Toxicological Assessment of Combined Chemicals in the Environment E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Comprehensive resource covering toxicology fundamentals, distribution of pollutants in the environment, and research methodologies for toxicological assessment of chemical mixtures
Toxicological Assessment of Combined Chemicals in the Environment offers an in-depth exploration of various approaches and molecular mechanisms regarding how minor alterations in chemical mixtures can influence an organism’s toxicity, along with discussion of the challenges associated with assessing mixtures.
The first section of the book provides a concise introduction to the background and significance of combined toxicity. Section two delves into the primary sources and enrichment mechanisms of different chemical mixtures, elucidating the biological exposure pathways of these compounds. Section three introduces both classical and emerging toxicological research models in detail. Building on the descriptions of compound emission, migration, accumulation, and transformation processes, and the analysis of combined molecular toxicity in the preceding sections, section four introduces computer mathematical modeling methods for hazard assessment of compound mixtures. The final section details the challenges and future trends in this field.
Written by a highly qualified author and seasoned research contributor in the field, Toxicological Assessment of Combined Chemicals in the Environment covers sample topics including:
- The degradation, oxidation, absorption, distribution, biotransformation, and excretion of various compounds in both the environment and in organisms
- A variety of cell models and in vivo research models of model organisms, supplemented with case studies
- Combined molecular toxicity mechanisms of heavy metals, pesticides, persistent organic pollutants (POPs), and pharmaceutical and personal care products (PPCPs)
- Principal sources, fate, and mechanism of chemical mixtures in the environment, as well as experimental designs and sampling strategies for combined toxicity studies based on concentrations
Toxicological Assessment of Combined Chemicals in the Environment serves as a valuable reference for researchers, students, and policymakers involved in environmental management and protection. It is particularly relevant for toxicologists, risk assessors, and those engaged in the molecular modeling of toxic mixtures.
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Table of Contents
Cover
Table of Contents
Title Page
Copyright
Dedication
Foreword
Preface
Acknowledgments
List of Contributors
Chapter 1 Introduction to Combined Toxicology, Background, Key Terminologies, and Significance
1.1 Introduction
1.2 Key Terminologies
1.3 Significance
References
Chapter 2 Toxicokinetics of Chemical Mixture Exposure in the Environment
2.1 Unveiling Toxicokinetics
2.2 Toxicokinetics and Chemical Mixture Assessment
2.3 List of Toxic Chemicals/Pollutants Present in the Environment
2.4 Toxicokinetics of Selected Organohalide Compounds/Mixtures
2.5 Conclusions
References
Chapter 3 Toxicodynamics of Chemical Mixtures Exposure in the Organism Body
3.1 Chemical Mixtures in Environment
3.2 Model Organism in Toxicology
3.3 Toxicodynamics of Chemical Mixtures
3.4 Conclusions
References
Chapter 4 Principal Sources, Fate, and Mechanism of Chemical Mixtures in the Environment
4.1 Introduction
4.2 MP Mixtures
4.3 Pesticide Mixtures
4.4 HM and Metalloid Metal Mixtures
4.5 Nanoparticle Mixtures
4.6 Persistent Organic Pollutants
4.7 Antibiotic Mixtures
4.8 Conclusions
Acknowledgments
Competing Interests
References
Chapter 5 Experimental Designs and Sampling Strategies for Combined Toxicity Studies Based on Concentrations
5.1 Introduction
5.2 Need for Risk Assessment Studies
5.3 Risk Assessment of Mixture Toxicity
5.4 Experimental Designs and Methodologies for Mixture Toxicity
5.5 Concentration of Mixture Substances
5.6 Concentration-based Strategy
5.7 Ecotoxicity Tests: Acute (Short-term Exposure) and Chronic Test (Long-term Exposure)
5.8 Sampling of Biomarkers
5.9 Animal Models for Combined Toxicity
5.10 Conclusions
References
Chapter 6 Migration and Transformation of Chemical Pollutants as Mixtures
6.1 Introduction
6.2 Volatile Organic Compounds
6.3 Polybrominated Diphenyl Ethers
6.4 Tetrabromobisphenol A and Its Derivatives
6.5 Per- and Polyfluoroalkyl Substances
6.6 Organophosphorus Flame Retardants
6.7 Phthalic Acid Esters
6.8 Polycyclic Aromatic Hydrocarbons
6.9 Alkylphenols
6.10 Methylsiloxanes
References
Chapter 7 Analytical Techniques Used to Detect Chemical Mixtures in the Environment
7.1 Introduction
7.2 Navigating the Complexities of Mixture Toxicity: A Persistent Challenge in Environmental Health
7.3 Advancing Environmental Monitoring: Toward a Holistic Understanding of Chemical Mixtures
7.4 Sample Preparation: Enhancing Specificity and Efficiency in Mixture Analysis
7.5 Expanding the Analytical Toolbox: Emerging Extraction Techniques for Complex Environmental Matrices
7.6 Analytical Techniques for Characterizing Organic Pollutants: Advancing Beyond Traditional Approaches
7.7 Outlook: Toward Holistic Environmental Monitoring with Advanced Analytical Tools
Acknowledgments
Conflicts of Interest
References
Chapter 8 Common Toxicological Experimental Models
8.1 Male Reproductive Function
8.2 Female Reproductive Function
References
Chapter 9 Combined Molecular Toxicity Mechanism of Heavy Metals Mixtures
9.1 Introduction: Heavy Metal Exposures Are Everywhere
9.2 Combined Molecular Toxicity of Heavy Metal Mixtures in the Cardiovascular System
9.3 Combined Molecular Toxicity of Heavy Metal Mixtures in the Nervous System
9.4 Combined Molecular Toxicity of Heavy Metal Mixtures in the Male Reproductive System
9.5 Combined Molecular Toxicity of Heavy Metal Mixtures in the Female Reproductive System
9.6 Combined Molecular Toxicity of Heavy Metal Mixtures in the Liver
9.7 Combined Molecular Toxicity of Heavy Metal Mixtures in the Immune System
9.8 Combined Toxicity of Heavy Metals Mixture in the Regulation of Immune Mediators
9.9 Combined Toxicity of Heavy Metals Mixture in the Immune Response to the Immunogen
9.10 Combined Molecular Toxicity of Heavy Metal Mixtures in the Tumorigenesis
9.11 Combined Molecular Toxicity of Heavy Metal Mixtures in the Orofacial Clefts
9.12 Combined Molecular Toxicity of Heavy Metal Mixtures in the Olfactory System
References
Chapter 10 Combined Molecular Toxicity Mechanism of Pesticide Mixtures
10.1 Introduction
10.2 Epidemiology of Pesticide Pollution
10.3 Diseases Caused by Pesticides
