Human toxicology of chemical mixtures : toxic consequences beyond the impact of one-component product and environmental exposures

Contents Preface xxi Part 1 Introduction to Chemical Toxicology of Mixtures 1 1 Introduction 3 References 6 2 Health Effects of Exposures to Chemical Mixtures 7 2.1 Traditional Toxicology 7 2.1.1 Additivity 7 2.1.2 Antagonism 7 2.1.3 Potentiation 8 2.1.4 Synergism 8 2.2 Sequential Effects 8 2.3 Unexplained Effects of Mixtures 9 2.4 Lipophiles and Hydrophiles 11 2.5 Octanol: Water Partition Coefficients 11 2.6 Summary 13 References 13 3 Absorption of Chemical Mixtures 17 3.1 Introduction 17 3.2 Permeability of Mucous Membranes and Octanol: Water Partition Coefficients 17 3.2.1 Partition Coefficients (Kow) 17 3.3 Absorption Enhancers 19 3.4 Absorption of Organic Molecules from Aqueous Solutions 20 3.5 Summary 20 References 21 4 Chemical Toxicology 23 4.1 Introduction 23 4.2 Toxicology 23 4.3 Molecular Toxicology 24 4.4 Exposure 25 4.5 Absorption 25 4.6 Distribution 26 viii CONTENTS 4.7 Metabolism 27 4.8 Factors Affecting Metabolism of Xenobiotics 29 4.8.1 Age 30 4.8.2 Gender 30 4.8.3 Pregnancy 30 4.8.4 Disease 30 4.8.5 Hormones 31 4.8.6 Cycles 31 4.8.7 Enzyme Induction or Inhibition 31 4.8.8 Induction 31 4.8.9 Inhibition 32 4.8.10 Diet and Nutrition 32 4.8.11 Dose and Timing 33 4.8.12 Genetics 34 4.9 Oxidative Stress 34 4.9.1 Electromagnetic Radiation 36 4.9.2 Mixture Effects 36 4.10 Receptor–Xenobiotic Interactions 36 4.11 Endocrine Disruptors 37 4.11.1 Effects on Humans 38 4.11.2 Endocrine-Disrupting Compounds (EDCs) 39 4.11.3 EDC Mixtures 40 4.12 Immunotoxicology 41 4.12.1 Immunosuppression 41 4.12.2 Immunostimulation 43 4.13 Multiple Site Responses 45 4.14 Mixture Effects 46 References 48 Part 2 Exposures to Chemical Mixtures 51 5 Scope and Sources of Toxic Exposures 53 5.1 Scope of Exposure and Introduction 53 5.2 Toxic Release 53 5.3 Unknown Toxicities 54 5.4 Proliferation 56 References 56 6 In Utero Exposure 59 6.1 Fetal Sensitivity 59 6.2 Toxic Chemicals in the Blood of Newborns 59 CONTENTS ix 6.3 Toxic Hazards Of Fetal Toxicants 60 6.4 Mixtures 61 References 62 7 Air Pollution 63 7.1 Introduction 63 7.2 Pervasive Air Pollutants 64 7.3 Chemical Reactions in the Air 64 7.4 Confined Air Pollutants 69 7.5 Air Pollution in the Breathing Zone 70 7.6 Air Pollution and Health Risk 71 7.7 Mixtures 72 7.8 Particulate Matter 73 7.9 Aerosols 74 7.10 Summary 75 References 75 8 Water Pollution 79 8.1 Introduction 79 8.2 Mining 79 8.3 Manufacturing 80 8.4 Farming 81 8.4.1 Silts 81 8.4.2 Pathogens 82 8.4.3 Nutrients 82 8.4.4 Pesticides 83 8.5 Power Production 83 8.5.1 Petroleum Production and Refining 83 8.5.2 Coal Mining 84 8.5.3 Petroleum Use and Combustion 84 8.5.4 Coal Combustion 84 8.5.5 Cooling Towers 85 8.6 Urban Runoff 85 8.7 Home and Personal Care Products 85 8.7.1 Cleaners 86 8.7.2 Cosmetics 86 8.7.3 Deodorizers 86 8.7.4 Disinfectants 86 8.7.5 House and Garden Pesticides 87 8.7.6 Laundry Products 87 x CONTENTS 8.7.7 Ointments 87 8.7.8 Paint and Paint Products 87 8.7.9 Photographic Chemicals 87 8.7.10 Polish 88 8.7.11 Preservatives 88 8.7.12 Soaps 88 8.7.13 Medicines 88 8.8 Priority Water Pollutants 89 8.9 Chemical Reactions in Water 89 8.9.1 Groundwater 89 8.9.2 Disinfection Byproducts 95 8.10 