Toxicology of Chemical Mixtures (eBook)

Front Cover 1
Toxicology of Chemical Mixtures: Case Studies, Mechanisms, and Novel Approaches 4
Copyright Page 5
Table of Contents 8
Contributors 18
Acknowledgment 7
Foreword 22
Chapter 1. Introduction to the Toxicology of Chemical Mixtures 26
I. Single Chemical Exposure? 26
II. Lack of Toxicologic Interaction at Low Levels? 30
III. Concept of "Generic Promoter" or "Cotoxicant" 32
IV. Organization and Philosophy of This Book 33
References 34
PART I: REAL LIFE CASE STUDIES OR SPECIAL PROBLEM-RELATED SITUATIONS 36
Chapter 2. Love Canal: Development of the Toxicologic Evaluation of Its Complex Chemical Contamination 38
I. Historical Perspective on the Love Canal 38
II. Initial Experimental Approaches to the Toxicology of a Complex Mixture: Application of Classical Methods of Toxicology to an Unusual Problem 41
III. Experimental Designs Based on Mechanisms of Action 53
IV. Use of the Ah Phenotype-Dependent Response Ratio to Evaluate Component Toxicity and Mechanisms of Interaction 64
V. Conclusion 72
References 73
Chapter 3. Toxicology Studies on Mixtures of Chemical Contaminants in the Great Lakes 76
I. Introduction 76
II. Studies on Mixtures of Great Lake Contaminants 77
III. Future Directions 82
IV. Conclusion 84
References 84
Chapter 4. Health Effect Studies on Recycled Drinking Water from Secondary Wastewater 88
I. Introduction 88
II. Water Quality Studies 91
III. Health Effects Studies 97
IV. Summary 106
References 106
Chapter 5. Assessing the Carcinogenic Potency of Environmental Coal Tars, By-Products of Coal Gasification 108
I. Introduction 108
II. Approaches to Assessing Carcinogenic Potency 112
III. Design of the Chronic Bioassay 115
IV. Design of Supporting Studies 118
V. Conclusions 121
References 121
Chapter 6. Toxicology of Chemical Mixtures Derived from Hazardous Waste Sites or Application of Pesticides and Fertilizers 124
I. Historical Perspectives on the Development of a Toxicology Program on Chemical Mixtures from Hazardous Waste Sites 125
II. Strategy to Study Chemical Mixtures 126
III. Chemical Mixtures of Groundwater Contaminants from Hazardous Waste Sites and Agricultural Activities 128
IV. Selected Findings from the NIEHS/NTP Chemical Mixture Toxicology Program 130
V. Some Unique Lessons in the Toxicology of Chemical Mixtures 136
VI. Immensity of the Problem of Dealing with Chemical Mixtures 137
VII. Future Directions 138
References 139
Chapter 7. Diesel Exhaust: An Approach for the Study of the Toxicity of Chemical Mixtures 144
I. Toxicity of Total Diesel Exhaust 145
II. Toxicity of Filtered Diesel Exhaust 150
III. Toxicity of Organic Phase Adsorbed to Soot 151
IV. Toxicity of Pure Carbon Black Compared with Diesel Soot 153
V. Summary and Conclusions 154
Acknowledgment 156
References 156
Chapter 8. Toxicologic Problems Associated with Pesticide Mixtures and Pesticide Impurities 160
I. Introduction 160
II. Alterations in Toxicity Resulting from Impurities in Pesticides 161
III. Alterations in Toxicity Resulting from Exposure to Two or More Chemical Agents 173
IV. Conclusions 177
Acknowledgment 177
References 177
Chapter 9. Carcinogenic Hazards from Eating Fish and Shellfish Contaminated with Disparate and Complex Chemical Mixtures 182
I. Introduction 183
II. Conceptual Options, Experimental Stratgies, and Potential Confounding Factors 188
III. Carcinogenesis Studies Using Fish 199
IV. Fish and Rodent Liver 202
V. Chemical Carcinogenesis 203
VI. Extrapolating from Animals to Humans 204
VII. Conclusions 206
References 208
PART II: TARGET ORGAN TOXICITY OR SPECIAL TOXICOLOGIC RESPONSES RELATED TO CHEMICAL MIXTURE EXPOSURES 220
Chapter 10. Immune Alteration Resulting from Exposure to Chemical Mixtures 222
I. Introduction 222
II. Overview of Immunotoxicology 223
III. Chemical Mixtures 225
IV. Considerations in Immunotoxicology Studies of Chemical Mixtures 237
V. Conclusions 238
References 238
Chapter 11. In Vivo Cytogenetic Effects from Exposures to Chemical Mixtures 244
I. Introduction 244
II. Cytogenetic Mechanisms and Methodologies 246
III. Cytogenetic Studies of Complex Mixtures 256
IV. Conclusions 263
Acknowledgment 263
References 263
Chapter 12. Multiple Chemical Exposure and Risks of Adverse Reproductive Function and Outcome 270
I. Introduction 270
II. Definitions and Terminology 272
III. Scope of Survey 274
IV. In Vitro Developmental Toxicity of Mixtures or Combinations of Chemicals 276
V. In Vivo Developmental Toxicity Studies of Environmentally Occurring Mixtures 282
VI. In Vivo Developmental Toxicity Studies of Chemicals in Combination 287
