Front Cover 1
Handbook of Toxicology of Chemical Warfare Agents 4
Copyright Page 5
Dedication 6
Contents 8
Contributors List 12
I. Introduction, Historical Perspective, and Epidemiology 16
1 Introduction 18
2 Historical Perspective of Chemical Warfare Agents 22
Introduction 22
The First Sustained Use of Chemicals as Agents of War 23
Initial Countermeasures 25
Events After World War I 25
World War II 26
Post–World War II 27
Incapacitants and Toxins 28
Recent Experience 28
Terrorist Use 29
Concluding Remarks and Future Research 29
References 30
3 Global Impact of Chemical Warfare Agents Used Before and After 1945 32
Introduction 32
Background 32
Military use of CWs 33
The Period Between World War I and World War II 33
World War II 35
The Period after World War II and the Cold War 35
Iraq–Iran and Afghanistan War 36
Vietnam War 36
Development of VX Agent 36
Persian Gulf War 37
Syria 37
Unintentional Use of Toxic Chemicals 38
Terrorist Use of CWs 38
Negotiations 38
Concluding Remarks and Future Direction 39
Acknowledgment 40
References 40
4 The Tokyo Subway Sarin Attack: Acute and Delayed Health Effects in Survivors 42
Introduction 42
Sarin Toxicity and Mechanism of Onset 42
Overview of the Tokyo Subway Sarin Attack 43
Emergency Treatment of Sarin Toxicity 44
Acute and Chronic Symptoms of Sarin Toxicity 46
Long-Lasting Indefinite Complaints of Sarin-Exposed Victims 47
Laboratory Findings in Sarin Toxicity 48
Concluding Remarks and Future Directions 48
Acknowledgments 49
References 49
5 Early and Delayed Effects of Sulfur Mustard in Iranian Veterans After the Iraq–Iran Conflict 52
Introduction 52
Brief Chemistry 52
Summarized Historical Uses 52
Types and Routes of Exposure 52
Human Toxicity 53
Main Mechanisms of Toxicity 53
Target Organs and Acute Clinical Features 53
Hematoimmunological Complications 55
Delayed Clinical Complications 55
Respiratory Tract 56
Chronic Bronchitis 56
Asthma 57
Bronchiectasis 57
Large Airway Narrowing 57
Pulmonary Fibrosis 57
Peripheral Neuromuscular Complications 57
Dermal Delayed Effects 58
Ophthalmologic Complications 58
Psychiatric Complications 58
Carcinogenicity 59
Reproductive 59
Cardiovascular Complications 59
Recent Advances in SM Poisoning and its Complications 59
Concluding Remarks and Future Directions 60
References 60
6 Epidemiology of Chemical Warfare Agents 62
Introduction 62
Pre-World War II 62
World War II 62
Post-World War II 63
Iran–Iraq War 64
1991 Gulf War 65
Terrorism 67
Concluding Remarks and Future Directions 68
References 68
7 Chemical Weapons of Mass Destruction and Terrorism: A Threat Analysis 70
Introduction 70
CWs for Terrorist Actions 70
“Classical” Chemical Warfare Agents: Vesicants and Nerve Agents 70
Incapacitating Agents 71
Riot Control Agents 72
Toxic Industrial Chemicals 72
Toxins 72
Extortion Activities with CWs 72
State Terrorism 73
Nationalist and Separatist Terrorist Groups 73
Left-Wing Terrorist Groups 74
Right-Wing Terrorist Groups and Lone Wolves 74
Apocalyptic Cults: Aum Shinrikyo 75
Jihadist Terrorism: Al Qaeda 75
Al Qaeda’s WMD Intentions 75
Al Qaeda’s CWs Capabilities 76
Al Qaeda Plots with CWs 77
Nerve Agents 77
Cyanides 78
Ricin 78
Toxic Industrial Chemicals 79
Concluding Remarks and Future Directions 79
References 79
II. Agents that can be Used as Weapons of Mass Destruction 82
8 Mustards and Vesicants 84
Introduction 84
Sulfur Mustards 84
Nitrogen Mustards 85
Lewisite 86
History and Background 87
Sulfur Mustards 87
Nitrogen Mustards 87
Lewisite 88
Toxicokinetics 88
Sulfur Mustards 88
Nitrogen Mustards 89
Lewisite 89
Mechanism of Action 89
Sulfur Mustards 89
Nitrogen Mustards 90
Lewisite 90
Toxicity 90
Sulfur Mustard 90
Nitrogen Mustards 92
Lewisite 93
Risk Assessment 94
Sulfur Mustards 94
Noncancer 94
Cancer 95
Nitrogen Mustards 96
Noncancer 96
Cancer 96
Lewisite 96
Noncancer 96
Cancer 96
Treatment 96
Sulfur Mustard 96
Nitrogen Mustards 97
Lewisite 97
Concluding Remarks and Future Directions 97
References 98
9 Organophosphate Nerve Agents 102
Introduction 102
Background 103
Development of Organophosphate Formulations as CW Agents 103
Physical and Chemical Properties of Nerve Agents 103
Mechanism of Action 105
Direct Nervous System Effects 105
Binding with Blood Cholinesterases 105
Binding with Other Enzymes 107
Toxicity 107
Effects 107
Minimal Potential for Delayed Neuropathy 107
Evaluation of Other Potential Effects 108
Inhalation/Ocular Toxicity in Human Subjects 108
Agent GB 108
Agents VX and Vx 109
Inhalation/Ocular Toxicity in Laboratory Species 109
G-Series Agents 109
Lethal Levels 109
Sublethal Levels 111
Agent VX 113
Lethal Levels 113
Sublethal Level 114
Risk Assessment 114
Acute Exposure Guideline Levels 114
Application of AEGL Values 116
Estimated Oral Reference Doses 116
Treatment 116
Critical Role of Decontamination 116
Signs and Symptoms Guiding Medical Management 117
Nerve Agent Antidotes 117
Ongoing Antidote Development 118
Pretreatment When Exposure Is Likely 119
Concluding Remarks and Future Directions 119
Acknowledgments 119
References 120
10 Russian VX 126
Introduction and Background 126
Monitoring of RVX 127
Ambient Monitoring and Environmental Persistence of RVX 127
Biomonitoring and Toxicokinetics of RVX 132
GC-MS and HPLC-MS Analyses of RVX Metabolites 132
MS/MS Analysis of Human Albumin 133
Mechanisms of Action and Principles of Therapy 135
Acute Intoxication with RVX 136
Delayed Effects: Chronic and Subchronic Intoxication with RVX 136
Delayed Effects: Embryo- and Gonadotoxicity, Mutagenesis, and Carcinogenesis 140
Principles of Therapy 140
Toxicometry and Hygienic Regulations 141
Concluding Remarks and Future Directions 141
References 143
11 Riot Control Agents 146
Introduction 146
History 146
Background 148
The Agents and Their Physicochemical Properties 148
Chloroacetophenone (CN) 148
Ortho-Chlorobenzylidene Malononitrile (CS) 149
Dibenz(b,f)-1:4-Oxazepine (CR) 150
Diphenylaminechlorarsine (DM) 150
Oleoresin Capsicum 151
Pelargonic Acid Vanillylamide 151
Mechanism of Action 152
CS, CN, and CR 152
Capsaicinoids 153
Toxicokinetics 153
Uptake, Distribution, and Metabolism of CS 153
Uptake, Distribution, and Metabolism of CR 153
Uptake, Distribution, and Metabolism of CN 153
Uptake, Distribution, and Metabolism of Capsaicins 154
Toxicity 154
Ophthalmological Effects 155
CN and CS 155
CR 156
Capsaicin 156
Nasal/Pharyngeal Toxicity 157
Cardiovascular Toxicity 157
Respiratory Toxicity 157
CN and CS Toxicity in Animals 158
CR 158
Capsaicin 158
Neurologic Toxicity 158
Gastrointestinal Toxicity 159
Dermatological Toxicity 159
Other Toxicity 160
Lethality 160
Risk Assessment 161
Identification of Intended and Unintended Effects 161
Dose Response 161
Exposure Assessment 161
Characterization of the Risk and Risk Management 162
Treatment 162
Eyes 162
Skin 162
Respiratory 162
Concluding Remarks and Future Direction 163
References 163
12 Psychotomimetic Agent BZ (3-Quinuclidinyl Benzilate) 166
Introduction 166
Background 167
Toxicokinetics and Mechanism of Action 167
Toxicity 168
Symptoms 168
Risk Assessment 169
Treatment 170
Analytical Methods 171
Concluding Remarks and Future direction 172
References 172
13 Neurological Effects and Mechanisms of Blast Overpressure Injury 174
Introduction 174
Blast Waves and Injury Physics 175
Defining and Diagnosing bTBI 175
Experimental Animal Models of bTBI 176
Neurological Effects 177
Injury and Recovery Mechanisms 178
Body Fluid–Based Biomarkers of Injury 179
Concluding Remarks and Future Directions 180
References 180
14 Thallium 182
Introduction 182
Background 182
Toxicokinetics 183
Mechanism of Action 183
Toxicity 183
Risk Assessment 183
Treatment 184
Concluding Remarks and Future directions 184
References 184