Drinking Water Contaminants in the United States 97 8.11 Mixtures 113 8.12 Toxic Landfill Runoff 114 8.13 Summary 115 References 115 9 Soil Pollution 121 9.1 Introduction 121 9.2 Depressed Microbial Activity 122 9.3 Toxicity to Soil-Dwelling Animals 122 9.4 Plant Absorption of Soil Toxins and Bioaccumulation 123 9.5 Effects of Mixtures 124 9.6 Summary 125 References 125 10 Food 129 10.1 Introduction 129 10.2 Persistent Organic Pollutants (POPs) 130 10.3 Mercury 130 10.4 Antibiotics in Meat 131 10.5 Steroids in Meat 132 10.6 Additives in Commercial Food Preparation 133 10.7 Chemical Impurities in Food—Allowable Xenobiotics 134 10.8 Flavor Additives 136 10.9 Artificial Food Colors 138 10.10 Flavor Enhancers—Monosodium Glutamate (MSG) 138 10.11 Aspartame Nonnutritive Sweetener 139 10.12 Nonnutritive Chemicals in Food 140 10.13 The Bread We Eat 142 10.14 Volatile Organic Compounds (VOCs) in Food 143 CONTENTS xi 10.15 Chemicals in Food Packaging 145 10.16 Irradiated Food 146 10.17 Toxic Mixtures in Food 146 10.17.1 TCDD 146 10.17.2 Genotoxic Food Additives 147 10.17.3 Carcinogenic Flavorants 147 10.17.4 Preservatives 147 10.17.5 BHA and Marijuana 148 10.17.6 Recycled Food Packaging 148 10.17.7 Enzyme Inhibition 148 10.17.8 Nonionizing Radiation 148 10.18 Excipients in Pharmaceuticals and Vitamin and Mineral Preparations 149 10.18.1 Sulfites 149 10.18.2 Aspartame 150 10.18.3 Saccharin 150 10.18.4 Coloring Agents 150 10.19 Summary 150 References 151 11 Chemicals in and around the Home 157 11.1 Introduction 157 11.2 Arts and Crafts 158 11.3 Automobiles and Small Engines 159 11.4 Cleaners and Fresheners 161 11.5 Maintenance Materials 163 11.6 Brominated Flame Retardants (BFRs) 164 11.7 Personal Care and Cosmetic Products 166 11.8 Pesticides 170 11.9 Other Mixture-Containing Products 171 11.10 Summary 171 References 172 12 Sick Building Syndrome 175 12.1 Introduction 175 12.2 Sick Building Syndrome Symptoms 175 12.3 Contributory Sources of Sick Building Syndrome 175 12.4 Volatile Organic Compounds in Buildings 177 12.5 Paint 177 12.6 Environmental Tobacco Smoke 179 12.7 Carpets 181 xii CONTENTS 12.8 Formaldehyde 185 12.9 Other Sources of Sick Building Syndrome Toxic Chemicals 185 12.9.1 Wood Smoke 185 12.9.2 Textile Wall Materials 186 12.9.3 Wood Dust 186 12.9.4 Dioxins in Wood Preservatives 187 12.9.5 Waterproofing Applications 187 12.9.6 Hot Asphalt Roof Applications 187 12.9.7 Radon, Asbestos and Tobacco Smoke 187 12.10 Biological Causes of Sick Building Syndrome 188 12.10.1 Molds 188 12.10.2 Dust Mites 189 12.10.3 Animal Allergens 189 12.11 Mixtures 189 12.12 Investigating an SBS Incident 190 12.13 Summary 192 References 192 13 Industrial Exposure 197 13.1 Introduction 197 13.2 Single Chemical Toxicities 197 13.3 Mixture Toxicities 199 13.4 Noise, Organic Solvents, and Hearing Loss 200 13.5 Foundry Fumes and Cancer 200 13.6 Painting and CNS Effects 200 13.7 Printers’ CNS and Mucous Membrane Effects 201 13.8 High Cancer Rates in Road Pavers and Roofers 201 13.9 Nail Salon Work and CNS Effects 202 13.10 Coke Oven Work and Smoking Synergism 202 13.11 Incinerator Fly Ash Toxicity 202 13.12 Naval Divers’ Cancer Cluster 203 13.13 Industrial Solid Waste (ISW) and Municipal Waste Leachate 203 13.14 Exposures of Workers to Aromatic Hydrocarbons 