Principles and Practice of Mixtures Toxicology

Principles and Practice of Mixtures Toxicology......Page 5
Foreword......Page 9
Contents......Page 13
Preface......Page 27
List of Contributors......Page 29
1.1 Chemical Mixtures Exposure......Page 37
1.2 Superfund Research Program......Page 40
1.3 SRP and Mixtures Research......Page 42
1.4 Drug–drug Interactions and Nanomaterials......Page 44
1.5 Waste Sites and Mixtures Risk Assessment......Page 46
1.6 Alternative Testing Methods......Page 52
1.7 Translational Research......Page 54
References......Page 57
2.1 Risk Assessment Paradigm: A Chemical Mixtures Context......Page 63
2.2 Occurrence of Chemical Mixtures in the Environment......Page 64
2.3 Drivers for Assessing Exposures to Chemical Mixtures......Page 65
2.4 Using Conceptual Models to Guide the Development of Mixture Exposure Assessments......Page 67
2.5 Overview of Environmental Fate for Chemical Mixtures......Page 68
2.6.1 Problem Formulation: Exposure Context......Page 70
2.6.1.2 Preliminary Evaluation of Environmental Fate......Page 72
2.6.1.3 Influence of the Dose-Response Metric......Page 73
2.6.2.1 Sources......Page 75
2.6.2.2 Environmental Fate of Mixture Components......Page 76
2.6.2.3 Characterizing the Exposure Scenario......Page 81
2.6.2.4 Exposure Quantification......Page 82
2.7 Illustrative Example: Assessing Exposures to DBP Mixtures in Drinking Water......Page 86
2.7.1 Problem Formulation......Page 87
2.7.1.2 Preliminary Analysis of Environmental Fate......Page 88
2.7.2 Exposure Assessment......Page 89
2.7.2.4 Estimating Exposures and Determining Coexposures to Mixture Components......Page 90
2.7.3 Results......Page 92
2.8 Summary......Page 93
2.9 Future Directions......Page 94
References......Page 95
3 Application of a Relative Potency Factor Approach in the Assessment of Health Risks Associated with Exposures to Mixtures of Dioxin-Like Compounds......Page 103
3.1 Dioxin-Like Chemicals......Page 104
3.2 Introduction of TEF Methodology......Page 105
3.3.1 Initial Proposal: The TEF Methodology, 1984......Page 107
3.3.4 Addition of PCBs, 1990–1993......Page 108
3.3.5 World Health Organization, 1998......Page 110
3.3.6 World Health Organization, 2006......Page 111
3.3.7 National Academy of Science, 2006......Page 112
3.4.1 REP1997 Database......Page 113
3.4.2 REP2005 Database......Page 114
3.4.3 Variability in REP Values......Page 115
3.5.1 TEF Derivation Process......Page 116
3.5.2 REP Weighting......Page 117
3.5.3 Use of REP Distributions to Characterize Uncertainty in Risk Assessment......Page 118
3.6 Assumptions, Limitations, and Uncertainties of the TEF Approach......Page 119
3.6.3 Additivity of DLCs......Page 120
3.6.3.1 Studies with Mixtures of DLCs......Page 121
3.6.3.4 Nonparallel Dose-Response Curves......Page 122
3.6.5.1 Natural Chemicals......Page 123
3.6.5.2 Anthropogenic Compounds......Page 124
3.7 Closing Remarks......Page 125
References......Page 126
4 Statistical Methods in Risk Assessment of Chemical Mixtures......Page 135
4.1 Principles of Statistics......Page 136
4.2.1 Definition of Additivity......Page 138
4.2.2 Testing for Departure from Additivity: Analysis of a Response Surface......Page 140
4.2.3 Example 1: Analysis of a Mixture of Three Chemicals from a 53 Study......Page 142
4.2.4 Example 2: Analysis of a Mixture of Nine Chemicals from a Fractionated 29 Study......Page 144
4.2.5 Interaction Threshold Model......Page 145
4.3 Alternative Approach: Use of Ray Designs with Focus on Relevant Mixing Ratios......Page 147
4.3.1 Example of SCR Method: Analysis of Functional Effects of a Mixture of Five Pesticides Using a Ray Design......Page 148
4.3.2 Example of "Single Chemicals Not Required" Method Using a Mixture of Five Pesticides......Page 150
4.4 Testing for Additivity in the Low-Dose Region......Page 152
4.5 Sufficient Similarity in Dose Responsiveness......Page 155
References......Page 157
5.1 Pharmacokinetic Modeling......Page 161
5.2.1.1 Absorption......Page 163
5.2.1.2 Distribution......Page 164
5.2.2 Experimental Approach......Page 166
5.2.3 Examples......Page 168
5.3.1.2 Distribution......Page 169