10.4 The Combined Molecular Toxicity Mechanisms of Pesticide Mixtures
10.5 Summary
Acknowledgments
Competing Interests
References
Chapter 11 Combined Molecular Toxicity Mechanism of Persistent Organic Pollutant Mixtures
11.1 Introduction
11.2 Design of the Components of POP Mixtures and Their Concentrations
11.3 Developmental Toxicity of POP Mixtures
11.4 Endocrine Effects of POP Mixtures
11.5 Molecular Toxicity Mechanisms of POPs
11.6 Conclusions
Acknowledgments
References
Chapter 12 Combined Molecular Toxicity Mechanism of Emerging Pollutant Mixtures
12.1 Introduction
12.2 ADIs or Reactions of Pharmaceutical Mixtures
12.3 Mechanistic Toxicology of PPCP Mixtures
12.4 Conclusions and Recommendations for Future Studies
Funding
Author Disclosure Statement
References
Chapter 13 Combined Molecular Toxicity Mechanism of Phthalate Mixtures
13.1 Human Exposure of Phthalates
13.2 PAEs and Diseases
13.3 The Toxic Molecular Mechanisms of PAEs Mixture
13.4 Conclusion
References
Chapter 14 Combined Molecular Toxicity Mechanism of Microplastics Mixtures
14.1 Introduction
14.2 Heavy Metals
14.3 Persistent Organic Pollutants
14.4 Pathogens
14.5 Engineered Nanomaterials
14.6 Other Contaminants
14.7 Conclusion and Prospect
References
Chapter 15 Combined Molecular Toxicity Mechanism of Flame Retardant Mixtures
15.1 Introduction
15.2 Synergistic Effects of OFR Co-exposure on Oxidative Stress and DNA Damage
15.3 Synergistic Effects of OFR Co-exposure on Endocrine Disruption and Reproduction Toxicity
15.4 Synergistic Effects of OFR Co-exposure on Neurotoxicity
15.5 Synergistic Effects of OFR Co-exposure on Immunotoxicity
15.6 Synergistic Effects of OFR Co-exposure on Growth, Development, and Organ
15.7 Antagonism Effects of OFR Co-exposure on Growth, Development, and Organ
15.8 Summary and Perspectives
Acknowledgments
References
Chapter 16 Adverse Outcome Pathways (AOPs) of Combined Pollutant Mixtures and Their Toxicogenetic Endpoints
16.1 Introduction
16.2 Originated AOP and Approaches of Research in Public Databases
16.3 AOP Development Program
16.4 Pollutants
16.5 Challenges and Future Perspectives
16.6 Conclusion
References
Chapter 17 Mathematical Model for Combined Toxicity Prediction
17.1 Significance of Predicting Combined Toxicity
17.2 Fundamental Concepts of Combined Toxicity
17.3 Relevance of Combined Toxicity in Environmental Hazard Evaluation
17.4 Mathematical Models for Combined Toxicity Prediction
17.5 Evaluation of Model and Selection Criteria
17.6 Future Directions and Research Needs
17.7 Conclusion
Acknowledgment
Competing Interests
References
Chapter 18 Novel Quantitative Structure–Activity Relationship Tox21 Techniques for Combined Toxicity Prediction
18.1 Introduction
18.2 Computational Approaches and the Policy
18.3 The Methods for QSAR Models
18.4 Tox21 and ToxCast
18.5 The Cases of QSAR Studies for Prediction of the Toxicity of Chemical Mixtures
18.6 Future Avenues of Chemical Mixture Toxicity Prediction Research
References
Chapter 19 Challenges and Prospects in the Application of Experimental, Analytical, and Predictive Models in Combined Toxicity Assessment
19.1 Introduction
19.2 Experimental Models
19.3 Analytical Methods
19.4 Mathematical Models
19.5 Challenges and Future Prospects Associated with Combined Toxicity Assessment
19.6 Conclusion
Acknowledgments
Declaration of Competing Interest
References
Chapter 20 Future Research Perspectives of Combined Toxicology
20.1 Introduction
20.2 General Terms of TA
20.3 Exposure to Combined Chemicals or Mixtures
20.4 Risk Exposure Assessment
20.5 Limitations in Current Knowledge of Combined Chemical Exposure
20.6 Data Limitations
20.7 Improvements and Future Perspectives
Acknowledgment
References
Chapter 21 Combined Toxicity of Chemicals: Final Thoughts and Concluding Remarks
21.1 Summary of Key Findings of This Book
21.2 Final Thoughts
21.3 Concluding Remarks
Acknowledgment
Conflict of Interest
References
Index
End User License Agreement
List of Illustrations
Chapter 1
Figure 1.1 The scope of environmental toxicology [22, 23].
Chapter 2
Figure 2.1 Steps/approaches adopted in chemical mixture assessment.
Figure 2.2 The list of compounds present in the environment.
Figure 2.3 List of selected toxic compounds.
Figure 2.4 Global concerns and initiatives regarding PFASs.
Figure 2.5 The toxicokinetic behavior of organochlorines.
Chapter 3
Figure 3.1 The sources of VOCs.
Figure 3.2 PAHs generation, migration, and transformation in the environment.
Figure 3.3 Schematic diagram of the atomic structure of Pb.
Figure 3.4 Schematic diagram of the atomic structure of Cr.
Figure 3.5 Schematic diagram of the atomic structure of Hg.
Figure 3.6 Schematic diagram of the atomic structure of Ni.
Figure 3.7. Schematic diagram of the atomic structure of Cd.
Figure 3.8 Zebrafish diagram.
Chapter 4
Figure 4.1 Principal sources, fate, and mechanism of chemical mixtures in the environment...
Chapter 5
Figure 5.1 Common experimental design on combined toxicity study.
Figure 5.2 Schematic illustration of each single chemical and/or combined chemical compou...
Chapter 6
Figure 6.1 The migration of POPs into the environment.
Figure 6.2 The molecular structure of the chemicals mentioned in this chapter.
Figure 6.3 The mechanism of VOCs leading to ozone accumulation in the atmosphere.
Figure 6.4 Comparison of pollution situation in industrial parks and their surrounding ar...
Chapter 7
Figure 7.1 Sampling and (bio)analytical methods for complex environmental mixtures ...
Figure 7.2 Three-dimensional representation of some determination techniques currently us...
Chapter 8
Figure 8.1 Reproductive organs (testis or ovary) in male and female zebrafish.
Figure 8.2 A representative image of HE staining of zebrafish testis.
Figure 8.3 Different germ cells during the spermatogenic process in zebrafish. SG(A), A-t...
Figure 8.4 Zebrafish sperm treated with the Halomax-SCD kit. The sperm with intact DNA ma...
Figure 8.5 The fish testicular organ culture system. (A) The classical agarose gel model....
Figure 8.6 A representative HE staining image of zebrafish ovary (upper, provided by the ...
Chapter 9
Figure 9.1 Potential toxicological effect of the metal mixture on the reproductive system...
Figure 9.2 Effects of heavy metals’ exposure on the liver.
Figure 9.3 Toxicological effect of mercury on lymphocyte and interaction with other metal...
Figure 9.4 Schematic depicting the zebrafish olfactory system, showing the olfactory bulb...
Figure 9.5 Microscopic anatomy of the zebrafish olfactory system. (A) Sagittal section of...
Figure 9.6 Olfactory sensory neurons express hsp70/eGFP following 3-hour exposure to 5 ...