15 Arsenicals: Toxicity, Their Use as Chemical Warfare Agents, and Possible Remedial Measures 186
Introduction 186
Background 186
Arsine 187
Synthesis of Arsine 187
Sources of Exposure 188
Human Arsine Exposure 188
Metabolism of Arsine 188
Animal Studies 188
Human Studies 188
Mechanism of Toxicity 188
Effects on Humans 189
Acute Arsine Poisoning 189
Physical Signs 189
Immediate Effects 189
Late Effects 190
Long-Term Exposure 190
Diagnostic Tests 190
Laboratory Studies 190
Complications 190
Organic Arsenicals 190
Background 190
Mechanism of Toxicity 191
Symptoms 191
Methyldichloroarsine 191
Structure of MD 191
Pathology 191
Diphenylchloroarsine 192
Structure 192
Effects of DA 192
Ethyldichloroarsine 192
Structure 192
Effects of ED 192
Lewisite 193
History and Background Information 193
Toxicity and Mechanism of Action 193
Toxicokinetics 193
Clinical and Pathological Findings 193
Skin 193
Eye 193
Respiratory System 193
Nervous System 193
Cardiovascular System 194
Other Systems 194
Inorganic Arsenic 194
Sources and Uses 194
Uses 194
Exposure 194
Absorption, Distribution, and Excretion 194
Biochemical and Toxic Effects 195
Hematopoietic 195
Skin (Dermal) 195
Hepatic 195
Gastrointestinal 195
Respiratory 195
Cardiovascular 196
Reproductive and Developmental 196
Neurological 196
Diabetes Mellitus 196
Mechanisms of Toxicity 196
Oxidative Stress 196
Diagnosis 197
Clinical Features 197
Other Biomarkers 197
Treatment 197
Chelating Agents and Chelation Therapy 198
2,3-Dimercaprol (Dimercaprol British Anti-Lewisite, BAL) 198
Drawbacks 198
Meso 2,3-Dimercaptosuccinic Acid 199
Drawbacks 199
Sodium 2,3-Dimercaptopropane-1-Sulfonate 199
Drawbacks 199
Monoesters of DMSA 199
Monoisoamyl DMSA 199
Drawbacks 200
Role of Antioxidants 200
Combination Treatment 201
Concluding Remarks and Future Directions 202
References 203
16 Fluoroacetate 208
Introduction 208
Background 208
Toxicokinetics 209
Detoxication 209
Analytical Procedure 209
Distribution in Tissues and Elimination 210
Mechanism of Action 210
Molecular Mechanism of Aconitase Inhibition 210
Physiological and Biochemical Effects of FA 211
Effects of FA and FC on Mitochondria and Other Intracellular Organelles 211
Effects of FA on Isolated Cells 212
Biochemical Parameters Under Intoxication with FA 213
Effects of FA on the Cells of Nervous System: Interaction of Glia and Neurons 216
Physiology of Blood Vessels Under Intoxication with FA 217
Body Temperature of Rats and Rabbits After Intoxication with FA 217
Electrophysiological Studies of FA Intoxication 217
Toxicity and Risk Assessment 220
Treatment 222
Concluding Remarks and Future Directions 224
References 225
17 Strychnine 230
Introduction 230
Background 230
Chemistry and Physico-Chemical Properties 230
History 230
Therapeutic Purpose 231
Pharmacokinetics and Toxicokinetics 231
Absorptin, Distribution, Metabolism, and Excretion 231
Toxicokinetics 232
Clinical Symptomatology 232
Mechanism of Action 232
Toxicity 233
Animal Toxicity 233
Human Toxicity 234
Diagnosis 234
Risk Assessment 234
Human Health Hazard 234
Safety Data 235
Treatment 235
Concluding Remarks and Future Directions 235
References 236
18 Superwarfarins 238
Introduction 238
Background 238
AAPCC Data on Superwarfarins 240
Classification of Superwarfarins 240
4-Hydroxycoumarins 240
Bromadiolone 240
Brodifacoum 241
Coumatetralyl 241
Coumafuryl 241
Difenacoum 242
Warfarin 242
Indanediones 242
Chlorophacinone 242
Diphacinone 242
Toxicokinetics 243
Absorption, Metabolism, and Excretion in Laboratory Animals and Humans 243
Mechanism of Action 243
Toxicity 243
Clinical Effects: Signs and Symptoms 243
Animal Toxicology 243
Pediatric Exposures 244
Adult Exposures 244
Household Pets and Farm Animal Exposures 244
Nontarget Wildlife Exposures 244
Laboratory/Monitoring and General Recommendations 244
Analytical Methods 245
General Treatment Recommendations 247
Referral to Healthcare Facilities 247
Home Observation Criteria 247
Treatment at Healthcare Facilities 247
Emesis 247
Activated Charcoal 248
Gastric Lavage 248
Laboratory Monitoring 248
Concluding Remarks and Future Directions 248
References 249
19 PCBs, Dioxins and Furans: Human Exposure and Health Effects 254
Introduction 254
Historical Background 254
Human Exposure to PCBs, PCDDs, and PCDFs 256
Physico-Chemical Properties and Global Distribution 257
Analytical Methods 258
Mechanism of Action and Toxicity 258
Concluding Remarks and Future Directions 261
References 261
20 Polycyclic Aromatic Hydrocarbons: Implications for Developmental, Molecular, and Behavioral Neurotoxicity 264
Introduction 264
Background 264
Epidemiological Evidence for the Negative Effects of PAHs on Pregnant Women 264
Conclusions from Prospective Epidemiology Cohort Studies 265
Effects of Maternal Stress 265
PAH-DNA Adducts 267
Refinement of Our Susceptibility-Exposure Paradigm to Access the Effects of In Utero Exposure to PAH Aerosols on Neurodevel ... 268
Refinement of our Susceptibility-Exposure Paradigm to Access the Effects of In Utero Exposure to PAH Aerosols on Behavioral ... 268
PAH Experimental Model Systems 269
Toxicological Observations from Modeling B(a)P Aerosols 269
In Situ Generation of “Oxidative Metabolites” in Neocortical Tissue from In Utero Exposure to B(a)P Aerosol 269
Temporal Modulation of NMDA-Mediated Developmental Processes as a Result of In Utero Exposure to B(a)P Aerosol 270
Rescue of Spatial Discrimination Deficit Phenotypes in Brain-Cpr-Null Offspring Subsequent to In Utero Exposure to B(a)P Ae ... 272
Implications 273
Concluding Remarks and Future Directions 279
References 279
21 Carbon Monoxide: From Public Health Risk to Painless Killer 282
Introduction 282
Historical Background 283
Epidemiological Considerations 284
Toxicokinetics and Toxicodynamics 284
Sources of CO 284
External Sources of CO 284
Endogenous Sources of CO 285
Physicochemical Properties of CO 286
Methods for CO Measurement 286
Measurement of Blood CO 286
Ambient Air CO 287
Home Detectors 287
CO in Expired Breath 287
Absorption, Distribution, and Elimination of CO 287
Mechanism of Toxicity 288
Toxicity of Carbon Monoxide 290
Acute Toxicity 290
Delayed Toxicity 292
Cardiovascular Toxicity 292
Maternal, Fetal, and Infant Toxicity of CO 292
Tolerance to CO Toxicity 293
Physiological Roles of Carbon Monoxide 293
CO as a Putative Neurotransmitter 294
Other Physiologic Effects of CO 294
Treatment of Carbon Monoxide Overdose 295
Oxygen 295
Other Therapeutic Measures 295
Allopurinol and N-Acetylcysteine 296
Insulin 296
Other Measures 296
Concluding Remarks and Future Directions 296
Acknowledgments 296
References 296
22 Methyl Isocyanate: The Bhopal Gas 302
Introduction 302
The Making of a Disaster 302
Toxicokinetics of Isocyanates 303
Chemistry of Isocyanates 303
Synthesis of MIC 304
Physicochemical Reactions with MIC 304
Quantification of MIC 305
Mechanism of Death Following Exposure to MIC 305
The Cyanide Controversy 305
Toxicity of Isocyanates 306
Toxicity of MIC 306
Toxicity of MIC in Animal Models 306
Mortality 306
Pulmonary Toxicity 307
Ocular Toxicity 307
Reproductive Toxicity 307
Immunotoxicity, Genotoxicity, and Carcinogenic Effects 307
Other Toxic Effects 307
Toxicity in Humans 308
Acute Toxicity 308
Nonlethal Effects 308
Fatal Effects 308
Subacute and Chronic Toxicity 308
Pulmonary Complications 308
Ocular Toxicity 309
Reproductive Toxicity 309
Genotoxicity 309
Carcinogenicity 309
Immunotoxicity 309
Neurotoxicity and Psychological Effects 309
Other Toxic Effects 310
Treatment 310
Toxic Potential of MIC Beyond the Bhopal Disaster 311
Benzyl Chlorines and Other Chemicals at Bhopal 311
Concluding Remarks and Future Directions 312
Acknowledgments 312
References 312
