920.5 Limitations in Current Knowledge of Combined Chemical Exposure 37220.6 Data Limitations 37220.7 Improvements and Future Perspectives 37421 Combined Toxicity of Chemicals: Final Thoughts and Concluding Remarks 381De-Sheng Pei, Marriya Sultan, YiYun Liu21.1 Summary of Key Findings of This Book 38121.2 Final Thoughts 38121.3 Concluding Remarks 382Index 385

De-Sheng Pei, PhD, Professor & Doctoral Supervisor, School of Public Health, Chongqing Medical University. He is currently engaged in research on animal disease models, germ-free fish models, toxicological effects of environmental pollutants, and molecular mechanisms of disease caused by environmental pollutants. His discoveries have been published in more than 180 research papers. Yiyun Liu, PhD, School of Public Health, Chongqing Medical University. In 2022, Dr. Liu graduated from the Research Center for Eco-Environmental Science (RCEES), Chinese Academy of Sciences.

• Foreword xiiiPreface xvAcknowledgments xviiList of Contributors xix1 Introduction to Combined Toxicology, Background, Key Terminologies, and Significance 1Yingjie Xia1.1 Introduction 11.2 Key Terminologies 51.3 Significance 72 Toxicokinetics of Chemical Mixture Exposure in the Environment 13Abdul Wahab Hussain, Mehvish Mumtaz, Asad Ullah Saeed, Maryam Mumtaz2.1 Unveiling Toxicokinetics 132.2 Toxicokinetics and Chemical Mixture Assessment 132.3 List of Toxic Chemicals/Pollutants Present in the Environment 152.4 Toxicokinetics of Selected Organohalide Compounds/Mixtures 162.5 Conclusions 243 Toxicodynamics of Chemical Mixtures Exposure in the Organism Body 29Chunjiao Lu, Ting Yang, Xin Meng, Xiaojun Yang3.1 Chemical Mixtures in Environment 293.2 Model Organism in Toxicology 323.3 Toxicodynamics of Chemical Mixtures 353.4 Conclusions 394 Principal Sources, Fate, and Mechanism of Chemical Mixtures in the Environment 47Bao-Fu Zhang, Yiyun Liu, De-Sheng Pei4.1 Introduction 474.2 MP Mixtures 474.3 Pesticide Mixtures 494.4 HM and Metalloid Metal Mixtures 504.5 Nanoparticle Mixtures 514.6 Persistent Organic Pollutants 514.7 Antibiotic Mixtures 524.8 Conclusions 535 Experimental Designs and Sampling Strategies for Combined Toxicity Studies Based on Concentrations 61Manoharan Saravanan, Karunanithi Vidhya5.1 Introduction 615.2 Need for Risk Assessment Studies 625.3 Risk Assessment of Mixture Toxicity 625.4 Experimental Designs and Methodologies for Mixture Toxicity 625.5 Concentration of Mixture Substances 645.6 Concentration-based Strategy 655.7 Ecotoxicity Tests: Acute (Short-term Exposure) and Chronic Test (Long-term Exposure) 665.8 Sampling of Biomarkers 715.9 Animal Models for Combined Toxicity 725.10 Conclusions 766 Migration and Transformation of Chemical Pollutants as Mixtures 83Xiang Ge, Yingxin Yu6.1 Introduction 836.2 Volatile Organic Compounds 846.3 Polybrominated Diphenyl Ethers 856.4 Tetrabromobisphenol A and Its Derivatives 876.5 Per- and Polyfluoroalkyl Substances 886.6 Organophosphorus Flame Retardants 896.7 Phthalic Acid Esters 906.8 Polycyclic Aromatic Hydrocarbons 916.9 Alkylphenols 926.10 Methylsiloxanes 937 Analytical Techniques Used to Detect Chemical Mixtures in the Environment 103Thodhal Yoganandham Suman7.1 Introduction 1037.2 Navigating the Complexities of Mixture Toxicity: A Persistent Challenge in Environmental Health 1047.3 Advancing Environmental Monitoring: Toward a Holistic Understanding of Chemical Mixtures 1047.4 Sample Preparation: Enhancing Specificity and Efficiency in Mixture Analysis 1067.5 Expanding the Analytical Toolbox: Emerging Extraction Techniques for Complex Environmental Matrices 1077.6 Analytical Techniques for Characterizing Organic Pollutants: Advancing Beyond Traditional Approaches 1087.7 Outlook: Toward Holistic Environmental Monitoring with Advanced Analytical Tools 1118 Common Toxicological Experimental Models 115Xuan Ma, Dejun Huang8.1 Male Reproductive Function 1158.2 Female Reproductive Function 1209 Combined Molecular Toxicity Mechanism of Heavy Metals Mixtures 125Kusheng Wu, Yuequn Chen, Wenlong Huang9.1 Introduction: Heavy Metal Exposures Are Everywhere 1259.2 Combined Molecular Toxicity of Heavy Metal Mixtures in the Cardiovascular System 1259.3 Combined Molecular Toxicity of Heavy Metal Mixtures in the Nervous System 1299.4 Combined Molecular Toxicity of Heavy Metal Mixtures in the Male Reproductive System 1339.5 Combined Molecular Toxicity of Heavy Metal Mixtures in the Female Reproductive System 1359.6 Combined Molecular Toxicity of Heavy Metal Mixtures in the Liver 1389.7 Combined Molecular Toxicity of Heavy Metal Mixtures in the Immune System 1399.8 Combined Toxicity of Heavy Metals Mixture in the Regulation of Immune Mediators 1459.9 Combined