Chapter 10
Figure 10.1 Combined molecular toxicity of pesticide mixtures.
Chapter 11
Figure 11.1 Schematics of epigenetic mechanisms in POP mixture–induced developmenta...
Chapter 12
Figure 12.1 A proposed scheme for four-level classification of the literature on molecular...
Chapter 13
Figure 13.1 Metabolic pathways for phthalates. Source: Adapted from Ref. [25]/John Wiley ...
Figure 13.2 Diseases caused by phthalates (PAEs) exposure.
Chapter 14
Figure 14.1 Environmental complex exposure of microplastic/nanoplastic and other contamina...
Chapter 16
Figure 16.1 Graphical diagram showing the chapter’s overview.
Figure 16.2 AOP building blocks, biological organization levels, and omics applications.
Figure 16.3 A simple example of using AOP knowledgebase to create an AO from AOP-Kaptis an...
Figure 16.4 Case studies on some pesticides employing adverse pathway frameworks using som...
Figure 16.5 Case studies on endocrine-disrupting chemicals in adverse pathway frameworks em...
Chapter 17
Figure 17.1 (a) Graphical representation of risk-based assessment approach for chemical mi...
Figure 17.2 Graphical representation of evaluation of synergism in drug combinations and r...
Figure 17.3 (a) Schematic isobologram illustrates combined effects of Drug A and Drug B at...
Figure 17.4 Recent advances in modeling the toxicity of environmental pollutants for risk ...
Figure 17.5 (a) Graphical representation of assessing the effects of field-relevant pestic...
Figure 17.6 (a) Machine learning construction outline [99]; (b) MRA Toolbox v. 1.0: a web-...
Chapter 18
Figure 18.1 A complete schematic representation of the development of a quantitative struc...
Figure 18.2 Schematic overview of the methods used to quantify the geospatial risk of mole...
Chapter 19
Figure 19.1 Analytical techniques applied in the quantification of joint emerging pollutan...
Figure 19.2 An overview of the previously reported quantitative structure–activity ...
Chapter 20
Figure 20.1 A conceptual representation of the framework.
List of Tables
Chapter 1
Table 1.1 The interaction types of chemical mixtures.
Chapter 2
Table 2.1 The toxicokinetic behavior of selected organohalides.
Chapter 5
Table 5.1 Commonly used experimental designs for the combined toxicity studies of mixtur...
Table 5.2 Combined toxicity studies on the most commonly used animal models during 2014...
Chapter 7
Table 7.1 Analytical methods for the determination of emerging organic contaminants in e...
Chapter 8
Table 8.1 Fluorescence microscopic observation of sperm plasma membrane integrity analys...
Chapter 9
Table 9.1 Population studies about the effects of metals on the cardiovascular system.
Table 9.2 A summary of neurotoxic effects caused by heavy metal exposure.
Table 9.3 Dysregulation of genes related to the reproductive system after exposure to me...
Table 9.4 Effect on immune mediators of the heavy metal mixture.
Table 9.5 Exposure to heavy metals and risks of cancers.
Table 9.6 Results of heavy metals and OFCs in epidemiology study.
Table 9.7 List of olfactory toxic metals identified using zebrafish model.
Chapter 10
Table 10.1 Synergistic toxicities of thiophanate-methyl and fenvalerate mixture to embryo...
Chapter 11
Table 11.1 All POPs listed in the Stockholm convention (http://chm.pops.int/TheConvention...
Table 11.2 POP mixtures (29) based on human estimated daily intake (EDI) levels for in vi...
Table 11.3 POP (29) mixtures based on human blood levels for in vitro assays.
Chapter 12
Table 12.1 List of PPCPs with some representative compounds under each subcategory.
Chapter 13
Table 13.1 The use of phthalates (PAEs).
Table 13.2 Diester phthalates and their metabolites.
Chapter 15
Table 15.1 Name, structure, properties, and bioconcentration factors of organic flame ret...
Table 15.2 Synergistic effects of organic flame retardant (OFR) co-exposure on oxidative ...
Table 15.3 Endocrine disruption and reproduction toxicity of combined exposure to organic...
Table 15.4 Study on neurotoxicity caused by combined exposure to organic flame retardants...
Table 15.5 Effects of combined exposure to OFRs on biological growth and development.
Chapter 16
Table 16.1 Definitions of some elements and terms relating to AOP.
Table 16.2 AOP networks (computation tools) to analyze and understand different pathways.
Table 16.3 Examples of AOP in mixtures of pesticides by Wiki Kaptis and AO by AOP-Wiki.
Table 16.4 Examples of AOP in mixtures of EDs by Wiki Kaptis and AO by AOP-Wiki.
Chapter 17
Table 17.1 Studies related to chemical interactions for toxicity assessment.
Table 17.2 Studies related to the assessment of chemical toxicity (using mathematical mod...
Chapter 19
Table 19.1 Combined toxicological effects of the legacy and emerging contaminants in in v...
Table 19.2 An overview of the major QSAR characteristics used in joint toxicity studies.
Chapter 20
Table 20.1 General terms of toxicological assessment.
Guide
Cover
Table of Contents
Title Page
Copyright
Dedication
Foreword
Preface
Acknowledgments
List of Contributors
Begin Reading
Index
End User License Agreement
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Toxicological Assessment of Combined Chemicals in the Environment
Edited by
De-Sheng Pei and Yiyun Liu
Chongqing Medical University
Chongqing, China
Copyright © 2025 by John Wiley & Sons, Inc. All rights reserved, including rights for text and data mining and training of artificial intelligence technologies or similar technologies.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
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Dedication
This book is in the memory of my parents, Mr. Chao Pei (1942–2020) and Ms. Jinhua Wang (1943–2014). This book is dedicated to the spirit of collaboration, recognizing that the protection of our environment is a shared responsibility that transcends borders and cultures.
De-Sheng Pei PhD
Professor of Chongqing Medical University
This book is dedicated to the invaluable mentors and steadfast supporters who have illuminated my journey in the realm of scientific research.
Yiyun Liu PhD
Assistant Researcher of Chongqing Medical University
Foreword
During the early stages of my research, I struggled to fully explain the toxicity of fluoride in drinking water on human health. It was only later that I realized the necessity of incorporating combined toxicology concepts to properly understand the problem. I would like to congratulate Prof. De-Sheng Pei, Dr. Yiyun Liu, and the contributing researchers for their arduous task of compiling this excellent monograph on combined toxicology.
Unlike toxicological research on single compounds, combined toxicology focuses on adverse reactions that reflect actual environmental exposure conditions, gaining increasing attention from researchers globally. The challenges of combined toxicity experiments, analysis, and predictive models indicate that this field is in its infancy and requires national and international cooperation to address these issues effectively.
This book begins with a comprehensive assessment of combined toxicological philosophy, elucidating toxicokinetic and toxicodynamic processes. The authors pay particular attention to developing essential routes for understanding the fate and mechanisms of toxicants and the detection techniques in combined chemical matrices. They propose carefully chosen experimental models and highlight the importance of advanced computational and “omics” technologies in researching chosen toxicant groups. Future research directions and knowledge transfer avenues are succinctly presented.