23 Cyanide Toxicity and its Treatment 316
Introduction 316
Sources of Exposure 317
Fire Smoke 317
Industrial Exposure 317
Drugs 318
Dietary 318
Other Sources 318
Toxic Levels of Cyanide 318
Detection and Estimation of Cyanide 319
Toxicokinetics of Cyanide 320
Absorption 320
Distribution 320
Elimination 320
Mechanism of Action 321
Diagnosis and Clinical Features of Cyanide Poisoning 322
Treatment of Cyanide Poisoning 323
Supportive Therapy 323
Specific Antidotal Therapy 323
Methemoglobin Inducers 324
Amyl Nitrite 324
Sodium Nitrite 324
4-Dimethylaminophenol 324
Sulfur Donors 324
Cobalt Compounds 324
Dicobalt Edetate (Kelocyanor) 325
Hydroxocobalamin (Cyanokit) 325
Investigational Drugs 325
Concluding Remarks and Future Directions 326
Acknowledgment 326
References 326
24 Chlorine 330
Introduction 330
History of Use 330
Absorption, Distribution, Metabolism, and Excretion 331
Mechanism of Toxicity 331
Toxicity 332
Human Studies 332
Laboratory Animal Studies 332
Risk Assessment 336
Treatment 338
Concluding Remarks and Future Directions 339
References 339
25 Phosgene 342
Introduction 342
Background 342
Toxicokinetics 343
Mechanism of Action 343
Toxicity 344
Human 344
Noncancer 344
Cancer 344
Animal 344
Noncancer 344
Animal Cancer 345
Risk Assessment 347
Treatment 347
Concluding Remarks and Future Directions 347
References 349
26 Other Toxic Chemicals as Potential Chemical Warfare Agents 352
Introduction 352
General 352
Chemical Weapons Convention: Article II, Definitions and Criteria 352
Specific Agents 353
Carbamates 353
Dioxin 354
Bicyclic Phosphates 354
Perfluoroisobutene 354
Organophosphates 354
Toxins 355
Aziridines 355
Tremorine 356
Imino-ß,ß-Dipropionitrile 356
Bioregulators 356
Angiotensins 356
Bombesin 356
Bradykinin 356
Endorphins 356
Endothelins 357
Enkephalins 357
Histamine Releasing Factor 357
Neuropeptide Y 357
Neurotensin 357
Oxytocin 357
Somatostatin 357
Substance P 357
Vasopressin 357
Thyroid-Stimulating Hormone 357
Nonlethal Weapons 358
Genetic and Ethnic Weapons 358
Concluding Remarks and Future Directions 359
Acknowledgments 359
References 359
27 Ricin 362
Introduction 362
History of Biological Weapons 363
The Weaponization of Biological Agents 364
The Family of Ribosome-Inactivating Proteins 365
The Ricin Toxin Structure and Biosynthesis 367
The Cellular Internalization of Ricin 368
N-glycosidase Activity of Ricin 369
Signs and Symptoms of Ricin Exposure 370
Field-Forward Biological Agent Detection 371
Immunoassays 371
DNA-Based Assays: The PCR 372
Concluding Remarks and Future Directions 373
References 374
28 Botulinum Toxin 376
Introduction 376
Background 377
Toxin Structure and Molecular Function 377
Background 377
Function of Heavy and Light Chains 377
Accessory Proteins of the Progenitor Toxin Complex 378
Overview of BoNT Action 378
Clinical Forms of Botulism in Humans and Animals 378
Infectious Forms of Botulism 379
Infant Botulism 379
Wound Botulism 379
Child or Adult Botulism from Intestinal Colonization 379
Noninfectious Forms of Botulism 379
Foodborne Botulism 379
Inhalational 380
Inadvertent Systemic Botulism 380
Human Intoxication 380
Epidemiology 381
Foodborne Botulism 381
Pathogenesis 383
Overview of Pathogenesis 383
Toxin Stability 383
Biological Stability of the Toxins in the Gastrointestinal Tract 383
Oral Intoxication: Toxin Absorption from the Gastrointestinal Tract 385
Role of Progenitor Toxin Accessory Proteins 385
Role of Enterocytes 386
Respiratory Intoxication 386
Toxin Absorption from Respiratory Tract 386
Toxin Binding and Uptake into Target Tissues 387
Toxicokinetics 387
Foodborne Toxicity 387
Toxin Persistence in Circulation and Transit to Target Tissues 387
Inhalation Toxicity 388
Toxin Persistence in Circulation and Transit to Target Tissues 388
Mechanism of Action 390
Heavy Chain 390
Light Chain 391
Toxicity 392
Lethality 392
Oral Toxicity 393
Inhalation Toxicity 393
Clinical Toxicity 394
Foodborne Botulism 394
Infant Botulism 395
Risk Assessment 395
Treatment 395
Antitoxin 395
Treatment for Infant Botulism 396
Vaccines 396
Concluding Remarks and Future Directions 396
Development of Animal Model Test Systems 397
Inadequacies of Current Animal Model Test Systems 397
Advantages of the Mouse Hemidiaphragm Assay 397
References 398
29 Anthrax 402
Introduction 402
History 402
Modern History: Weaponizing Anthrax and Terrorism 403
Epidemiology 404
Persistence 404
Infection 404
Dissemination 404
Forms of Anthrax Disease 404
Pathogenesis 405
Overview 405
Uptake of Spores 405
Uptake via Lungs 406
Uptake via Skin 406
Uptake via Gastrointestinal Route 407
Spore Function 407
Time Course of Spore Germination 408
Spore Germination 408
Vegetative Anthrax and its Capsule 409
Systemic Infection and Septicemia 409
Anthrax Infection Cycle 410
Release of Soluble Factors 410
Toxicokinetics 410
Inhalational Anthrax 410
Cutaneous Anthrax 411
Gastrointestinal Anthrax 411
Mechanism of Toxicity 412
Protective Antigen 412
Structure and Activity: Edema factor (EF) 413
Structure and Activity: Lethal Factor (LF) 413
Mechanism of Toxicity: Edema Toxin (ET) 414
Mechanism of Toxicity: Lethal Toxin (LT) 415
Interactions Between LT and ET 416
Toxicity 416
Cutaneous Anthrax 416
Inhalational Anthrax 417
Gastrointestinal and Oropharyngeal Anthrax 417
Meningitis 417
Detection and Diagnosis 417
Detection 417
Diagnostics 418
Microbiological Tests 418
Molecular Tests 418
Histopathology 418
Radiology 419
Risk Assessment 419
Treatment 420
Overview 420
Inhalational, Oral, and Gastrointestinal Anthrax 420
Cutaneous Anthrax 420
Bacteremia 420
Anthrax Meningitis 421
Vaccines 422
Concluding Remarks and Future Directions 422
References 423
30 Onchidal and Fasciculins 426
Introduction 426
Background 427
Onchidal 427
Fasciculin 428
Mechanism of Action and Biological Effects 429
Onchidal 429
Fasciculin 430
Experimental and Human Toxicity 431
COMPUTATIONAL TOXICOLOGY Assessment 432
Treatment 433
Concluding Remarks and Future Directions 433
Acknowledgments 434
Disclosures 434
References 434
31 Cyanobacterial (Blue-Green Algae) Toxins 436
Introduction 436
Hepatotoxins 437
Microcystins and Nodularins 437
Introduction 437
Chemistry 437
Toxic Effects 437
Mechanism of Action 438
Chemical Warfare Potential 438
Cylindrospermopsin 438
Introduction 438
Chemistry 438
Toxic Effects 439
Mechanism of Action 439
Chemical Warfare Potential 439
Neurotoxins 439
Anatoxin-a 439
Introduction 439
Chemistry 439
Toxic Effects 440
Mechanism of Action 440
Chemical Warfare Potential 440
Anatoxin-a(s) 440
Introduction 440
Chemistry 440
Toxic Effects 441
Mechanism of Action 441
Chemical Warfare Potential 441
Saxitoxins 441
Introduction 441
Chemistry 441
Toxic Effects 441
Mechanism of Action 441
Chemical Warfare Potential 441
Concluding Remarks and Future Directions 442
References 442
32 Radiation and Health Effects 446
Introduction 446
Historical Perspective 446
Basic Radiation Concepts 447
Alpha and Beta Particles 447
Gamma Rays (Photon) Emission 449
X-Rays 450
Interaction of Radiation with Matter 450
Alpha Particles 450
Beta Particles 451
Gamma and X-Rays 451
Absorbed Dose 451
Total Dose and Dose Rate 451
Dose Equivalent and Cancer Risk 451
Committed Dose Equivalent 452
Negligible Individual Risk Level (Negligible Dose) 452
Consequences of Radiation-Induced DNA Damage 453
Chromosomal Aberrations and Radiation-Induced Genomic Instability 453
Radiation-Induced Bystander Effect 453
Human Exposures and Radiation Toxicity 454
Human Population and Health Risks 455
Radium Exposures 455
Atomic Bomb Survivors 456
Children Treated with X-Irradiation for Ringworm of the Scalp (Tinea Capitis) 456
Chernobyl, Three Mile Island, and Fukushima Dai-ichi Nuclear Reactor Accidents 456
Patients Irradiated with X-Rays for AS 457