5.3.1.3 Metabolism......Page 170
5.3.2.3 Metabolism......Page 175
5.3.3 Examples......Page 176
5.3.3.2 Trichloroethylene and 1,1-Dichloroethylene......Page 177
5.3.3.3 Benzene and Toluene......Page 178
5.3.3.4 Mirex, Phenobarbital, or Chlordecone and Bromotrichloromethane......Page 179
5.3.3.7 Carbaryl and Chlorpyrifos......Page 181
5.4.1 Theoretical Considerations......Page 182
5.4.2 Experimental Approach......Page 183
5.4.3.1 n-Hexane......Page 184
5.4.3.3 Benzene, Toluene, m-Xylene, Ethylbenzene, and Dichloromethane......Page 186
5.4.3.4 Gasoline and JP-8 Jet Fuel......Page 187
5.5 Summary and Future Directions......Page 188
References......Page 189
6.1 Introduction......Page 195
6.2.1 Love Canal......Page 196
6.2.2 Times Beach......Page 197
6.2.3 Rice Bran Oil Contaminated with PCBs in Japan and Taiwan......Page 198
6.2.5 Great Lakes......Page 199
6.3 Current Status......Page 200
6.4 Tissue Repair......Page 201
6.4.1 Studies That Brought TR to the Forefront......Page 202
6.4.2 CD + CCl4 Toxicity......Page 203
6.5 Interactions Leading to Increased Liver Injury, But Not Death......Page 206
6.6 Two-Stage Model of Toxicity......Page 207
6.7 Tissue Repair Follows a Dose Response After Exposure to Chemical Mixtures......Page 208
6.7.1.1 Thioacetamide......Page 209
6.7.1.2 CCl4......Page 210
6.7.2.1 CHCl3 + AA......Page 211
6.7.2.4 CHCl3 + TCE + AA......Page 213
6.8 Tissue Repair Determines the Outcome of Toxicity......Page 215
6.8.1 Factors Affecting Tissue Repair......Page 218
6.8.1.1 Species, Strain, and Age Difference......Page 219
6.8.1.3 Diet Restriction......Page 220
6.8.1.4 Disease Condition: Diabetes......Page 221
6.9 Molecular and Cellular Mechanisms of Tissue Repair......Page 223
6.9.1 How Does Injury Progress?......Page 225
6.9.2 Why Newly Divided Cells Are Resistant to Progression of Injury?......Page 227
6.10 Implications for Risk Assessment......Page 228
6.11 Conclusions......Page 229
References......Page 230
7.1 Introduction......Page 243
7.2 Statistical Analysis for Interaction Thresholds......Page 246
7.3 Predictive Modeling of the Interaction Threshold......Page 247
7.4 "No Interaction" Exposure Levels......Page 248
References......Page 249
8.1 Introduction......Page 251
8.3 Mathematical Proteomics Approaches......Page 252
8.3.2 The Graph Invariant Approach......Page 253
8.3.3 The Protein Biodescriptor Approach......Page 256
8.3.4 The Information Theoretic Method......Page 258
8.4.1 Cell Culture and JP-8 Exposure......Page 259
8.4.3 Two-Dimensional Electrophoresis......Page 260
8.5 Theoretical Calculation of Information Theoretic Biodescriptors......Page 261
8.6.1 Peroxisome Proliferators......Page 262
8.7 Discussion and Conclusion......Page 266
References......Page 268
9.1 Introduction......Page 271
9.2.2 Dermal Absorption......Page 272
9.2.3 Gastrointestinal Absorption......Page 273
9.3 Distribution-Level Interactions......Page 274
9.4 Metabolism-Level Interactions......Page 275
9.5 Elimination-Level Interactions......Page 280
9.7 Conclusions......Page 281
References......Page 283
10.1 Introduction......Page 289
10.2 Toxicology Basis for Mixtures and Cumulative Risk Assessment......Page 294
10.2.1 Mode of Action Characterization......Page 295
10.2.2 Chemical Grouping Strategy......Page 297
10.3 Mixtures and Cumulative Risk Assessment Methods......Page 300
10.3.2 Whole Mixture Approaches......Page 301
10.3.3 Sufficient Similarity......Page 302
10.3.4 Component-Based Approaches......Page 303
10.3.5 Additivity Models and Single-Chemical Data......Page 304
10.3.5.1 Hazard Index Approaches......Page 305
10.3.5.2 Relative Potency Factors......Page 307
10.3.6 Response Addition......Page 309
10.3.8 Chemical Interactions......Page 310
10.3.9 Interaction-Based Hazard Index......Page 311
10.4 Future Directions......Page 312
References......Page 314
11.1 Introduction......Page 319
11.2 ATSDR's Process for Evaluating Chemical Mixtures......Page 320
11.3 Case Studies......Page 328
11.3.1.1 Site Description and History......Page 329
11.3.1.2 Groundwater Contaminant Levels......Page 330
11.3.1.3 Brief Review of Exposure Pathways......Page 331