The concepts of combined toxicology also provide crucial information and expertise for regulatory authorities, decision-makers, and others to develop programs and policies that limit human exposure to toxic substances, thereby preventing or reducing the risk of disease and other adverse health outcomes.
Therefore, I believe this book will be an invaluable resource for students, researchers, scientists, and policymakers dedicated to managing and protecting the environment. It will also serve as a valuable reference for emerging scientists in the field of combined toxicology.
Rohan Weerasooriya, PhD
Fellow of the National Academy of Sciences, Sri Lanka
Professor, National Institute of Fundamental Studies, Kandy, Sri Lanka
Professor, China-Sri Lanka Joint Research and Demonstration Center for Water Technology, University of Peradeniya, Ministry of Water Supply
Distinguished Professor, Hefei University of Technology, China
Preface
Toxicology is known as the study of poisons and intoxication, which allows for the evaluation of dangers posed by industrial chemicals, plant protection products, biocides, medicinal medications and equipment, and consumer goods to humans, animals, and the environment. With the development of science and technology, the types and quantities of pollutants in water, atmosphere, and soil are increased. Many of the same or different kinds of pollutants exist together bringing harm to the environment. Pollutants in the environment can interact physically or chemically to generate new toxic substances. These substances, which can have stronger or weaker toxicity, can affect the balance of the ecosystem. The toxicity study of a single substance is not suitable for analyzing a variety of environmental pollution effects, but the combined toxicity effect can more accurately and truly reflect the biological toxicity of pollutants. Therefore, this book aims to focus on the research methods of combined toxicity, the progress of research on the combined toxicity of environmental pollutants, and propose the challenges of establishing relevant technical means and models in future research strategies
Introductory Chapter 1 proposes the concept of combined toxicology, including its background, key terminologies, and significance for assessing risks from environmental contaminants. Although it can provide a more realistic understanding of the potential environmental risks and health effects of exposure to multiple chemicals, it also poses some challenges for research due to the complexity of chemical mixtures, lack of standardized methods, and limited availability of data. Chapter 2 provides information on the toxicokinetics of chemical mixtures, such as organic halides, insecticides, and plasticizers, and understands the degradation, oxidation, and distribution processes of the mixture in the environment. The application of toxicokinetic evaluation models and methods can help predict the harmful effects of chemical mixtures on organisms and provide guidance for health risks. Chapter 3 provides an overview of the toxicological effects of several major chemical contaminants present in the environment, using chemical mixtures as an entry point and the common model animals as the main research objects. The toxicological effects of the major environmental chemical pollutants on the target organs of the heart, nerves, blood vessels, liver, and kidneys are analyzed. We hope to let readers understand the importance and practical significance of combined toxicity research by clarifying the causes and hazards of compound mixed exposure in Section 1.
It is an important research subject and premise of toxicology to understand the mixing mode and the fate of the environmental behavior of compounds before the biological toxicity test. Therefore, in Section 2, we will introduce the main sources and enrichment mechanisms of different chemical mixtures, and clarify the biological exposure pathways of different compounds. Chapter 4 comprehensively investigates the sources, pathways, and mechanisms involved in the formation of chemical mixtures containing heavy metals and pesticides in soil environments, as well as those comprising heavy metals, microplastics, and nanoparticles in various environmental media. Chapter 5 interpretes how the interaction between the multi-chemicals in the mixture form changed their toxicity to aquatic vertebrates and invertebrates and provided valuable insights into critical impacts on the ecological hazard of their combinations. Chapter 6 highlights the overall geochemical behavior of volatile organic pollutants (VOCs) mixtures. The concentration, dispersion, and disappearance of pollutants caused by spatial motion are defined as migration. At the same time, pollutants will be converted into new compounds, which may cause greater harm to the environment. Their migration and transformation are not only affected by their solubility, adsorption constant, volatility, and other properties but also limited by environmental conditions such as photolysis and microbial hydrolysis. Chapter 7 emphasizes analytical methods for identifying, characterizing, and monitoring classes of hazardous compounds in intricate matrices and techniques that integrate chemical analyses, which may make it easier to identify chemical mixes that cause a combined risk.
The use of an experimental model is a common method of toxicological research. Chapter 8 introduces the toxicological model of zebrafish, analyzes the research cases, and proposes the parameters that can be used to characterize the reproductive function of zebrafish and the corresponding detection methods. This chapter provides a reference for model organism selection and model establishment. At the same time, based on the different toxicological effects of different compounds, Chapter 9 describes the combined molecular toxicity of heavy metals in cardiovascular, nervous, reproductive, liver, immune, and olfactory systems from the perspective of population investigation and experimental testing. Chapter 10 highlights pesticide pollution has been linked to a wide range of human diseases and disorders including neurodevelopmental disorders, neurodegenerative diseases, cancers, neurotoxicity, and congenital defects. Pesticides alter the body’s antioxidant defensive mechanisms and increase the accumulation of reactive oxygen species leading to oxidative stress. Pesticides also inhibit cytochrome P450 enzymes competitively binding at the enzyme’s active site and interfering with the electron transfer chain. Chapter 11 reviews the developmental toxicity and endocrine effects caused by mixtures of persistent organic pollutants (POPs) in epidemiological and experimental studies. Meanwhile, it discusses the molecular toxicity mechanisms of POPs, including epigenetic changes, hormone receptors, oxidative stress, cell death-related signaling pathways, and mitochondrial dysfunction. Chapters 12 and 13 provide an overview of the “state of the art” literature data on the effects and molecular toxicity mechanisms of pharmaceuticals and personal care products (PPCPs) and phthalates (PAEs), with special emphasis on their mixture scenarios. Chapter 14 highlights the impact of microplastic mixtures on molecular toxicity mechanisms. By considering the varying toxicological effects of different pollutants, it explores the combined toxicity mechanisms of heavy metals, persistent organic pollutants, pathogens, engineered nanoparticles, and other pollutants with microplastics. Chapter 15 provides a useful summary of the combined toxicity and molecular mechanisms of exposure to flame retardants (FRs) mixtures, presenting the scientific challenges and potential research directions. Chapter 16 discusses the challenges of adverse outcome pathway (AOP) as a theoretical framework and method for obtaining and analyzing toxicological data and suggests that omics could be employed as a more specific tool to differentiate between mode and mechanism of action.
Section 4 introduces the computer mathematical modeling method for hazard assessment of chemical mixtures. This is a fast and promising risk assessment method, which can predict the physical and chemical properties related to the fate of compounds and predict the toxicological endpoint. Chapter 17 delves into the vital realm of combined toxicity prediction and offers a comprehensive insight into mathematical models for combined toxicity prediction. Chapter 18 reviews the quantitative structure-activity relationships (QSARs) models for predicting endocrine disrupting activities and acute toxicities, as well as the QSAR models based on machine learning method, biomolecular interaction networks, toxicokinetic–toxicodynamic studies, high-throughput transcriptomics approach, and geospatial modeling approach.