Miners Exposed to Radon 457
Natural Radioactivity and Background Radiation 457
Radiation Hormesis 457
Biomonitoring and Biomarkers of radiation 458
Concluding Remarks and Future Directions 459
Acknowledgments 459
References 459
33 Depleted Uranium 462
Introduction 462
Background 462
Civilian Uses of DU 463
Military Uses of DU 463
Exposure Pathways and Body Retention of DU 464
Inhalation 464
Ingestion 465
Dermal Contact and Embedded Fragments 465
Pharmacokinetics 465
Adsorption 465
Ingestion 465
Inhalation 466
Dermal 466
Distribution 466
Metabolism and Excretion 466
Oral Exposure 467
Inhalation Exposure 467
Embedded Fragment Exposure 467
Mechanism of Action 467
Toxicity of DU Exposure 468
Nephrotoxicity 468
Carcinogenicity 468
Bones 468
Lungs 468
Reproductive/Developmental Toxicity 469
Neurotoxicity 469
Treatment 470
Concluding Remarks and Future Directions 471
Acknowledgments 471
References 471
III. Target Organ Toxicity 476
34 Chemical Warfare Agents and the Nervous System 478
Introduction 478
Overview of the Nervous System 478
Special Features of Neurons and High Energy Demand 480
Blood–Brain Barrier 480
Types of Neurotoxicity 481
Selected cwas That Affect the Nervous System 481
Organophosphorus (OP) Nerve Agents 481
Cyanides 485
Sulfur Mustard 486
3-Quinuclidinyl Benzilate 487
Concluding Remarks and Future Directions 487
References 487
35 Behavioral Toxicity of Nerve Agents 492
Introduction 492
Methods Used to Evaluate Behavioral Effects of Nerve Agents 492
Functional Observatory Battery 492
Performance on the RAM Task 494
Acoustic Startle Response and Prepulse Inhibition 494
Performance on Y-Maze 494
Performance on T-Maze 495
Performance on Morris Water Maze 495
Performance on Passive Avoidance Test 495
Long-Term Behavioral Effects of Acute High-Level Exposure to Nerve Agents 496
Chronic Behavioral Effects of Single or Repeated Low-Level Exposure to Nerve Agents 498
Concluding Remarks and Future Direction 500
References 501
36 The Respiratory Toxicity of Chemical Warfare Agents 504
Introduction 504
History of CWA Use 504
The Respiratory System 505
Pulmonary Agents 506
Arsine 506
Exposure Physiology 506
Exposure Biochemistry 507
Exposure Histopathology 507
Chlorine 507
Exposure Physiology 507
Exposure Biochemistry 508
Exposure Histopathology 508
Phosgene 509
Exposure Physiology 510
Exposure Biochemistry 510
Exposure Histology 511
Nerve Agents 511
Volatile Agents 511
Exposure Physiology 512
Exposure Biochemistry 514
Exposure Histopathology 515
Nonvolatile Agents 515
Exposure Physiology 515
Exposure Biochemistry 516
Exposure Histopathology 517
Cyanides 517
Exposure Physiology 517
Exposure Biochemistry 517
Exposure Histopathology 518
Riot Control Agents 518
2-Chlorobenzylidene Malononitrile (CS) 518
Exposure Physiology 518
Exposure Biochemistry 520
Exposure Histopathology 521
Dibenz (b,f)-1:4-oxazepine (CR) 521
Exposure Physiology 521
Exposure Biochemistry 521
Exposure Histopathology 521
10-Chloro-5,10-diphenylaminochlorarsine (DM-Adamsite) 521
Exposure Physiology 522
Exposure Biochemistry 522
Exposure Histopathology 522
Oleoresin of Capsicum (OC—Pepper Spray) 522
Exposure Physiology 522
Exposure Biochemistry 523
Exposure Histopathology 524
Chloropicrin (PS) 524
Exposure Physiology 524
Exposure Biochemistry 524
Exposure Histopathology 524
1-Chloroacetophenone (CN) 524
Exposure Physiology 524
Exposure Biochemistry 524
Exposure Histopathology 525
DA and DC 525
Vesicating Agents 525
Sulfur Mustard—bis-(2-chloroethyl) Sulfide (HD) 525
Exposure Physiology 526
Exposure Biochemistry 526
Exposure Histopathology 527
Lewisite—b-Chlorovinyldichloroarsine (Agent L) 528
Exposure Physiology 528
Exposure Biochemistry 528
Exposure Histopathology 528
Concluding Remarks and Future Directions 528
Acknowledgments 529
References 529
37 Cardiovascular System as a Target of Chemical Warfare Agents 534
Introduction 534
Background 534
Cardiac Anatomy 534
B Innervation of the Heart 535
Neuropeptides 536
Energetics of the Heart 536
Electrophysiology 536
Signatures of Cardiac Toxicity 537
The ECG as a Diagnostic Tool for Poisoning 537
Recorded Morphological Changes on the ECG 537
Long QT 537
Biochemical Markers of Tissue Injury 537
Conventional Biomarkers 537
miRNA 538
Indices of the Toxicity of Warfare Agents 538
Classes of Warfare Agents 538
Background 539
Signatures of Toxicity 539
Nerve Agents 539
Mechanism of Action 540
Electrocardiographic Signature of OPs 540
Toxic Effects of OPs on the Heart 540
Specific Warfare Agents of Concern Regarding the Heart 541
Nerve Agents 541
VX 541
Tabun (GA) 541
Sarin (GB) 542
Soman (GD) 542
Novichok 543
Antidotes for OP Nerve Agents 543
Cyanide 543
Toxicity 543
Antidotes for CN Poisoning 544
Other Terror Agents 545
Arsenic 545
Ricin 545
Therapeutics Undergoing Development 545
Concluding Remarks and Future Directions 546
References 547
38 Ocular Toxicity of Chemical Warfare Agents 550
Introduction 550
Background 551
The Structure of the Eye 551
Neuromodulation of Ocular Tissues 553
Structure and Regenerative Capacity of the Corneal Tissues 553
Vesicants 555
The Mustard Gases 555
Toxicokinetics of the Acute Ocular Mustard Injury in Human Victims 556
Evidence for a Delayed Ocular Mustard Injury in Human Victims 557
Toxicokinetics of the Acute and Late-Onset Ocular Mustard Injuries 558
Mechanistic Studies of HD Toxicity 559
Etiogenesis of the Delayed Ocular HD Injury: Current Theories 559
Lewisite 562
Toxicokinetics of Ocular Lewisite Injuries 562
Phosgene Oxime 562
Nerve Agents 563
Psychomimetic Incapacitating Agents 564
Blood Agents 564
Choking Agents 565
Riot Control Agents 565
Biological Toxins 566
Biological Neurotoxins 566
Ricin 567
Staphylococcus Enterotoxin B 568
Concluding Remarks and Future directions 568
Acknowledgments 568
References 568
39 Dermal Toxicity of Sulfur Mustard 572
Introduction 572
Background 572
Military Use 572
Wound Repair 572
Pathogenesis 573
Cytotoxicity of SM 574
Alkylation of DNA/Poly(ADP-Ribose) Polymerase Activation 574
Reactions with Glutathione/Oxidative Stress 575
Reactions with GSH/Calcium Homeostasis 575
Inflammation 575
Protease Activation 576
Apoptosis 577
Signal Transduction Pathways 578
Models of Dermal SM Exposure 578
Introduction 578
Model Systems for Screening SM 578
Decontamination 580
Treatment of Blisters 581
Therapeutics 581
Antioxidants 581
Proteolytic Inhibitors 583
Steroids, Corticosteroids, and Glucocorticoids 584
Nonsteroidal Anti-Inflammatory Drugs 584
TRPV1 Ligands 585
Cooling 585
Concluding Remarks and Future Directions 585
References 586
40 Skeletal Muscle 592
Introduction 592
Behavioral Effects 592
Cholinergic System 593
Normal Activity of AChE and its Molecular Forms 593
Inhibition of AChE and its Molecular Forms by Nerve Agents 593
Butyrylcholinesterase 595
Choline Acetyltransferase 596
Acetylcholine Receptors 596
Noncholinergic System 598
Muscle Excitotoxicity 598
Oxidative/Nitrosative Stress 599
High-Energy Phosphates Depletion and Myonecrosis 600
Muscle Activity—EMG 601
Muscle Fiber Histopathology 602
Muscle Cytotoxicity Biomarkers 605
CK and CK isoenzymes 605
LDH and LDH Isoenzymes 605
Skeletal Muscle and Tolerance Development 606
Skeletal Muscle Involvement in IMS 607
Prevention/Treatment of Myopathy 607
AChE Reactivators and ACh Receptor Blockers 607
NMDAR Antagonist 608
Anticonvulsants and Anesthetics 609
Antioxidants, Spin-trapping Agents, and Creatine 609
Concluding Remarks and Future Directions 610
Acknowledgments 610
References 610
41 Reproductive Toxicity and Endocrine Disruption of Potential Chemical Warfare Agents 614
Introduction 614
Important Definitions and Concepts 615
Chemical Warfare Agents 615