204 13.15 Polyhalogenated Aromatic Compounds 205 13.16 Color Vision Impairment in Workers 205 13.17 Irradiated Mail Sensitivity 205 13.18 “Aerospace Syndrome” 206 CONTENTS xiii 13.19 Hospital Histology Technicians 206 13.20 Persistent Toxic Chemical Compounds 207 13.21 Regional Impact Assessment 207 13.22 Summary 208 References 209 14 Pesticides 213 14.1 Introduction 213 14.2 Definitions 213 14.3 Human Toxicities of Pesticides 214 14.4 Toxicity of Pesticide Mixtures 217 14.5 Inert Ingredients in Pesticides 220 14.6 Low Level Pesticide Poisonings 222 14.7 Summary 224 References 225 15 Alcohol and Tobacco: Recreational Toxins 229 15.1 Introduction 229 15.2 Ethanol: Introduction 229 15.3 Mechanisms of Ethanol Mixture Toxicity 230 15.4 Effect of Ethanol on Nutrients and Drugs 231 15.5 Toxicity of Ethanol Mixtures with Other Chemicals 231 15.6 Ethanol and Cancer 234 15.7 Tobacco Toxicity: Introduction 235 15.8 Tobacco and Cancer 236 15.9 Tobacco Smoke Mixtures and Lung Cancer 236 15.10 Noncarcinogenic Tobacco Smoke Synergism 238 15.11 Combined Toxicity of Ethanol and Tobacco 238 15.12 Summary 240 References 240 16 Electromagnetic Radiation and Toxic Exposure 245 16.1 Introduction 245 16.2 The Electromagnetic Spectrum 246 16.3 Ionizing Radiation and Toxic Chemical Mixtures 246 16.4 Ultraviolet Radiation and Toxic Chemical Mixtures 248 16.5 Nonionizing Radiation: Introduction 251 16.6 RF Radiation and Toxic Chemical Mixtures 252 16.7 ELF Radiation and Toxic Chemical Mixtures 253 16.8 Summary 255 References 255 xiv CONTENTS Part 3 Mixture Effects on Body Systems 259 17 Respiratory System 261 17.1 Introduction 261 17.2 Respiratory Irritant Mixtures 262 17.3 Respiratory Sensitization Mixtures 268 17.4 Asthma And Chemical Mixtures 271 17.5 Reactive Airways Dysfunction Syndrome (RADS) 275 17.6 Respiratory Carcinogens 277 17.7 Unanticipated Respiratory Effects of Chemical Mixtures 279 17.8 Summary 287 References 287 18 Nervous System 295 18.1 Introduction 295 18.2 Neurotoxic Chemicals 297 18.3 Indicators and Symptoms of Neurotoxic Poisoning 300 18.4 Mechanisms of Neurotoxic Action 300 18.5 Neurodegenerative Diseases and Toxic Chemical Exposures 303 18.5.1 Parkinson’s Disease (PD) 303 18.5.2 Alzheimer’s Disease (AD) 303 18.5.3 Amyotrophic Lateral Sclerosis (ALS) 304 18.5.4 Multiple Sclerosis (MS) 304 18.6 Neurotoxicity of Chemical Mixtures 304 18.6.1 Pesticide Mixtures 305 18.6.2 Organic Solvent Mixtures 308 18.7 Case Studies: Neurotoxic Chemical Mixtures 312 18.8 Summary 319 References 319 19 Developmental Neurotoxicology 327 19.1 Introduction 327 19.2 Mixture Neurotoxicity 327 19.3 Summary 331 References 332 20 Autism: Effect of Maternal Exposure to Neurotoxic Chemicals 335 20.1 Autism 335 20.2 Chemical Mixtures 337 CONTENTS xv 20.5 Summary 344 References 345 21 Attention Deficit Hyperactivity Disorder (ADHD) 351 21.1 Introduction 351 21.2 Prevalence of ADHD 351 21.3 Environmental Factors in ADHD 351 21.4 Chemical Mixtures as Triggers for ADHD 354 21.5 Summary 357 References 357 22 Endocrine System 361 22.1 Introduction 361 22.2 Endocrine Disrupting Chemicals 361 22.3 Diabetes and Endocrine Disrupting Chemicals 365 22.4 Breast Cancer and Endocrine Disruptors 367 22.5 Mixture Effects on Endocrine Function—Case Studies 370 22.6 Tobacco Smoke 