Although the combined toxicity of chemical mixtures has attracted more and more attention, there are still many challenges to overcome. Therefore, Chapter 19 emphasizes the mechanistic combined toxicity of the legacy and emerging environmental pollutants, both in vivo and in vitro models, and discusses the challenges of applying experimental, analytical, and predictive models in combined toxicity assessment. Chapter 20 highlights that these mixtures can exhibit diverse interactions, including additive, synergistic, or antagonistic effects, that cannot be precisely anticipated by isolating the constituent chemicals. Employing the procedure of toxicological assessment is a thorough approach to scrutinizing the possible dangers and perils posed by chemicals. This new technology is expected to effectively assess the hazards of simultaneous exposure to chemical substances and propose mitigation strategies.
Chapter 21 provides final thoughts and concluding remarks. The increasing pollution rate has resulted in numerous chemical pollutants in complex mixtures, severely threatening human and environmental health. This book systematically examines combined toxicity, environmental behavior, sampling and detection techniques, experimental programs, toxicity mechanisms, and model analysis strategies. However, challenges persist due to vast chemical combinations, exposure scenarios, and mixture interaction complexities. This book is a comprehensive resource for research on combined toxicology. It highlights current progress in the field and underscores the need for continued research, collaboration, and the application of scientific findings to practical solutions.
Prof. De-Sheng Pei and Dr. Yiyun Liu
School of Public Health
Chongqing Medical University
Chongqing
China
Acknowledgments
The editors are sincerely thankful to all contributing authors, who worked hard to improve the quality of this book.
This work was supported by the Chongqing Technology Innovation and Application Development Sichuan-Chongqing Special Key Project (CSTB2024TIAD-CYKJCXX0017), Scientific Research Foundation of Chongqing Medical University (R4014 and R4021), Chongqing Postdoctoral Innovation Mentor Studio (X7928 D.S.P.), China and Chongqing Postdoctoral Science Foundation (2022TQ0394, CSTB2022NSCQ-BHX0641), and Chongqing Special Funding for Postdoctoral Research Projects (2022CQBSHTB1006 and X7947).
List of Contributors
Abdul Wahab Hussain
College of Earth and Environmental Sciences
University of the Punjab
Lahore
Pakistan
Ali Omar Jimale
School of Public Health
Chongqing Medical University
Chongqing
China
Anam Ashraf
Landscape Lab Xishuangbanna Tropical Botanical Garden Chinese Academy of Sciences
Menglun
Mengla
Yunnan
China
Asad Ullah Saeed
Pakistan Council for Scientific and Industrial Research
Lahore
Pakistan
Bao-Fu Zhang
School of Public Health
Chongqing Medical University
Chongqing
China
Chunjiao Lu
Engineering Research Center of Key Technique for Biotherapy of Guangdong Province
Shantou University Medical College
Shantou
China
Department of Public Health
School of Medicine, Guangxi University of Science and Technology
Liuzhou
Guangxi
China
Dejun Huang
Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution
School of Life Sciences
Lanzhou University
Lanzhou
China
De-Sheng Pei
School of Public Health
Chongqing Medical University
Chongqing
China
Fasiha Javaid
School of Public Health
Chongqing Medical University
Chongqing
China
Quaid-i-Azam University
Islamabad
Pakistan
Hossam El Din H. Abdelhafez
Mammalian and Aquatic Toxicology Department
Central Agricultural Pesticides Laboratory
Agricultural Research Center
Dokki
Giza
Egypt
Jun Wang
Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation
College of Marine Sciences
South China Agricultural University
Guangzhou
China
Karunanithi Vidhya
PG & Research Department of Physics
Sri Sarada College for Women (Autonomous)
Salem
Tamil Nadu
India
Kousar Parveen
The Department of Environmental Sciences
The Women University Multan
Pakistan
Kusheng Wu
Shantou University Medical College
Shantou
China
Licheng Peng
Key Laboratory of Ecological Prewarning
Protection and Restoration of Bohai Sea
Ministry of Natural Resources
School of Life Sciences
Shandong University
Qingdao
China
Magdy Moheb El-Dein Saad
Department of Food Toxicology and Contaminants
Institute of Food Industries & Nutrition
National Research Centre
Dokki
Cairo
Egypt
Manoharan Saravanan
Department of Environmental Science
Periyar University
Department of Zoology
Padmavani Arts & Science College for Women (Autonomous)
Salem
Tamil Nadu
India
Marriya Sultan
Chongqing Institute of Green and Intelligent Technology
Chinese Academy of Sciences
Chongqing School
University of Chinese Academy of Sciences
Chongqing
China
Maryam Mumtaz
Department of Pathology
University of Veterinary and Animal Sciences
Lahore
Pakistan
Mehvish Mumtaz
College of Earth and Environmental Sciences
University of the Punjab
Lahore
Pakistan
Mohamed Bedair M. Ahmed
Department of Food Toxicology and Contaminants
Institute of Food Industries & Nutrition
National Research Centre
Dokki
Cairo
Egypt
Muhammad Azher Hassan
Tianjin Key Lab of Indoor Air Environmental Quality Control
School of Environmental Science and Engineering
Tianjin University
Tianjin
China
Muhammad Fahad Sardar
Key Laboratory of Ecological Prewarning
Protection and Restoration of Bohai Sea
Ministry of Natural Resources
School of Life Sciences
Shandong University
Qingdao
China
Muhammad Faheem
Department of Civil Infrastructure and Environmental Engineering
Khalifa University of Science and Technology
Abu Dhabi
United Arab Emirates
Muhammad Junaid
Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation
College of Marine Sciences
South China Agricultural University
Guangzhou
China
Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region
Shaoguan University
Shaoguan
China
Na Li
Key Laboratory of Drinking Water Science and Technology
Research Center for Eco-Environmental Sciences
Chinese Academy of Sciences
Beijing
China
Naima Hamid
Faculty of Science and Marine Environment
University Malaysia Terengganu
Kuala Nerus
Terengganu
Malaysia
Predrag Ilić
PSRI Institute for Protection and Ecology of the Republic of Srpska
Vidovdanska
Banja Luka
Republic of Srpska
Bosnia and Herzegovina
Qiang Yue
Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region
Shaoguan University
Shaoguan
China
Ruijia Zhang
School of Environmental Science and Engineering
Hainan University
Haikou
China
Shakeel Ahmad
School of Environment
Tsinghua University
Beijing
China
Tariq Mehmood
Helmholtz Centre for Environmental Research - UFZ
Department of Environmental Engineering
Permoserstr
Leipzig
Germany
Tauseef Ahmad
Key Laboratory of Ecological Prewarning
Protection and Restoration of Bohai Sea
Ministry of Natural Resources
School of Life Sciences
Shandong University
Qingdao
China
Thodhal Yoganandham Suman
Department of Environmental Engineering
School of Smart and Green Engineering
Changwon National University
Changwon
Gyeongsangnamdo
Republic of Korea
Tiangang Luan
Guangdong Provincial Laboratory of Chemistry and Fine Chemical Engineering Jieyang Center
Jieyang
China
Smart Medical Innovation Technology Center
Guangdong University of Technology
Guangzhou
China
School of Environmental and Chemical Engineering
Wuyi University
Jiangmen
China
State key Laboratory of Biocontrol
School of Life Sciences, Sun Yat-sen University
Guangzhou
China
Ting Yang
Engineering Research Center of Key Technique for Biotherapy of Guangdong Province
Shantou University Medical College
Shantou
China
Wenlong Huang
Shantou University Medical College
Shantou
China
Xiang Ge
School of Environmental Science and Engineering
Institute of Environmental Health and Pollution Control
Guangdong University of Technology
Guangdong
China
Xiangsheng Hong
National Engineering Research Center of Industrial Wastewater Detoxication and Resource Recovery
Research Center for Eco-Environmental Sciences
Chinese Academy of Sciences
Beijing
China
Xiaojun Yang
Engineering Research Center of Key Technique for Biotherapy of Guangdong Province
Shantou University Medical College
Shantou
China
Xin Meng
Engineering Research Center of Key Technique for Biotherapy of Guangdong Province