Environmental Contaminants Associated with Industrial or Agricultural Terrorism 615
Reproduction 615
Reproductive Toxicity 616
Teratogenesis 616
Mechanisms of Reproductive Toxicity and Teratogenesis 616
Reproductive Toxicants 617
Teratogens 617
Endocrine Disruption 617
Mechanisms of Endocrine Disruption 618
Endocrine-Disrupting Chemicals, Endocrine Disruptors, and Hormonally Active Agents 618
The Reproductive Toxicity of Selected Toxicants 618
The Reproductive Toxicity of Riot Control Agents 619
The Reproductive Toxicity of CWAs 620
Vesicants 620
Arsenicals 620
Chlorine Gas 620
Phosgene and Phosgene Oxime 620
Sulfur Mustard 621
Inhibitors of Protein Synthesis 621
Ricin 621
Inhibitors of Cellular Respiration (“Blood Agents”) 621
Hydrogen Cyanide and Cyanide-Related Compounds 621
Nerve Agents 621
Organophosphate Nerve Agents 621
The Reproductive Toxicity of Environmental Contaminants Resulting from Acts of Terrorism 622
Ionizing Radiation 623
Pesticides and Other Organic Contaminants 623
Adverse Effects of Pesticides and Other Organic Contaminants on Male Reproductive Function 624
Adverse Effects of Pesticides and Other Organic Contaminants on Female Reproductive Function 624
Adverse Effects of Pesticides and Other Organic Contaminants on Embryonic/Fetal Development 625
Heavy Metals 625
Adverse Effects of Heavy Metals on Male Reproductive Function 625
Adverse Effects of Heavy Metals on Female Reproductive Function 625
Adverse Effects of Heavy Metals on Embryonic/Fetal Development 626
Concluding Remarks and Future Directions 626
References 626
42 Liver Toxicity of Chemical Warfare Agents 630
Introduction 630
Structural Organization of the Liver 630
Hepatic Functional Capacity 631
Hepatic Cellular Components 631
Factors Influencing Hepatic Toxicity 632
Preferential Hepatic Uptake 632
Xenobiotic Metabolic Bioactivation 632
Phase II/Conjugation Reactions 632
Phase III Reactions 633
Pathologic Manifestations of Hepatic Injury 633
Hepatic Steatosis/Fatty Liver 633
Steatohepatitis 634
Apoptosis Versus Necrosis 634
Hepatic Pigment Accumulation 634
Hepatic Cholestasis 634
Hepatic Fibrosis/Cirrhosis 635
Cirrhosis 635
Pathomechanisms of Hepatic Injury 635
Oxidative Stress and Free Radicals with Classic Examples 635
Disruption of Calcium Homeostasis 637
Inhibition of Mitochondrial Function 637
Disruption of Cytoskeleton 638
Cholestatic Mechanisms 638
Idiosyncratic Reactions 638
Warfare Agents Affecting Liver 639
Fungal and Plant Toxins 639
Microcystins 639
Aflatoxins 639
Ricin 639
Abrin 640
Bacterial (Anthrax) 640
Concluding Remarks and Future Directions 640
References 640
43 Renal System 642
Introduction 642
Anatomy and Physiology 642
Functional Anatomy 642
Biotransformation 644
Toxic Responses of the Urinary System 645
Acute Renal Failure 645
Chronic Renal Failure 645
Patterns of Toxic Injury 646
Glomerular Injury 646
Proximal Tubular Injury 646
Distal Nephron/Renal Papillary Injury 647
Lower Urinary Tract 647
Toxic Effects of Chemical Warfare Agents 648
Vesicants 648
Nerve Agents 648
Depleted Uranium 649
Thallium 649
Ricin 649
Anthrax Toxins 650
Cyanobacterial Toxins 650
Other Agents 650
Concluding Remarks and Future Directions 651
References 651
44 The Immune System as a Target for Chemical Warfare Agents 654
Introduction 654
The Immune System 655
Innate Immune System 655
Adaptive Immune System 656
Targets of Immunotoxicity 657
Effects on Precursor Stem Cells 657
Effects on Maturation of Lymphocytes 657
Effects on the Initiation of Immune Responses 657
Induction of Inflammation and Noncognate T–B Cooperation 658
Exposition of Autoantigens and Interference with Co-Stimulatory Signals 658
Regulation of the Immune Response 658
Immunotoxicity of CWAs 659
Nerve Agents 660
Immunotoxicity of Nerve Agents 660
Blister or Vesicant Agents 662
Immunotoxicity 662
Choking Agents 664
Immunotoxicity 664
Blood Agents 666
Immunotoxicity 667
Concluding Remarks and Future Directions 667
References 668
45 Alternative Animal Toxicity Testing of Chemical Warfare Agents 672
Introduction 672
Brief History of Chemical Warfare Use 674
Top Five Chemical Warfare Agents 674
The Concept of 3Rs 677
International Cooperation on Alternative Test Methods 679
Alternatives to Animal Testing of Chemical Warfare Agents 680
Animal Efficacy Rule 683
Human on a Chip 685
New Predictive Models of Toxicity 686
Concluding Remarks and Future Directions 687
References 687
IV. Special Topics 690
46 Genomics and Proteomics in Brain Complexity in Relation to Chemically Induced PTSD 692
Introduction 692
The Effect of PTSD on Different Regions of the Brain 693
The Hypothalamic-Pituitary-Adrenal Axis 693
Hippocampus 693
Amygdala 694
Cortex 694
Understanding PTSD: Genomics and Proteomics 695
Applications of Genomic and Transcriptomics Methods 696
The Role of ncRNA and Epigenetics in PTSD 697
Toxic Chemical Exposure and Human Diseases 698
Genomic Applications: Understanding the Relationship Between PTSD and Chemical Toxicity 699
Proteomics 700
Neuroproteomics: Proteomics Applications in Neuroscience 701
Proteomics Approaches to Understanding Natural and Chemical Toxicity-Induced PTSD 701
Concluding Remarks and Future Directions 702
Acknowledgments 702
References 702
47 Clinical and Cellular Aspects of Traumatic Brain Injury 706
Introduction 706
A Variety of Mouse Models Are Used to Study TBI 706
Clinical Manifestation and Management of TBI 707
TBI Is Usually Classified Using the Glasgow Coma Scale 707
Primary Brain Injury and Secondary Insults Are Two Distinctive Phases of TBI 708
Immediate Care After TBI Shares the Same Principles as Advanced Life Support 710
Surgical Management is Often Necessary for Primary Injury 710
Targeted Therapies Are Used to Prevent Secondary Injury in the Intensive Care Unit 710
Maintenance of Adequate Cerebral Perfusion Improves Outcome after TBI 710
Other Targeted Therapies 711
TBIs Increase ICP 711
Cognitive Impairments After TBI Result from Neuronal and Synaptic Loss 712
Neuronal Loss Is an Irreversible Cause of Cognitive Impairment 712
Synaptic Loss is a Potentially Reversible Cause of Cognitive Impairment 714
Primary and Secondary Injuries Initiate Cell Death Through Distinct Pathways 715
Initial Primary Injuries Cause Necrosis 716
Later Secondary Injuries Initiate Programmed Cell Death 717
Apoptotic Markers Are Detectable Postmortem in TBI Patients and Experimental Models 717
Glutamate Dysregulation Can Lead to Cell Death Through Necrotic Swelling, Excitotoxic Calcium Elevations, or Hyperactivatio ... 717
ROS and Inflammatory Cytokines are Upregulated After TBI 719
In Neurons, Cell Death Is Also Caused by Attempted Reentry into the Cell Cycle 719
Potential Mechanisms of Subtle Synaptic Impairments in TBI 719
TBIs Reproduce Pathological Hallmarks of Alzheimer Disease 720
Alzheimer Disease Is a Dementia Associated with Aberrant Aß and Tau Signaling 720
TBI Patients Have Elevated Levels of Aß 720
Tau Is Hyperphosphorylated After TBI 721
Concluding Remarks and Future Directions 721
References 721
48 Excitotoxicity, Oxidative Stress, and Neuronal Injury 724
Introduction 724
Excitotoxicity and Oxidative Injury 725
Lipid Peroxidation and In Vivo Markers of Oxidative Damage 727
Anti-AChE-Induced Seizures, Oxidative Injury, and Neurodegeneration 728
Oxidative Damage and Dendritic Degeneration Following KA-Induced Excitotoxicity 730
Neuroinflammation and Oxidative Injury 731
Suppression of Seizure-Induced Oxidative Injury and Neurodegeneration 732
Antioxidants 732
NMDA Receptor Antagonist (Memantine) 734
Concluding Remarks and Future Directions 736
Acknowledgments 736
References 736
49 Blood–Brain Barrier Damage and Dysfunction by Chemical Toxicity 740
Introduction 740
Structure and Function of the BBB 741