Toxicity of Heavy Metals Mixture in the Immune Response to the Immunogen 1469.10 Combined Molecular Toxicity of Heavy Metal Mixtures in the Tumorigenesis 1479.11 Combined Molecular Toxicity of Heavy Metal Mixtures in the Orofacial Clefts 1499.12 Combined Molecular Toxicity of Heavy Metal Mixtures in the Olfactory System 15210 Combined Molecular Toxicity Mechanism of Pesticide Mixtures 173Ali Omar Jimale, Yiyun Liu, De-Sheng Pei10.1 Introduction 17310.2 Epidemiology of Pesticide Pollution 17410.3 Diseases Caused by Pesticides 17410.4 The Combined Molecular Toxicity Mechanisms of Pesticide Mixtures 17510.5 Summary 17811 Combined Molecular Toxicity Mechanism of Persistent Organic Pollutant Mixtures 183Ruijia Zhang, Tiangang Luan11.1 Introduction 18311.2 Design of the Components of POP Mixtures and Their Concentrations 18411.3 Developmental Toxicity of POP Mixtures 18911.4 Endocrine Effects of POP Mixtures 18911.5 Molecular Toxicity Mechanisms of POPs 19111.6 Conclusions 19212 Combined Molecular Toxicity Mechanism of Emerging Pollutant Mixtures 195Xiangsheng Hong12.1 Introduction 19512.2 ADIs or Reactions of Pharmaceutical Mixtures 19712.3 Mechanistic Toxicology of PPCP Mixtures 19812.4 Conclusions and Recommendations for Future Studies 20113 Combined Molecular Toxicity Mechanism of Phthalate Mixtures 209Yiyun Liu, De-Sheng Pei13.1 Human Exposure of Phthalates 20913.2 PAEs and Diseases 21113.3 The Toxic Molecular Mechanisms of PAEs Mixture 21513.4 Conclusion 22414 Combined Molecular Toxicity Mechanism of Microplastics Mixtures 239Ya Liu, Yin Liu14.1 Introduction 23914.2 Heavy Metals 23914.3 Persistent Organic Pollutants 24114.4 Pathogens 24314.5 Engineered Nanomaterials 24414.6 Other Contaminants 24514.7 Conclusion and Prospect 24515 Combined Molecular Toxicity Mechanism of Flame Retardant Mixtures 249Xinyan Li, Tiangang Luan15.1 Introduction 24915.2 Synergistic Effects of OFR Co-exposure on Oxidative Stress and DNA Damage 25015.3 Synergistic Effects of OFR Co-exposure on Endocrine Disruption and Reproduction Toxicity 25715.4 Synergistic Effects of OFR Co-exposure on Neurotoxicity 25915.5 Synergistic Effects of OFR Co-exposure on Immunotoxicity 26215.6 Synergistic Effects of OFR Co-exposure on Growth, Development, and Organ 26215.7 Antagonism Effects of OFR Co-exposure on Growth, Development, and Organ 26615.8 Summary and Perspectives 26716 Adverse Outcome Pathways (AOPs) of Combined Pollutant Mixtures and Their Toxicogenetic Endpoints 275Hossam El Din H. Abdelhafez, Mohamed Bedair M. Ahmed, Magdy Moheb El-Dein Saad16.1 Introduction 27516.2 Originated AOP and Approaches of Research in Public Databases 27716.3 AOP Development Program 27816.4 Pollutants 28216.5 Challenges and Future Perspectives 28816.6 Conclusion 28817 Mathematical Model for Combined Toxicity Prediction 293Fasiha Javaid, De-Sheng Pei17.1 Significance of Predicting Combined Toxicity 29317.2 Fundamental Concepts of Combined Toxicity 29417.3 Relevance of Combined Toxicity in Environmental Hazard Evaluation 30117.4 Mathematical Models for Combined Toxicity Prediction 30217.5 Evaluation of Model and Selection Criteria 33517.6 Future Directions and Research Needs 33517.7 Conclusion 33618 Novel Quantitative Structure–Activity Relationship Tox21 Techniques for Combined Toxicity Prediction 343Na li18.1 Introduction 34318.2 Computational Approaches and the Policy 34318.3 The Methods for QSAR Models 34418.4 Tox21 and ToxCast 34418.5 The Cases of QSAR Studies for Prediction of the Toxicity of Chemical Mixtures 34618.6 Future Avenues of Chemical Mixture Toxicity Prediction Research 34919 Challenges and Prospects in the Application of Experimental, Analytical, and Predictive Models in Combined Toxicity Assessment 351Naima Hamid, Qiang Yue, Jun Wang, Muhammad Junaid19.1 Introduction 35119.2 Experimental Models 35219.3 Analytical Methods 35519.4 Mathematical Models 35619.5 Challenges and Future Prospects Associated with Combined Toxicity Assessment 35719.6 Conclusion 35920 Future Research Perspectives of Combined Toxicology 365Tariq Mehmood, Anam Ashraf, Kousar Parveen, Muhammad Azher Hassan, Muhammad Fahad Sardar, Muhammad Faheem, Licheng Peng, Shakeel Ahmad, Tauseef Ahmad, Predrag Ilić20.1 Introduction 36520.2 General Terms of TA 36620.3 Exposure to Combined Chemicals or Mixtures 36720.4 Risk Exposure Assessment 36920.5 Limitations in Current Knowledge of Combined Chemical Exposure 37220.6 Data Limitations 37220.7 Improvements and Future Perspectives 37421 Combined Toxicity of Chemicals: Final Thoughts and Concluding Remarks 381De-Sheng Pei, Marriya Sultan, YiYun Liu21.1 Summary of Key Findings of This Book 38121.2 Final Thoughts 38121.3 Concluding Remarks 382Index 385