Shantou University Medical College
Shantou
China
Xinyan Li
School of Biomedical and Pharmaceutical Sciences
Guangdong University of Technology
Guangzhou
China
Guangdong Provincial Laboratory of Chemistry and Fine Chemical Engineering Jieyang Center
Jieyang
China
Smart Medical Innovation Technology Center
Guangdong University of Technology
Guangzhou
China
Xuan Ma
Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution
School of Life Sciences
Lanzhou University
Lanzhou
China
Ya Liu
School of Environment
Hangzhou Institute for Advanced Study
University of Chinese Academy of Sciences
Hangzhou
China
Yin Liu
School of Environment
Hangzhou Institute for Advanced Study
University of Chinese Academy of Sciences
Hangzhou
China
Yingjie Xia
Division of Life Science
Hong Kong University of Science and Technology
Clear Water Bay
NT
Hong Kong
China
Yingxin Yu
School of Environmental Science and Engineering
Institute of Environmental Health and Pollution Control
Guangdong University of Technology
Guangdong
China
Yiyun Liu
School of Public Health
Chongqing Medical University
Chongqing
China
Yuequn Chen
Shantou University Medical College
Shantou
China
Chapter 1Introduction to Combined Toxicology, Background, Key Terminologies, and Significance
Yingjie Xiaa,*
a Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, NT, Hong Kong, China
*Corresponding author.
E-mail: [email protected]
1.1 Introduction
Toxicology is the study of harmful effects of chemicals on living organisms. Traditionally, toxicology has focused on studying the effects of individual chemicals in isolation. However, in reality, human beings are exposed to multiple chemicals simultaneously, and effects or the toxicity of these chemical mixtures can differ from those of individual chemicals. This has led to the emergence of a new subfield of toxicology known as combination toxicology. Investigations into the toxicological characteristics of compound mixtures have been pursued over several decades. Initial research predominantly focused on simple combinations, such as binary combinations. Next, investigations expanded to include both explicitly defined mixtures consisting of more than two substances, and complex, undefined mixtures. Recently, researchers realized that the interpretation of toxicological effects is complicated due to the indeterminate composition of the mixture and the potential for significant variation in that composition. Nonetheless, this complexity is frequently overlooked in favor of a more simplistic understanding. In addition to the composition of the mixture, there are many factors that significantly affect its toxicity: the dosage level, dosage rate, the order of exposure, the method of administration, and the potential interaction among the components, all of which contribute significantly to the final toxicological response. Therefore, the assessment of combined toxicology would provide a realistic approach to evaluate the health risks of chemical cocktails that coexisted in the environment. In this chapter, we would like to provide the background of the development of combination toxicology, key terminologies, and its significance for assessing risks from environmental contaminants.
1.1.1 History and Drivers of Combined Toxicology
The advent of the chemical and industrial revolutions during the mid-nineteenth centuries led to extensive emissions of naturally present chemicals into the environment, alongside the manufacturing and discharge of novel substances that were previously nonexistent. This led directly to the emergence of several branches of toxicology, such as pharmacology, occupational toxicology, pesticide toxicology, and environmental toxicology. The formal concept of toxicology as an academic discipline was recognized around 1959, although the toxicological studies had been conducted throughout the early twentieth century [1, 2].
However, early toxicologic research were devoted to exploring the toxicity of individual chemicals, which makes it impossible to explain the exposure toxicity of complex mixtures of chemicals or pollutants at a time in the real world. In the environment, organisms are exposed to complex mixtures of chemicals from diverse sources such as industrial emissions, agricultural runoff, and consumer products. This has led to the growing recognition of the importance of studying chemical interactions and combined effects of multiple toxicants, known as combined toxicology. The early discussion of combined toxicity was defined as synergistic or antagonistic action, when the effect of the combination is weaker or greater than that suggested by the component toxic effects [3]. The study of combined toxicology can be traced back to the early twentieth century from studies in pharmacology on the combined toxicity of two drugs [4, 5]. However, it was not until the late twentieth century that scientists started systematically investigating mixture effects beyond the simple addition of individual component toxicities. Hence, research about combined toxicity has intensified over the past decades [6–8].
The intensive study of combined toxicology was driven primarily by two factors: first, rise of environmentalism and enactment of regulations. For instance, the Clean Air Act (CAA) revealed widespread pollution from complex chemical mixtures discharged into the air and water. Under the CAA, US Environmental Protection Agency (EPA) initiated to consider the combined effects of chemicals from various sources and has been mandated to incorporate information on air pollutants [9]. Under the Clean Water Act, the US EPA suggested that the cumulative effects of individual chemicals and chemical combinations should be addressed using approaches such as single-chemical testing, whole-effluent toxicity (WET) testing, and bioassays [10]. Measuring and interpreting the combined impacts of these contaminant cocktails posed new challenges for toxicologists. Second, advances in analytical chemistry allowed more accurate measurement of very-low-concentration mixtures in the parts-per-billion or parts-per-trillion range that organisms commonly encounter. These detection capabilities highlighted the need to study interactive toxic effects below normal individual “no observed adverse effect levels.”
Nowadays, combination toxicology considers how chemical mixtures interact in biological systems and impact health. Examining chemical interactions, especially at concentrations that are relevant to the environment, represents a crucial stride in enhancing our comprehension of the effects of mixtures on human well-being and the environment. A major goal is to understand and predict the toxicity of environmental contaminant mixtures based on the individual constituent chemicals. This field has gained more and more attention due to uncertainties surrounding the additive, synergistic, or antagonistic effects that can occur when organisms are exposed to chemical mixtures.
1.1.2 Combined Toxicology on Environmental Pollutants
Environmental pollution is a major public health concern as various pollutants from industrial activities, vehicles, waste disposal, and agricultural sources are released into the environment, as shown in Figure 1.1. Exposure to these pollutants, which include heavy metals, pesticides, particulate matter (PM), and volatile organic compounds (VOCs), has been associated with increased risks of cardiovascular disease [11], neurological disorders [12], reproductive problems [13], respiratory disorders [14], immunological diseases [15], and developmental disorders [16]. The most concerning pollutants include ozone (O3), VOCs, nitrogen oxides (NOx), PM, heavy metals, and pesticides such as organophosphates and pyrethroids [17–21]. Unfortunately, most toxicological research has focused on studying the effects of individual pollutants in isolation, which does not reflect real-world exposures. In reality, populations are exposed to mixtures of pollutants that may interact and produce synergistic toxic effects that are greater than the sum of individual components. Therefore, understanding the combined toxicology of real-world environmental pollutant mixtures is crucial for fully assessing health risks and guiding regulatory policies.