In vivo and in vitro Models to Study the BBB 741
In Vivo Model 742
In Vitro Models 742
Gender Differences in the BBB 743
The BBB in Young and Adult Brains 744
Transport of Molecules Across the BBB 744
Effects of Toxic Agents on the BBB 746
Anticholinesterase Nerve Agents 746
Oxime Reactivators of AChE Inhibited by OPs and the BBB 746
NMDAR Antagonist Memantine and the BBB 747
Melatonin and the BBB 748
Drugs of Abuse-Induced BBB Damage 748
Metals 748
Bacterial Toxin-Induced BBB Damage 749
GWI and the BBB 749
Effects of Blasts on the BBB 750
Excitotoxicity, Stress and the BBB 750
Brain Barriers and CNS Diseases 751
Concluding Remarks and Future Directions 752
Acknowledgments 752
References 752
50 Neuropathologic Effects of Chemical Warfare Agents 756
Introduction 756
Background 756
Acute Effects of Symptomatic Exposure 757
Ischemic/Hypoxic Injury 757
Nerve Agent-Associated Excitotoxic Injury 757
Additional Acute Effects of Nerve Agents on Brain Tissue 758
Prolonged Effects of Symptomatic Exposure 759
Organophosphate-Induced Delayed NEUROPATHY 759
OP-Associated Muscle Weakness 761
Effects of Subsymptomatic Exposure to Nerve Agents 761
Concluding Remarks and Future Directions 762
References 762
51 The Effects of Organophosphates in the Early Stages of Human Muscle Regeneration 766
Introduction 766
Regeneration Process in Human Skeletal Muscle 767
Noncholinergic Effects of DFP in Regenerating Human Skeletal Muscle 768
The Effect of DFP on IL-6 Secretion from the Mononuclear Myoblasts and Myotubes 768
Heat Shock Proteins in Human Myoblasts and Myotubes After Treatment with DFP 769
Response of Human Myoblasts to Hypoxia 769
The Effects of DFP on the NRE in Human Myoblasts 769
Expression and Role of AChE in Human Myoblasts 770
Recovery of AChE mRNA Expression and AChE Activity After Gene Silencing of AChE and After Exposure to DFP 770
The Role of AChE in Myoblast Apoptosis 772
Concluding Remarks and Future Directions 773
Acknowledgments 773
References 773
52 Cholinesterase Inhibitors: From Molecular Mechanisms of Action to Current and Future Prospects 776
Introduction 776
Human Cholinesterases 776
Human Cholinesterases: The Common Core 776
Human Cholinesterases: Myriad Molecular Forms 778
Regulation of Cholinesterase Gene Expression 779
Cholinesterases Primarily Function as Acetylcholine-Hydrolyzing Enzymes 780
Cholinergic Hyperexcitation and Induction of AChE-R Production 780
Nonclassical Cholinesterase Functions 781
Anti-ChEs and the Cholinergic System 782
Molecular Mechanisms of Cholinesterase Inhibition 782
Short-Term Effects of Anti-ChE Exposure 783
Long-Term Effects of Anti-ChEs 784
Anti-ChEs as Therapeutic Agents 785
Detection and Prevention of Anti-ChE Toxicity 785
Detection and Use of Nanoparticles and Other Technologies 785
Recombinant Cholinesterases as Therapeutic Agents 787
Catalytic Bioscavengers 788
Selective RNA-Targeted Suppression of AChE-R Overexpression Effects 789
Antagomir-Mediated Suppression of the AChE Targeting miRNA-132 790
Concluding Remarks 790
Acknowledgments 790
References 791
V. Risks to Animals and Wildlife 794
53 Potential Agents That Can Cause Contamination of Animal Feedstuffs and Terror 796
Introduction 796
Terror Objectives 796
Agricultural Food Ecosystem and Terror 797
Upsetting the Margins Between Safe and Unsafe Practices 797
Mycotoxins and Toxigenic Fungi 797
Background 797
Applications of Biotechnology 798
Potential Use of Fungal Biocontrol Agents 798
Economic Losses from Use of Mycotoxins as Weapons 798
Use of Mycotoxin Contaminated Feedstuffs 798
Residues in Edible Tissues 798
Mycotoxicology 799
Microbial Toxins 799
Botulism Toxin 799
Background 799
Mechanism of Action 799
Potential Production and Use 799
Plant Toxins 799
Background 799
Castor Beans (Ricin) 799
Background 799
Ricin as a Weapon 800
Toxicity and Mechanism of Action 800
Analytical Methods 801
Clinical and Pathological Findings 801
Other Plant Source Type 2 RIPs 801
Rapidly Acting and Easily Available Substances 801
Cyanide 801
Mechanism of Action 801
Plant Sources—Ruminants 801
Treatment of Cyanide Poisoning 801
Insecticides 801
Persistent Organic Compounds 802
Background 802
Potential Economics of Terror Attack Using POCs 802
Human Exposures 803
Heavy Metals and Metalloids 803
Lead 803
Lead in Feedstuffs 803
Treatment of Lead Poisoning 803
Arsenic 803
Toxicology 803
Contaminated Transport Vessels 803
Concluding Remarks and Future Directions 803
References 804
54 Chemical Warfare Agents and Risks to Animal Health 806
Introduction 806
CWAs 807
Chlorine Gas 807
Clinical Signs 807
Kinetics 807
Decontamination and Treatment 807
Species Susceptibility 808
Phosgene 808
Clinical Signs 808
Kinetics 808
Decontamination and Treatment 808
Species Susceptibility 809
Mustard Gas 809
Clinical Signs 809
Kinetics 809
Decontamination and Treatment 810
Species Susceptibility 810
Lewisite 810
Clinical Signs 810
Kinetics 811
Decontamination and Treatment 811
Species Susceptibility 812
Phosgene Oxime 812
Clinical Signs 812
Kinetics 812
Decontamination and Treatment 812
Species Susceptibility 812
Cyanide and HCN 813
Clinical Signs 813
Kinetics 813
Decontamination and Treatment 813
Species Susceptibility 814
Military Nerve Agents 814
Clinical Signs 814
Kinetics 814
Decontamination and Treatment 815
Species Susceptibility 816
3-Quinuclidinyl Benzilate (bz) 816
Clinical Signs 816
Kinetics 817
Decontamination and Treatment 817
Species Susceptibility 817
RCAs (Lacrimators) 817
Clinical Signs 817
Kinetics 818
Decontamination and Treatment 818
Species Susceptibility 818
Ricin and Abrin (Toxalbumins) 818
Clinical Signs 818
Kinetics 819
Decontamination and Treatment 819
Species Susceptibility 819
Concluding Remarks and Future Directions 819
References 820
55 Threats to Wildlife by Chemical and Warfare Agents 824
Introduction 824
Background 824
Illicit and Restricted Substances 825
Background 825
Tetramethylenedisulfotetramine 825
Background 825
Mechanism of Action 825
Pathology and Detection 825
Sodium Monofluoroacetate and Sodium Fluoroacetamide 825
Background 825
Toxicology of Sodium Monofluoroacetate 825
Clinical Signs of Intoxication 826
Pathology 826
Cyanide 826
Background 826
Toxicology 826
Ricin (Castor Bean) 827
Background 827
Pathology and Toxicology 827
Pesticides 827
Background 827
Incidents of Intoxication 828
Concluding Remarks and Future Directions 828
References 828
VI. Toxicokinetics, Toxicodynamics and Physiologically-Based Pharmacokinetics 830
56 Toxicokinetic Aspects of Nerve Agents and Vesicants 832
Introduction 832
Overview of Invasion Processes of CWAs 833
Percutaneous Uptake by Contact with Skin 833
Epidermis 833
Dermis 834
Respiratory Uptake by Inhalation 834
Airways and Absorption 834
Absorption in the Upper Respiratory Tract 835
Absorption in the Middle Respiratory Tract 835
Absorption in the Alveoli 835
Nose-only Exposure Model for Controlled Respiratory Uptake in Animal Studies in Vivo 835
Gastrointestinal Uptake by Ingestion 836
Uptake by Intravenous Injection 836
Nerve Agents 837
OPCs as Nerve Agents 837
Physicochemical Properties 837
Water Solubility 837
Octanol:Water Partition Coefficient 837
Hydrolysis 838
Chirality 838
Toxicity 840
Inhibition of AChE 840
Additional Targets with Potential Clinical Relevance 841
Elemental Steps of Nerve Agent Toxicokinetics 842
Invasion 842
Distribution 842
Biotransformation and Elimination 843
Enzymatic Hydrolysis 843
Phosphotriesterases 843
Nonmammalian Enzymes 845
Nonproteinaceous Scavengers and Hydrolyzing Compounds 845
Formation of Protein Adducts 845
Carboxylesterase 846
Acetyl Monoalkylglycerol Ether Hydrolase 846
Acetylcholinesterase 847
Butyrylcholinesterase 849
Albumin 850
Keratins 850
Ubiquitin 851