VII. Reproductive Toxicity Studies of Chemical Mixtures and Combinations 307
VIII. Summary and Future Directions 314
References 315
Chapter 13. Mechanism of the Interactive Amplification of Halomethane Hepatotoxicity and Lethality by Other Chemicals 324
I. Introduction 324
II. Carbon Tetrachloride–Chlordecone Model of Interactive Toxicity 327
III. Implications for Assessment of Risk to Public Health 352
Acknowledgment 354
References 354
Chapter 14. Nephrotoxicity Resulting from Multiple Chemical Exposures and Chemical Interactions 360
I. Introduction 360
II. Complex Chemical Mixtures 362
III. Simple Mixtures 373
IV. Summary 380
Acknowledgment 382
References 382
Chapter 15. Effects of Low Level Exposure to Multiple Carcinogens in Combination 386
I. Introduction 386
II. Manner of Response to Multiple Agent Exposure 387
III. Factors Involved in Low Level Exposure 388
IV. Experimental Examples 390
V. Conclusions 403
References 403
PART III: CONTEMPORARY ISSUES 408
Chapter 16. New Approaches to Bioassay- and Biomarker-Directed Identification of Genotoxic Components in Complex Mixtures: DNA Adduct Identification and Mutation Spectra 410
I. Bioassay-Directed Fractionation and Analysis from Classical Macro Methods to Analytical Micro Methods 410
II. New Molecular Approaches 411
References 421
Chapter 17. Physiologically Based Pharmacokinetic Modeling of Chemical Mixtures 424
I. Pharmacokinetic Modeling 424
II. PBPK Modeling of Individual Chemicals 425
III. PBPK Modeling of Binary Chemical Mixtures 435
IV. PBPK Modeling of Complex Chemical Mixtures 453
V. Summary and Future Directions 458
References 458
Chapter 18. Application of Physicochemical Concepts to Mechanistic Elucidation of Toxicologic Interactions 464
I. Introduction 464
II. Estimation of Hazards 466
III. Priorization of Mechanisms 468
IV. Specific Hazards of Redox Reactions 471
V. Hazards of Defensive Oxidase Systems 472
VI. Mechanistic Hazard Prediction 473
VII. Formulation of a Controlled Correlation 476
VIII. Pathological Prediction from Controlled Correlations 484
IX. Xenobiotic Chemical Recognition 487
X. Practical Consequences of Nonlinear Response to Mixtures 492
References 494
Chapter 19. Defining Populations Potentially Exposed to Chemical Waste Mixtures Using Computer-Aided Mapping and Analysis 498
I. Environmental Health Studies around Hazardous Waste Sites 498
II. Computer-Aided Mapping and Analysis of Health Effects Data 507
III. Summary 526
Acknowledgment 527
References 527
Chapter 20. Challenges for in Situ Bioremediation of Chemical Mixtures 530
I. Introduction 530
II. Challenges for in Situ Bioremediation 536
III. Special Challenges for in Situ Bioremediation of Chemical Mixtures 546
IV. Conclusions 558
Acknowledgment 558
References 558
Chapter 21. Chemical Mixture Toxicity Assessment Using an Alternative-Species Model: Applications, Opportunities, and Perspectives 564
I. Introduction 564
II. Background 565
III. Frog Embryo Test Methodology 567
IV. Experimental Findings 569
V. Applications and Opportunities 581
VI. Conclusions 584
References 584
Chapter 22. Approaches and Challenges in Risk Assessments of Chemical Mixtures 590
I. Introduction 590
II. Background 592
III. Practical Application of Additivity 599
IV. Approaches to Assessing Interaction Data 605
V. Considerations Regarding Interactions in Risk Assessments 617
VI. Perspective 619
References 621
Chapter 23. Statistical Methods for the Toxicological Evaluation of the Additivity Assumption as Used in the Environmental Protection Agency Chemical Mixture Risk Assessment Guidelines 624
I. Introduction 624
II. United States Environmental Protection Agency Risk Assessment Guidance 627
III. Discussion of Additivity 633
IV. Types of Experimental Design 648
V. Examples of the Use of Designs and Estimation Strategies 650
VI. Usefulness of Exploratory Data Analysis 660
VII. Graphical Methods for Describing Study Results 662
VIII. Conclusions and Areas of Further Research 663
References 665
Chapter 24. Analysis of Chemical Combinations: Relating Isobolograms to Response Surfaces 668
I. Introduction 668
II. Relating the Interaction Index to the Concentration Response Surface 672
III. Experimental Design Implications 679
IV. Visualizing and Interpreting Multidimensional Isobolograms 681
Acknowledgment 687
References 687
Chapter 25. Potential Effects of Chemical Mixtures on the Carcinogenic Process within the Context of the Mathematical Multistage Model 690
I. Introduction 690
II. Multistage Models of Carcinogenesis 692
III. Multistage Models and Chemical Mixtures 702
IV. Summary 710
References 710
Index 712