Figure 1.1 The scope of environmental toxicology [22, 23].
Here, the combined toxicology of major environmental pollutant mixtures has been classified according to the resources, including air pollution, pesticide mixtures, heavy metal–pesticide mixtures, and electronic waste mixtures. In addition, the advances and challenges in evaluating the combined toxicology of major environmental pollutant mixtures are discussed.
1.1.2.1 Air Pollution Mixtures
Air pollution is a complex mixture resulting largely from motor vehicle emissions, power generation, and industrial activities. Major hazardous components include particulate matter (PM2.5 and PM10), ground-level O3, NOx, CO, and VOCs such as benzene and formaldehyde [24]. Epidemiological studies clearly link air pollution exposure to increased cardiovascular and respiratory mortality [25–27]. Controlled exposure studies in animals and humans demonstrate inflammation [28], oxidative stress [29], and pulmonary dysfunction [30] as underlying mechanisms. Interactions between air pollutants may enhance toxicity. For example, co-exposure to O3 and PM2.5 in mice shows synergistic effects on inflammation and tissue damage compared to individual exposure [31]. This synergy likely results from oxidative stress caused by O3 rendering lung tissues more susceptible to physical injury from PM2.5. Combined exposure to O3 and PM2.5 also produces greater inflammatory effects and oxidative stress in rats than individual chemicals [32]. However, air pollution mixtures consist of numerous chemical compounds and vary with time. These compounds can interact with one another in the atmosphere, forming new compounds or changing their properties. The large number of chemicals and their interactions make it difficult to identify and quantify the toxic effects.
1.1.2.2 Pesticide Mixtures
Pesticides, such as organophosphates, carbamates, pyrethroids, and neonicotinoids, are used ubiquitously in agriculture. Given their acute neurotoxicity, most studies have focused on the neurological effects of individual pesticides [33]. However, several pesticides are applied together and interact to increase neurotoxicity in animal studies. In salmon, mixtures of organophosphates and carbamates inhibit cholinesterase enzymes additively compared with individual pesticides [34]. It was reported that formamidine pesticides, such as chlordimeform and amitraz, effectively synergize the toxic actions of certain pyrethroid and neonicotinoid insecticides in some insect species, which is based on the ability to activate the octopamine receptor [35]. Beyond acute toxicity, combined lifelong exposure to multiple pesticides may contribute to chronic neurodegenerative disease [36, 37]. The ability of pesticide mixtures to induce oxidative stress, inflammation, and mitochondrial dysfunction is likely an underlying mechanism for neurological damage [38–40]. Analyzing the role of pesticide mixtures is critical for understanding chronic neurodegenerative risks among agricultural populations.
1.1.2.3 Heavy Metal–Pesticide Mixtures
Heavy metals and pesticides are major food and water contaminants that can interact and increase toxicity. The combined toxicity of heavy metal–pesticide mixtures can have detrimental effects on ecosystems. The presence of heavy metals can affect the degradation and bioavailability of pesticides, altering their environmental fate and persistence. Furthermore, heavy metals can interact with pesticides in soil, leading to increased mobility and potential groundwater contamination. These mixtures can have adverse effects on various organ systems, including the nervous, respiratory, and immune systems [41, 42]. For instance, the combination of Cr and fenitrothion elevated testicular toxicity compared with that of single exposure in rats, which was mediated through the increased oxidative stress, androgenic hormone changes, and reduction of free radical scavenging capacity [43]. The combined Cd and chlorpyrifos could synergistically induce hepatic toxicity through the increased levels of cholesterol and triglyceride in the cells [44, 45]. Overall, these studies demonstrate the importance of considering metal–pesticide mixtures for accurately assessing health risks. More research is still needed on the toxicological interactions between heavy metals and the wide variety of pesticides and herbicides used in agriculture.
1.1.2.4 Electronic Waste Mixtures
Rapid generation of electronic waste (e-waste) containing complex chemical mixtures is an emerging environmental threat [46, 47]. E-waste is defined as those electronic devices which are broken, unwanted, or discarded by their users. Recycling e-waste to recover valuable metals using crude techniques in developing countries exposes workers and communities to mixtures of metals, flame retardants, and plastic additives. Developmental neurotoxicity has been recognized as a serious concern, but studies on the toxic effects and underlying mechanisms in humans are scarce [48]. Toxicological studies show that e-waste mixtures generate systemic DNA damage, oxidative stress, upregulation of inflammatory cytokines, and endocrine disruption at lower doses [49, 50]. More research is urgently needed on e-waste recycling mixtures to develop proper remediation strategies.
1.1.3 The Challenges in Analyzing the Combined Toxicity of Environmental Pollutant Mixtures
Tons of pollutants can be released into the environment, and the mixture could be much more complicated. Besides, the components of a mixture may be altered depending on previous use, the mixture, route of release into the environment, and time in the environment. Hence, it is not easy to assess the toxicity of environmental mixtures. Here are some key challenges in analyzing the combined toxicity of complex environmental mixtures: (1) Very large number of chemicals – environmental mixtures may contain hundreds or thousands of compounds, making it unfeasible to test every combination. This creates uncertainties in predicting interactions. (2) Complex interactions – chemicals can interact through multiple mechanisms like addition, synergism, or antagonism. These interactions are difficult to model without extensive data [51]. (3) Unknown mixture components – many chemicals in mixtures have not been identified, limiting the ability to predict toxicity. Analytical chemistry techniques are still developing to comprehensively profile mixtures. (4) Variability in mixtures – the composition of mixtures in different locations and over time is highly variable [52]. This makes it difficult to generalize results across studies. (5) Route-specific effects – toxicity can depend on the route of exposure (inhalation, ingestion, dermal) [53]. Most studies only assess one route, creating uncertainties in extrapolating real-world exposures. (6) Low-dose effects – mixtures may exert effects at very low doses of individual components that are missed by traditional testing [54, 55] and require more sensitive models like in vitro assays. (7) Inter-individual variability – factors like genetics, age, and health status affect susceptibility to mixtures, complicating determinations of “safe” levels [56]. (8) Limited experimental models – Current in vitro and animal models have limited ability to capture complex processes and low-dose effects relevant to mixtures. (9) Regulatory challenges – Policies focused on individual chemicals need to evolve to account for cumulative risks from mixtures. Lack of data is a barrier. Overall, addressing these challenges requires a combination of computational modeling, high-throughput screening methods, analytical chemistry advancements, and evolving regulatory guidance. Significant interdisciplinary research is still needed in this emerging area.