Additional Proteins 851
Muscarinic Receptors 851
Excretion 851
Concentration–Time Profiles of Nerve Agents in Blood After Various Routes of Administration 851
Intravenous Uptake 852
Subcutaneous Uptake 853
Percutaneous Uptake 853
Respiratory Uptake (Nose-only Model) 853
Mathematical Simulation for Prediction of Nerve Agent Toxicokinetics 854
Bioanalytical Techniques Relevant to Toxicokinetics 854
Determination of Nerve Agents 854
Detection of Enzyme and Protein Adducts of Nerve Agents 854
Vesicants 855
Sulfur Mustard 855
Overview of Sulfur Mustard 855
Toxicity of Sulfur Mustard 855
Invasion 857
Percutaneous Absorption 857
Respiratory Absorption 858
Distribution 858
Biotransformation 859
Elimination 860
Lewisite 861
Overview of Lewisite 861
Toxicity of Lewisite 862
Invasion 862
Percutaneous Absorption 862
Respiratory Absorption 862
Distribution 863
Biotransformation 863
Elimination 863
Bioanalytical Techniques for Quantification of Vesicants 864
Determination of Vesicants and Direct Biotransformation Products 864
Detection of DNA and Protein Adducts of Vesicants 864
Concluding Remarks and Future Directions 865
References 866
57 Toxicokinetics and Toxicodynamics of DFP 872
Introduction 872
Physico-Chemical Properties and Chemical Identification of DFP 874
Chemical Structure and Analogy with Other Nerve Agents 874
Physico-Chemical Properties 874
History of DFP Synthesis and its Relationship with Development of Warfare Nerve Agents 874
Toxicokinetic and Biotransformation of DFP and Studies on DFPase 876
Absorption, Distribution, and Toxicokinetic Studies 876
Distribution after Inhalation Exposure 876
Distribution After Intravenous Administration 876
Skin Penetration 877
Physiologically Based Pharmacokinetic/Pharmacodynamic Studies 877
Biotransformation of DFP 878
Detoxication of DFP via Protein Binding 878
Role of Albumin in the Detoxication of DFP 879
Acute Toxicity of DFP and Interaction with AChE 879
DFP in Studies on Neurotoxicity and Therapy with Reactivators 881
Neuropharmacological Studies of Cholinergic System 881
Neurobehavior and Neurodevelopment 881
Therapy Against Anticholinesterase Toxicity 882
DFP in Other Biological Studies 882
Interaction of DFP with Other Esterases 882
Serine Proteases and Albumin: Role of Tyrosine Residues 882
Inhibition of Soluble PVases of Peripheral Nerve by DFP 882
DFP, OPIDN and NTE 883
Phosphorylation Site Identified by Radiolabeled DFP 883
Target Site Identified as an Esterase: NTE 883
Protection and Induction of Neuropathy: The Role of the Aging Reaction 883
Testing Delayed Neuropathy 885
Molecular and Genomic Characterization of NTE and its Role in Embryonic Development 885
Concluding Remarks and Future Directions 885
References 885
58 Physiologically Based Pharmacokinetic Modeling of Chemical Warfare Agents 890
Introduction 890
Development of PBPK Models 891
Need for Improved Measures of CWNA Exposure—The Use of PBPK Analysis of Data 892
Relationship Between Regenerated Sarin and AChE Activity and Its Use as a Dose Surrogate 893
General PBPK Model Structure 893
PBPK Simulation of Cholinesterase Inhibition and Regenerated GB 894
Concluding Remarks and Future Directions 896
References 897
59 Biotransformation of Warfare Nerve Agents 898
Introduction 898
Chemical Aspects of Biotransformation of WNAs 899
Esterases Involved in Metabolism of WNAs 901
A-Esterases 901
Toxicological Relevance of A-Esterases 903
B-Esterases 903
Serum ChE 903
Carboxylesterases (EC 3.1.1.1) 904
The Relationship Between CarbE Activity and Toxicity of WNAs 904
The Role of CarbE in Detoxification of OP 905
Prolidase (EC 3.4.13.9) 906
Protein Binding 906
Concluding Remarks and Future Directions 907
Acknowledgments 907
References 907
VII. Analytical Methods, Biosensors and Biomarkers 910
60 On-Site Detection of Chemical Warfare Agents 912
Introduction 912
Properties of CWAs 912
Concept of On-Site Detection 913
The CURRRENT Situation of Detection Technology 916
Classical Manual Method 916
Photometric Method 917
IMS Method 918
Fourier Transform/Infrared Spectrometry 920
Gas Chromatography 921
Mass Spectrometry 921
Other Sensor Technologies 922
Comparison of Existing On-Site Detection Technologies 923
Development of New On-Site Detection Technologies 924
Concluding Remarks and Future Directions 925
References 927
61 Laboratory Analysis of Chemical Warfare Agents, Adducts, and Metabolites in Biomedical Samples 930
Introduction 930
Nerve Agents 931
Analysis of Nerve Agents 933
G-Agents 933
VX 934
Sulfur Mustard and Lewisite 935
Concluding Remarks and Future Directions 936
References 937
62 Biosensors for the Detection of OP Nerve Agents 940
Introduction 940
Biosensors 940
Electrochemical Biosensors for Detecting OP Compounds 942
ChE–ChOx Bienzyme-Modified OP Biosensors 942
AChE-Modified OP Biosensors 943
OPH-Modified OP Biosensors 946
Miscellaneous Biosensors for OP Detection 947
Concluding Remarks and Future Directions 948
References 948
63 Neuropathy Target Esterase as a Biomarker and Biosensor of Delayed Neuropathic Agents 950
Introduction 950
OP Compounds 950
Conventional Nerve Agents Versus DN Agents 950
OP Compounds of Pentavalent Versus Trivalent Phosphorus 951
OPIDN 952
NTE 952
Definition of NTE and its Potential Normal or Pathogenic Roles 952
Role of NTE in OPIDN 953
Kinetics of OP Inhibitor–Serine Hydrolase Interactions 954
Introduction 954
Inhibition 955
Reactivation 956
Aging 957
Relative Inhibitory Potency 957
Biomarkers 959
Introduction 959
Enzymological Measurements of NTE Inhibition and Aging 959
Identification of NTE–OP Conjugates Using Mass Spectrometry 959
Biosensors 961
Nanostructured Electrochemical Biosensors to Measure Enzyme Activity 961
Electrochemical Biosensor Arrays for High-Throughput Analysis 962
Assembly of Electrochemical Biosensor Interfaces for Serine Hydrolases 962
Electrochemical Measurements of Serine Esterase Activity 963
Concluding Remarks and Future Directions 964
References 965
64 Biomarkers of Exposure to Organophosphorus Poisons: A New Motif for Covalent Binding to Tyrosine in Proteins That Have N ... 968
Introduction 968
Use of AChE and BChE Biomarkers in the Clinic 969
Tokyo Subway Attack with Sarin 969
Suicide Attempts 969
Methods to Detect OP Adducts on AChE and BChE 969
Cholinesterase Activity Assay 969
Fluoride Reactivation Followed by GC–MS 969
Identification of OP-BChE Adducts by Electrospray–Ionization Tandem MS 969
Single-Step Purification of BChE from Human Plasma 971
Why Are New Biomarkers Needed? 972
Not All OPs Inhibit AChE 972
OP doses too Low to Inhibit AChE Cause Toxicity 972
Only Some People Have Symptoms 972
Toxic Symptoms Depend on the OP 973
New Biomarkers 973
Beta-Glucuronidase in Rat Plasma 973
Acylpeptide Hydrolase in Rat Brain 973
Albumin in Mouse and Guinea Pig Plasma 973
Albumin in Human Plasma is a Biomarker of OP Exposure 973
M2 Muscarinic Receptors in Heart and Lung 974
Covalent Binding of OP to Tyrosine 974
Motif for OP Binding to Tyrosine 974
Characteristics of OP Binding to Tyrosine 975
On-Rate 975
Off-Rate 975
No Aging 975
Methods for Detecting OP Binding to Tyrosine 975
MS for OP Adducts on Unknown Proteins 975
Fluoride Treatment to Release OP from Albumin 975
MRM LC-MS/MS for OP Adducts When the Protein and the Modified Amino Acid Are Known 977
Pronase Digestion to Yield Single Amino Acids Modified by OPs 977
Enrichment of OP-Albumin Pepsin Peptides on PHOS-Select Iron Affinity Beads 977
Antibody 977
OPs Make a Covalent Bond with Serine, Threonine, Tyrosine, Lysine, and Histidine 977
Concluding Remarks and Future Directions 978
Acknowledgments 978
References 978
65 Monitoring of Blood Cholinesterase Activity in Workers Exposed to Nerve Agents 982
Introduction 982