373 22.7 Summary 374 References 374 23 Toxic Infertility 381 23.1 Introduction 381 23.2 Xenobiotics and Female Infertility 383 23.3 Smoking and Female Fertility 384 23.4 Chemically Induced Spontaneous Abortion 385 23.4.1 Shoe Industry Employees 385 23.4.2 Semiconductor Manufacturing 385 23.4.3 Toluene Mixtures 386 23.4.4 Agricultural Mixtures 386 23.4.5 Anesthetic Gases 387 23.4.6 Laboratory Workers 387 23.4.7 Environmental Tobacco Smoke Exposure 387 23.4.8 Marijuana Use 387 23.4.9 Formulated Pesticide Use 388 23.4.10 Water Disinfection Byproducts 388 23.5 Xenobiotics and Male Infertility 389 23.5.1 Genital Malformations 390 23.5.2 Impaired Spermatogenesis 390 23.5.3 Decreasing Semen Quality 390 23.5.4 Testicular Cancer 391 xvi CONTENTS 23.6 Chemicals Affecting Male Infertility 391 23.7 Effects of Chemical Mixtures on Male Fertility 391 23.7.1 Organic Solvent Mixtures 391 23.7.2 Pesticide Mixture 393 23.7.3 Mild Steel Welding Fumes 393 23.7.4 Tobacco Smoke 393 23.7.5 PCBs and Phthalate Interaction 394 23.7.6 Diesel Exhausts 394 23.7.7 Acrylates 394 23.8 Testicular Dysgenesis Syndrome 395 23.9 Summary 395 References 396 24 Teratogens 401 24.1 Introduction 401 24.2 Single Chemical Teratogens 402 24.3 Paternally Transmitted Teratogenic Effects 402 24.4 Transgenerational Teratogenic Effects 405 24.5 Teratogenic Mixtures 405 24.5.1. Organic Solvents 405 24.5.2 Wood Preservative Chemicals 408 24.5.3 Pesticides 408 24.5.4 Chemical–Radiation Mixture 409 24.5.5 Ethanol Mixtures 409 24.5.6 Air Pollution 410 24.5.7 Paint 410 24.5.8 Hazardous Waste Site Proximity 411 24.5.9 Tobacco Smoke 412 24.6 Summary 412 References 412 25 Immune System 417 25.1 Introduction 417 25.2 Immunosuppressants 418 25.3 Immunostimulants 420 25.4 Autoimmune Toxins 420 25.5 Immunotoxic Mixtures 421 25.5.1 Benzene and Toluene 421 25.5.2 Pesticides and Fertilizers 422 25.5.3 Propoxur and Heavy Metals 422 25.5.4 Environmental Tobacco Smoke Sensitization 422 CONTENTS xvii 25.5.5 Tobacco Smoke and Organic Solvents 422 25.5.6 Tobacco Smoke and House Dust Mites 423 25.5.7 Air Pollution 423 25.6 Multiple Chemical Sensitivity (MCS) and Chronic Fatigue Syndrome (CFS) 424 25.7 Summary 424 References 424 26 Chemical Sensitivity: Multiple Chemical Sensitivity (MCS), Chronic Fatigue Syndrome (CFS), Fibromyalgia (FM), and Gulf War Syndrome (GWS) 429 26.1 Introduction 429 26.2 Multiple Chemical Sensitivity (MCS) 429 26.3 MCS Symptoms 432 26.4 Causative MCS Chemicals 434 26.5 MCS Mechanistic Considerations 435 26.6 MCS Mixture Effect 440 26.7 Chronic Fatigue Syndrome (CFS) 442 26.8 CFS and Chemical Exposure 443 26.9 Fibromyalgia (FM) 445 26.10 Gulf War Syndrome (GWS) 446 26.11 Comorbidity of MCS, CFS, and FM 447 26.12 Chemical Sensitivity Trigger Hypothesis 447 26.13 Summary 452 References 453 27 Skin 459 27.1 Introduction 459 27.2 Skin Permeability 459 27.3 Allergic Contact Dermatitis (ACD) 465 27.4 Dermally Induced Respiratory Hypersensitivity 467 27.5 Chemical Burns 467 27.6 Mixtures 468 27.7 Summary 469 References 469 28 Musculoskeletal System 473 28.1 Introduction 473 28.2 Rheumatoid Arthritis (RA) 473 28.3 Scleroderma (Systemic Sclerosis) 473 28.4 Systemic Lupus Erythematosus (SLE) 476 xviii CONTENTS 28.5 Osteoporosis and Osteomalacia 476 28.6 Mixtures 477 28.7 Summary 478 