11.3.1.4 Evaluating Oral Exposure to the Mixture of Chemicals in Endicott.s Water......Page 333
11.3.1.6 Presentation to Residents on the Community Advisory Board......Page 334
11.3.2.1 Site Description and History......Page 336
11.3.2.2 Investigation of Groundwater Contamination......Page 337
11.3.2.3 Exposure Pathway Analysis......Page 338
11.3.2.4 Toxicity Assessment for Individual Chemicals......Page 339
11.3.2.5 Hazard Assessment for the Mixture of TCE and CCl4......Page 346
11.4 Overall Conclusions from the Case Studies......Page 349
References......Page 351
12.1 Introduction......Page 355
12.2 Occupational Exposure Limits......Page 356
12.3 Regulating Mixed Exposures in the United States......Page 358
12.4 Hazard Communications......Page 361
12.5 Emerging Approaches......Page 362
References......Page 363
13.1 Safety Considerations for Drug Combination Products......Page 365
13.1.1 Categories of Drug Combinations......Page 366
13.1.2 Regulatory Guidance......Page 367
13.1.3 Considerations for Nonclinical Development of Drug Combinations......Page 369
13.1.3.2 Species Selection......Page 370
13.1.3.4 Dose Selection......Page 371
13.2.1 Magnitude of the Problem......Page 373
13.2.2 Evidence that Interactions Occur is a Scientific Question, Requiring Data......Page 376
13.2.3 Criteria for Evaluating Interactions......Page 378
13.2.4 Scoring Algorithm......Page 382
References......Page 383
14.1 Introduction......Page 385
14.2 Mechanisms of Interactions......Page 387
14.3 Mixture Interactions in Skin......Page 389
14.3.1 Compound Susceptibility to Solvent Interactions......Page 390
14.3.2 Mixture Interactions Across Model Systems......Page 392
14.3.3 Can Partition Coefficient Predict Mixture Behavior?......Page 394
14.3.4 Solvent–Water Interactions......Page 395
14.3.5 Modified QSPR Equations that Predict Chemical Absorption from a Mixture......Page 397
14.3.6 Novel MCF Approach to Calibrate Dermal Absorption of Mixtures......Page 400
14.4 Potential Impact of Multiple Interactions ug/hr......Page 405
References......Page 409
15.1 Introduction......Page 413
15.2 Synergy......Page 414
15.3 Risk Management and Synergy......Page 415
15.4.1 Additive Models......Page 417
15.4.2 Independence Models......Page 418
15.5 Placing Doses Used in Studies Demonstrating Synergy into a Risk Management Framework......Page 419
15.6 Extending the Approach to Mixtures of Three or More Chemicals......Page 423
15.7 Using the Graphic Framework to Place Data on Synergy into a Risk Management Context......Page 424
15.8.1 Recent Findings on the Relationship Between Chronic Toxicity in Sensitive Humans and Reference Doses......Page 427
15.8.2 Impact of the Current System of Safety Factors on the Moser et al. [23] Data......Page 428
15.9.2 Does Synergy Occur at Low Doses?......Page 430
15.10 Discussion......Page 431
15.11 Summary and Conclusions......Page 432
References......Page 433
16.1 Introduction......Page 437
16.2 Regulation of DBPs in the United States......Page 438
16.3 DBP Mixture Health Effects Data Collection and Related Risk Assessment Approaches......Page 439
16.4.1 Epidemiological Data......Page 441
16.4.2 Toxicological Data on Individual DBPs and Simple Defined DBP Mixtures......Page 442
16.4.3 Multiple-Purpose Design Approach......Page 443
16.4.4 In Vitro Toxicological Data on Defined and Complex DBP Mixtures......Page 444
16.4.5 In Vivo Toxicological Data on Complex DBP Mixtures......Page 445
16.4.6 Reproducible Disinfection Scenarios......Page 448
References......Page 449
17.1 Introduction......Page 457
17.2 Common Characteristics of EAC Mixtures......Page 458
17.2.1 Rivers and Aquatic Environments......Page 459
17.2.2 Human Exposure......Page 460
17.3 Toxicity of EAC Mixtures......Page 462
17.3.1 Mixtures of EACs in Aquatic Organisms......Page 463
17.3.2 Mixtures of EACs In Vitro......Page 464
17.3.3 Mixtures of EACs in Mammalian Animal Models......Page 465
17.4.1 Receptor, Cell, and Tissue Specificity......Page 467
17.4.2 Signaling Pathways......Page 468
17.4.3 Evidence from Toxicogenomics Data......Page 470
17.5 Summary and Conclusions......Page 471
References......Page 473
18.1 Introduction......Page 479