1.1.4 The Methodology to Analyze the Combined Toxicity of Environmental Pollutant Mixtures
How to assess the combined toxicity of environmental mixtures is an intractable and challenging question. At present, some high-throughput screening methods have been applied to analyze the toxicity of complex environmental mixtures.
Cell-based reporter gene assays: Cells are engineered to express a reporter gene like luciferase when specific pathways are activated, allowing rapid screening of mixtures for effects like endocrine disruption or oxidative stress. For example, the aryl hydrocarbon receptor (AhR)-mediated activity has been identified as one of the key targets in the toxicity of polycyclic aromatic hydrocarbons (PAHs). Hence, a human gene reporter AZ-AhR cell line was developed to evaluate the AhR-mediated activities of a lot of environmental PAHs and further perform the risk assessment of PAHs [
57
]. Similarly, the
CALUX
reporter gene was introduced to the human osteosarcoma cell line to investigate and characterize the endocrine-disrupting potencies of the chemical mixtures, such as the crude extracts of indoor dust [
58
]. However, these assays have certain limitations, e.g. single-target assessment, that reporter gene assays typically focus on a specific molecular target or pathway; lack of metabolic considerations; and absence of tissue-specific responses.
Microfluidic organ-on-a-chip models: Miniaturized systems recreate organ structures and functions to model the toxicity of mixtures at the tissue level. This model can combine tissue engineering and micro-manufacturing to simulate the critical physiological functions and environment of the human organs, which can be applied to assess the combined toxicity of chemical mixtures. For example, the gut-on-a-chip system has been established for drug screening because of the critical role of the gut in drug administration and absorption [
59
]. This application provides new directions to evaluate the toxicity of environmental pollutants [
60
]. The drawback of this methodology lies in the fact that the simulation of an individual organ fails to account for crucial biological phenomena that transpire within the intricate network of physiological processes in the human body. Consequently, this oversimplification significantly constrains the scope of inferences that can be derived.
Zebrafish embryos: Transparent zebrafish embryos can be used for rapid developmental toxicity screening of mixtures to assess their effects. The zebrafish embryo model is sensitive to quantifying the combined effects of chemical mixtures of water contaminants [
61
]. For example, a transgenic zebrafish strain tg (cyp19a1b-GFP) has been developed to assess the endocrine disruption of five different oestrogenic chemicals [
62
], which was also predicted to serve as an available model to determine the combined toxicity of other pollutant mixtures.
Quantitative high-throughput screening (qHTS): Robotic systems conduct dose–response testing for mixtures across a wide concentration range, allowing the generation of large datasets for computational modeling [
63
].
High-content imaging: Automated microscopy combined with fluorescent dyes/tags allows multiple cellular endpoints such as oxidative stress, apoptosis, or mitochondrial damage to be rapidly assayed.
OMICS approaches: OMICS approaches techniques like transcriptomics, proteomics, and metabolomics profile global changes across thousands of biomolecules to identify mechanisms and biomarkers.
Computational modeling: Algorithms predict interactions between untested chemicals in mixtures using quantitative structure–activity relationship (QSAR) models.
Most studies have only examined interactions between a handful of chemicals, while real-world exposures involve hundreds of pollutants. High-throughput screening approaches combining computational toxicology with in vitro bioassays show promise for comprehensively profiling environmental mixtures. Advanced analytical chemistry techniques like nontargeted gas chromatography–mass spectrometry (GC/MS) and chromatography tandem mass spectrometry (LC/MS) can help exhaustively identify mixture components as a starting point. Overall, substantial research is still needed on developing biomarkers, nonanimal testing models, and computational approaches to predict synergies between untested chemicals. Moving forward, understanding the health risks of complex environmental mixtures requires an interdisciplinary approach combining environmental chemistry, toxicology, and public health expertise. Regulatory policies also need to evolve to account for cumulative risks from pollutant mixtures rather than individual chemicals. Implementing these science-based reforms is critical for protecting public health from complex environmental exposures.
1.2 Key Terminologies
Combined toxicology, also known as mixture toxicology or mixture risk assessment, is a multidisciplinary field that investigates the combined effects of multiple chemical substances on living organisms. Here, we aim to provide a comprehensive overview of key terminologies commonly used in combined toxicology research. It discusses essential concepts and definitions related to this field, such as mixture toxicity, interaction types, does–responses, and exposure assessment.
1.2.1 Mixture Toxicity
The first term is “mixture toxicity,” which refers to the combined toxic effects of multiple chemicals. Combined toxicology focuses on understanding the potential interactions and cumulative effects that arise from exposure to mixtures of chemical substances. Mixture toxicity refers to the combined effects of two or more chemical substances in a mixture that differ from the effects of individual chemicals when tested alone. This term encompasses both synergistic (enhanced effects) and antagonistic (reduced effects) interactions between the components of the mixture.
1.2.2 Types of Combined Action
Studies on mixture toxicity or combined toxicity are often accompanied by statements about the type of combined action, which requires an understanding of the basic concepts of the combined toxicology, i.e. dose-addition, effect, or response-addition, and interaction such as synergism, potentiation, and antagonism. The main interaction types of the chemical mixtures include additivity, synergism, antagonism, and potentiation, which result in distinct effects of the mixtures, as shown in Table 1.1.
Table 1.1 The interaction types of chemical mixtures.
Type of interaction
Toxic effects of chemical A (%)
Toxic effects of chemical B (%)
Combined effect of chemical A + B (%)
Notes
Additivity
20
30
50
A combination of two or more chemicals is the sum of the expected individual responses
Antagonism
20
30
<50
Two or more chemicals in combination have an overall effect that is less than the sum of their individual effects
Potentiation
0
30
50
A chemical that does not have a specific toxic effect makes another chemical more toxic
Synergism
20
30
>50
Combined two or more chemicals have an overall effect that is more than the sum of their individual effects
1.2.2.1 Additivity
Additivity refers to an event where the combined effect of two or more chemicals is equal to the sum of their individual effects. The chemicals act independently of each other to produce a combined effect that is predictable based on their individual effects. According to the way of action among the mixtures, additivity can be further divided into two types, including dose-addition and response-addition. Dose-addition refers to that mixture components contribute to toxicity as if they acted through a common mechanism, and toxic units are summed. The concept of dose-addition originally stated that when noninteracting chemicals are combined in a mixture, their behavior resembles that of diluted substances, and as a result, their effects can be quantitatively related using potency factors [64]. From a risk assessment perspective, the practical implication of dose-addition is that a mixture comprising two or more chemicals, each present at a concentration equating to half of its toxic threshold, is expected to induce a quantifiable toxic effect. The notable case to this concept is the approach to dealing with the carcinogenicity of dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)]-like chemicals since they share the same target organ via the same mechanism of action with 2,3,7,8-TCDD, the designated reference compound [65]. In contrast, response-addition assumes that the mixture components act through different pathways to produce an overall effect. Each contributes independently to the total response [66].
1.2.2.2 Nonadditivity
However, nonadditivity refers to a situation where the combined effect of two or more chemicals is different from the sum of their individual effects. Nonadditivity can be further divided into three categories: synergism, antagonism, and potentiation.