References 479 29 Cardiovascular System 481 29.1 Introduction 481 29.2 Leachates 484 29.3 Air Pollution 485 29.4 Tobacco 488 29.5 Cancer 490 29.6 Summary 490 References 490 30 Liver 495 30.1 Introduction 495 30.2 Single Chemical Hepatotoxins 495 30.3 Hepatotoxic Mixtures—Animal Studies 498 30.4 Human Case Studies 501 30.5 Hepatic Cancer 504 30.6 Summary 504 References 505 31 Kidneys 507 31.1 Introduction 507 31.2 Single Chemical Renal Toxins 507 31.3 Nephrotoxic Chemical Mixtures 510 31.4 Summary 511 References 512 32 Cancer 515 32.1 Introduction 515 32.2 Cancer Incidence Rates 515 32.3 Chemical Carcinogens 516 32.4 Mechanisms of Carcinogenesis 522 32.5 Single Chemical Carcinogens 526 32.5.1 Cadmium 526 32.5.2 Benzene 526 32.5.3 Arsenic 527 32.5.4 1,3-Butadiene 527 32.5.5 Other Organic Solvents and Intermediates 527 CONTENTS xix 32.5.6 Benzo[a]pyrene 527 32.5.7 Electromagnetic Radiation 527 32.6 Occupational Exposures Known to be Carcinogenic 528 32.7 Mixture Exposures Known to be Carcinogenic—Many Component Mixtures 529 32.7.1 Metalworking fluids 529 32.7.2 Lung Cancers Not Related to Smoking 530 32.7.3 PAH Exposure and Cancer 530 32.7.4 Painters 531 32.7.5 Pressmen 532 32.7.6 Rubber Industry Workers 532 32.7.7 Oil Refinery and Petrochemical Workers 532 32.7.8 Hazardous Waste Sites and Water Pollution 533 32.7.9 Asphalt Fumes 534 32.7.10 Combined Action of Microwave Fields and Environmental Pollution 535 32.7.11 Leather Tanning Industry 535 32.7.12 Pesticides 536 32.7.13 Hematolymphopoietic Malignancies (HLPMs) 539 32.8 Mixture Exposures Known to Be Carcinogenic—Two Component Mixtures 541 32.9 Tobacco and Cancer 542 32.9.1 Tobacco and Asbestos 543 32.9.2 Tobacco and Arsenic 543 32.9.3 Tobacco and Alcohol 543 32.9.4 Tobacco and Radon 544 32.10 Summary and Outlook 544 References 544 33 Childhood Cancer 553 33.1 Introduction 553 33.2 Prevalent Childhood Cancers 553 33.3 Childhood Cancer Studies 554 33.3.1 Tobacco Smoke 554 33.3.2 Solvents 554 33.4 Summary 556 References 556 34 Cancer Clusters 559 34.1 Introduction 559 34.2 Mixture-Induced Cancer Clusters 559 xx CONTENTS 34.2.1 Cluster 1: Childhood Leukemia 560 34.2.2 Cluster 2: Prostate Cancer 560 34.2.3 Clusters 3–6: Testicular Cancer 560 34.2.4 Cluster 7: Brain Cancer Cluster—Electronics Workers 561 34.2.5 Cluster 8: Brain Cancer Cluster—Petrochemical Workers 562 34.2.6 Cluster 9: Brain Cancers in Offspring of Electronics Workers 562 34.2.7 Cluster 10: Kidney Cancer Cluster 563 34.2.8 Cluster 11: Colorectal Cancer Cluster 563 34.2.9 Cluster 12: Multiple Cancer Cluster 564 34.2.10 Cluster 13: Lung Cancer Cluster 564 34.2.11 Cluster 14: Childhood Leukemia 565 34.2.12 Cluster 15: Multiple Cancer Clusters 566 34.2.13 Cluster 16: Toxic Waste Disposal Site Related Clusters 567 34.3 Summary 568 References 568 Part 4 Regulatory Requirements and Conclusions 571 35 Regulatory Requirements 573 35.1 Introduction 573 35.2 Warning Requirements 573 35.3 Warning Deficiencies 574 35.4 Warnings for Multiple Exposures 575 35.5 Warnings for Mixtures 576 35.6 Odor 576 35.7 Warning Recommendations 579 35.8 Summary 580 References 581 36 Conclusions and Recommendations 583 36.1 Introduction 583 36.2 Conclusions 583 36.3 Recommendations 586 36.4 The Future 587 References 588 Abbreviations 589 Index 593