Determination of ChEs 983
Factors Influencing Activity of ChEs 983
Diagnosis of OP Poisoning 985
Monitoring of Blood ChE Activity in Workers with Nerve Agents 987
Methods for Determination 987
Correlation Among Methods 987
Subjects 987
Data Analysis and Findings 987
Concluding Remarks and Future Directions 989
Acknowledgments 989
References 989
VIII. Prophylactic, Therapeutic and Countermeasures 992
66 Pharmacological Prophylaxis Against Nerve Agent Poisoning: Experimental Studies and Practical Implications 994
Introduction 994
Protection of AChE Against Inhibition 995
Scavengers 996
Prophylaxis with Current Antidotes 997
Prophylactic Use of Other Drugs 997
Concluding Remarks and Future Directions 1000
Acknowledgments 1000
References 1000
67 Prophylactic and Therapeutic Measures in Nerve Agents Poisoning 1004
Introduction 1004
Background 1004
Mechanism of Action 1004
Prophylactic Measures 1005
Animal Studies 1005
Human Use 1008
Therapeutic Measures 1009
Animal Studies 1009
Human Use 1014
Concluding Remarks and Future Directions 1014
References 1015
68 Medical Management of Chemical Toxicity in Pediatrics 1018
Introduction 1018
Background 1018
History of Pediatric Chemical Casualties 1019
Challenges to Managing Pediatric Chemical Casualties 1021
Overview 1021
Respiratory Vulnerability 1022
Volume Status Vulnerability 1022
Neurological Vulnerability 1022
Dermatological Vulnerability 1022
Plasma Protein Binding, Volume of Distribution, and Organ Maturity 1023
Metabolic Vulnerability 1024
Traumatic Injury Vulnerability 1024
Neurobehavioral Vulnerability 1024
Psychological Vulnerability 1024
Other Vulnerabilities 1025
Medical Response Vulnerability 1025
Effects of Specific Agents 1026
Nerve Agents 1026
Introduction 1026
Mechanism of Toxicity 1026
Clinical Presentation 1026
Laboratory Findings 1027
Pediatric Vulnerability 1027
Treatment 1027
Perioperative Care of Children with Nerve Agent Intoxication 1030
Summary 1031
Carbamates/Organophosphates 1031
Introduction 1031
Mechanism of Toxicity 1032
Clinical Presentation 1032
Laboratory Findings 1032
Pediatric Vulnerabilities 1032
Treatment 1034
Summary 1034
Vesicants 1034
Introduction 1034
Mechanism of Toxicity 1035
Clinical Presentation 1035
Laboratory Findings 1036
Pediatric Vulnerability 1036
Treatment 1037
Dermatological Management 1037
Ophthalmology 1038
Respiratory System 1038
Gastrointestinal Tract 1038
Bone Marrow Suppression 1038
Other Treatment Considerations 1039
Summary 1039
Pulmonary Agents 1039
Introduction 1039
Clinical Presentation 1039
Pediatric Vulnerability 1040
Treatment 1040
Summary 1040
Cyanide 1040
Introduction 1040
Mechanism of Toxicity 1041
Clinical Presentation 1042
Laboratory Findings 1042
Pediatric Vulnerability 1042
Treatment 1042
Supportive Therapy 1043
Antidotal Therapy 1043
Alternative Strategies 1044
Summary 1044
Decontamination of Children 1044
Preparation for a Chemical Event 1046
Concluding Remarks and Future Directions 1047
References 1047
69 Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling of Countermeasures to Nerve Agents 1050
Introduction 1050
Background 1050
Current Countermeasures 1051
Novel Countermeasures 1051
PBPK/PD Modeling 1052
Development of PBPK/PD Models 1053
Experimental and QSAR Methodologies to Predict Blood and Tissue Partition Coefficients 1055
Interaction PBPK/PD Model for NAs and Countermeasures 1056
Health Effects Assessment and Countermeasure Optimization 1059
Concluding Remarks and Future Directions 1060
References 1061
70 Strategies to Enhance Medical Countermeasures After the Use of Chemical Warfare Agents on Civilians 1064
Introduction 1064
Overall Strategic Approach 1064
CounterACT Program Structure 1065
Scope of Research 1065
The Civilian Versus Military Threat Spectrum 1066
Basic/mechanistic Research and Target Identification 1067
In Vitro and In Vivo Models for Efficacy Screening 1067
Advanced Preclinical Development and Clinical Studies 1068
Pretreatments 1069
Post-exposure (Pretarget) Prophylactic Therapies 1069
Post-exposure Posttarget Treatment 1070
Concluding Remarks and Future Directions 1071
Disclaimer 1071
References 1071
71 Pyridinium Oximes in the Treatment of Poisoning with Organophosphorus Compounds 1072
Introduction 1072
Interaction of Cholinesterases with OP Inhibitors 1072
Clinical Aspects of Acute OP Poisoning 1073
Antidotes in the Treatment of OP Poisoning 1074
Atropine 1074
Diazepam 1075
Oximes 1075
Pyridinium Oximes in Management of Poisoning with Warfare Nerve Agents 1076
Pralidoxime (2-PAM) 1076
Trimedoxime (TMB-4) 1077
Obidoxime (LüH-6, Toxogonin) 1077
Asoxime (HI-6) 1078
HLö-7 1079
Methoxime (MMB-4) 1079
Pyridinium Oximes in Management of Poisoning with OP Pesticides 1079
Concluding Remarks and Future Directions 1082
Acknowledgments 1082
References 1082
72 Novel Cholinesterase Reactivators 1086
Introduction 1086
OP AChE Inhibitors 1086
Acetylcholinesterase (AChE EC 3.1.1.7) 1087
Antidotes for AChE Inhibited by OP Compounds 1088
Design and Synthesis of New AChE Reactivators 1088
In Vitro Evaluation of Selected AChE Reactivators 1095
The Structure–Activity Relationship of AChE Reactivators 1096
Presence of the Oxime Group in Reactivator Structure 1096
Position of the Oxime Functional Group 1096
Number of Oxime Groups in the Reactivator Molecule 1097
Length and Shape of the Linker Between Aromatic Rings 1097
Presence of Quaternary Nitrogen in the Reactivator Structure 1098
Promising Oximes 1099
Recent Trends in Development of New AChE Reactivators 1099
Concluding Remarks and Future Directions 1100
Acknowledgments 1100
References 1100
73 Paraoxonase (PON1) and Detoxication of Nerve Agents 1104
Introduction 1104
PON1 Polymorphisms: Defining PON1 Status 1104
PON1 and the Toxicity of OP Insecticides 1105
PON1 and the Toxicity of Nerve Agents 1107
PON1 as a Therapeutic Agent 1109
Concluding Remarks and Future Directions 1110
Acknowledgments 1110
References 1110
74 The Role of Carboxylesterases in Therapeutic Intervention of Nerve Gases Poisoning 1114
Introduction 1114
Enzymology 1114
Classification 1114
Active Site 1115
Substrate Specificity 1115
Inhibition of CarbE with OP Compounds 1116
Reactivation by Oxime of Nerve Gas-Inhibited CarbE 1116
Origin of Plasma CarbE 1116
Role of Plasma CarbE 1117
Scavenger Function 1117
Toxicity of Nerve Gases 1118
Therapeutic Intervention 1119
Concluding Remarks and Future Directions 1119
References 1120
75 Catalytic Bioscavengers: The New Generation of Bioscavenger-Based Medical Countermeasures 1122
Introduction 1122
Stoichiometric Scavengers 1123
Pseudocatalytic Bioscavengers 1124
Catalytic Scavengers 1125
Requirements 1125
Potential Enzymes 1127
Phosphotriesterases 1127
Bacterial PTEs 1127
Human Paraoxonase (PON-1) 1129
Other Enzymes 1130
Other Mammalian PTEs 1130
Oxidases 1130
Engineered ChEs and CarbEs 1131
Concluding Remarks and Future Directions 1132
References 1133
IX. Decontamination and Detoxification 1140
76 Rapid Decontamination of Chemical Warfare Agents from the Skin 1142
Background: The Nature of Human Skin 1142
Background: Nerve Agents 1143
Background: Vesicating Agents (Distilled Sulfur Mustard, HD Impure Sulfur Mustard, H Lewisite, L) 1144
Model Systems to Measure Absorption, Removal, and Decontamination 1145
Rats 1145
Guinea Pigs 1145
Swine 1145
Decontamination Requirements 1146
Decontamination Schemes 1146
Classical Liquid: Sodium Hypochlorite (Bleach) 1146
Powder Decontamination Material: M291 SDK 1147
Liquid Decontamination Material: Sandia Foam 1148
Liquid Decontamination Material: Diphoterine 1149
Liquid and Sponges: RSDL 1149
Polyurethane Sponge 1150
Immobilized Enzyme Badges 1152
Concluding Remarks and Future Directions 1152
References 1152
Index 1156