18.3 Methodology for the Joint Toxicity Assessment of Mixtures......Page 480
18.4.1 Air Pathway......Page 482
18.4.2 Water Pathway......Page 484
18.4.3 Food Pathway......Page 486
18.5.1 Air and Water Pathways......Page 487
18.5.2 Soil Pathway......Page 492
18.5.3 Hazardous Waste Sites with Radioactive Chemicals......Page 495
18.6 Future Directions......Page 497
References......Page 498
19.1 Thyroid-Active Environmental Pollutants......Page 505
19.1.1 Inhibitors and Potential Inducers of Iodide Uptake into the Thyroid......Page 506
19.1.3 Alteration in Thyroid Hormone Metabolism......Page 507
19.2 Interaction of Chemical Mixtures on the HPT Axis......Page 508
19.3.1 Exposure Design......Page 510
19.3.2 Results and Discussion......Page 511
19.4 Experimental Challenges......Page 514
19.5 Dose-Response Computational Modeling of Chemical Effects on the HPT Axis......Page 515
References......Page 516
20.1 Introduction......Page 521
20.2 Sources......Page 522
20.3 Source Apportionment......Page 525
20.4.1 Ecological Effects......Page 526
20.4.2 Human Cancer Risk......Page 527
20.4.3 Birth Defects......Page 530
20.5 Pharmacokinetics......Page 531
20.6 Genetic Sensitivities......Page 533
20.7 Biomarkers of Exposure......Page 534
References......Page 538
21.1 Introduction......Page 549
21.2.1 Lung Nanotoxicity......Page 550
21.2.2 Dermal Toxicity......Page 551
21.2.4 Neuronal Neurotoxicity......Page 552
21.2.5 Reproductive Nanotoxicity......Page 553
21.3 Toxicology of Nanomixtures......Page 554
21.4 The In Vitro Debate......Page 558
21.5 Characterization of Nanomaterials......Page 559
21.5.2 Inductively Coupled Plasma Mass Spectrometry......Page 561
21.6 Conclusions......Page 562
References......Page 563
22.1 Why is Computer Simulation Not Only Important But Also Necessary for Chemical Mixture Toxicology?......Page 567
22.2 What Do We Mean by "Computer Simulation?" What Does it Entail?......Page 569
22.3.2 How Does PBPK Modeling Work?......Page 570
22.4 What is Bayesian Inference and Population PBPK Modeling? What is Markov Chain Monte Carlo Simulation? Why Do We Need These Technologies?......Page 573
22.5.1 Biochemical Reaction Network Modeling......Page 575
22.5.2 BioTRaNS: A New Framework......Page 576
22.5.3 BRN Modeling of Chemical Mixtures......Page 578
22.6 What is "Multiscale Modeling?" How Do PBPK, Bayesian Population PBPK Modeling, and BRN modeling Fit Into "Multiscale Modeling?" Any Possible Inclusion of Other Types of Computer Modeling?......Page 581
22.7 Can We Predict Chemical Mixture Toxicities? What is the Potential Real-World Application of Such a "Multiscale Computer Simulation" Approach?......Page 582
22.8 Concluding Remarks......Page 585
References......Page 586
23.1 Introduction......Page 591
23.2 Safety Evaluation......Page 592
23.3 Description of the Priority-Based Assessment of Food Additives......Page 593
23.4 Food Additives......Page 594
23.5 Color Additives......Page 595
23.6 GRAS Substances......Page 596
23.8 Natural Flavor Complexes......Page 598
23.9 Botanical Ingredients......Page 599
23.11 Conclusions......Page 601
References......Page 602
24.1 Introduction......Page 605
24.1.1 Air Contaminants......Page 610
24.1.2 Food Contaminants......Page 611
24.1.3 Water Contaminants......Page 612
24.2.1.1 Persistent Organic Chemicals......Page 613
24.2.1.2 Nonpersistent Organic Chemicals......Page 615
24.2.1.3 Bioaccumulative Metals......Page 616
24.2.2 Biological Sampling......Page 617
24.2.3 Biological Specimens......Page 618
24.2.4 Data Analysis and Evaluation......Page 619
24.3 Interpretation......Page 620
References......Page 625
25.1 Introduction......Page 631
25.2.1 Hepatic Toxicity......Page 633
25.2.2 Nephrotoxicity......Page 634
25.2.3 Hematologic Toxicity......Page 635
25.2.4 Immunologic Toxicity......Page 636
25.3 Drug Interactions......Page 637
25.3.1 Drug–Drug Interactions......Page 638
25.3.2 Drug–Food Interactions......Page 639
25.3.3 Drug–Natural Products Interactions......Page 640
25.3.4 Drug–Environmental Contaminant Interactions......Page 641
25.4 Conclusions......Page 642
References......Page 643
Index......Page 647