Handbook of Toxicology of Chemical Warfare Agents

__Handbook of Toxicology of Chemical Warfare Agents, Third Edition__, covers every aspect of deadly toxic chemicals used in conflicts, warfare and terrorism. Including findings from experimental as well as clinical studies, this essential reference offers in-depth coverage of individual toxicants, target organ toxicity, major incidents, toxic effects in humans, animals and wildlife, biosensors and biomarkers, on-site and laboratory analytical methods, decontamination and detoxification procedures, and countermeasures. Expanding on the second edition, __Handbook of Toxicology of Chemical Warfare Agents__ has been completely updated, presenting the most recent advances in field. Brand new chapters include a new chapter on emergency preparedness, coverage of the chemical warfare agents used in Syria, the use of the Novichok agent in the UK, and more. Handbook of Toxicology of Chemical Warfare Agents Copyright Dedication Contents Section I Historical perspective and epidemiology1 Section II Agents that can be used as weapons of mass destruction95 Section III Target Organ Toxicity479 Section IV Special Topics705 Section V Toxicokinetics, toxicodynamics and physiologically-based pharmacokinetics873 Section VI Analytical methods, biosensors and biomarkers967 Section VII Risks to animals and wildlife1047 Section VIII Prophylactic, therapeutic and countermeasures1089 Section IX Decontamination and detoxification1231 List of contributors Introduction 1 History of toxicology: from killers to healers 1.1 Introduction 1.2 Ancient times 1.3 The Middle Ages 1.4 The modern era 1.5 Concluding remarks and future directions Acknowledgment References 2 Historical perspective of chemical warfare agents* 2.1 Introduction 2.2 The first sustained use of chemicals as agents of war 2.3 Initial countermeasures 2.4 Events after World War I 2.5 World War II 2.6 Post–World War II 2.7 Incapacitants and toxins 2.8 Recent experience 2.9 Terrorist use 2.10 Concluding remarks and future directions References 3 Global impact of chemical warfare agents used before and after 1945 3.1 Introduction 3.2 Background 3.3 Military use of chemical weapons 3.4 The period between World War I and World War II 3.5 World War II 3.6 The period after World War II, and the Cold War 3.7 Iraq–Iran War and the Afghanistan War 3.8 Vietnam War 3.9 Development of VX agent 3.10 Persian Gulf War 3.11 Syria 3.12 Unintentional use of toxic chemicals 3.13 Terrorist use of chemical weapons 3.14 Negotiations 3.15 Concluding remarks and future directions Acknowledgment References 4 Sarin attacks in Japan: acute and delayed health effects in survivors 4.1 Part 1 Sarin attacks in Japan: acute and delayed health effects in survivors of the Matsumoto incident 4.1.1 Introduction 4.1.2 Matsumoto sarin incident 4.1.3 Acute impacts 4.1.4 Long-lasting complaints 4.1.5 Psychological impacts 4.1.6 Ten years after the sarin incident 4.1.7 Conclusion References Chapter 4.2 Part 2 Tokyo sarin attack: acute health effects 4.2.1 Overview of the Tokyo subway sarin attack 4.2.2 Emergency treatment of sarin toxicity 4.2.3 Laboratory findings in sarin toxicity Acknowledgments References Chapter 4.3 Part 3 Structural changes in the human brain related to sarin exposure Acknowledgments References 5 Early and delayed effects of sulfur mustard in Iranian veterans after the Iraq–Iran conflict 5.1 Introduction 5.1.1 Brief chemistry 5.1.2 Summarized historical uses 5.2 Types and routes of exposure 5.3 Human toxicity 5.4 Main mechanisms of toxicity 5.5 Target organs and acute clinical features 5.6 Hematoimmunological complications 5.7 Delayed clinical complications 5.8 Respiratory tract 5.8.1 Chronic bronchitis 5.8.2 Asthma 5.8.3 Bronchiectasis 5.8.4 Large airway narrowing 5.8.5 Pulmonary fibrosis 5.9 Peripheral neuromuscular complications 5.10 Dermal delayed effects 5.11 Ophthalmologic complications 5.12 Psychiatric complications 5.13 Carcinogenicity 5.14 Reproductive complications 5.15 Cardiovascular complications 5.16 Recent advances in sulfur mustard poisoning and its complications 5.17 Concluding remarks and future directions References 6 Epidemiology of chemical warfare agents 6.1 Introduction 6.2 Pre-World War II 6.3 World War II 6.4 Post-World War II 6.5 Iran–Iraq War 6.6 1991 Gulf War 6.7 Syrian War 6.8 Terrorism 6.9 Concluding remarks and future directions References 7 Chemical weapons of mass destruction and terrorism: a threat analysis 7.1 Introduction 7.2 Chemical weapons for terrorist actions 7.2.1 “Classical” chemical warfare agents: vesicants and nerve agents 7.2.2 Incapacitating agents 7.2.3 Riot control agents 7.2.4 Toxic industrial chemicals 7.2.5 Toxins 7.3 Tampering with chemical weapons 7.4 State terrorism 7.5 Nationalist and separatist terrorist groups 7.6 Left-wing terrorist groups 7.7 Right-wing terrorist groups and lone actors 7.8 Apocalyptic cults: Aum Shinrikyo 7.9 Jihadist terrorism: Al Qaeda, Daesh, and the Global Jihad Movement 7.9.1 Weapons of mass destruction intentions 7.9.2 Chemical weapon capabilities 7.9.2.1 Al Qaeda 7.9.2.2 Daesh 7.9.2.3 Trends 7.9.3 Plots with chemical weapons 7.9.3.1 Nerve agents 7.9.3.2 Cyanides 7.9.3.3 Ricin 7.9.3.4 Toxic industrial chemicals 7.10 Concluding remarks and future directions References 8 Organophosphate nerve agents 8.1 Introduction 8.2 Background 8.2.1 Development of organophosphate formulations as chemical warfare agents 8.2.2 Destruction of nerve agent stockpiles 8.2.3 Physical and chemical properties of nerve agents 8.2.4 Mode of action and clinical signs 8.2.5 Direct nervous system effects 8.2.6 Binding with blood cholinesterases 8.2.7 Binding with other enzymes 8.3 Toxicity 8.3.1 Effects 8.3.2 Minimal potential for delayed neuropathy 8.3.3 Long-term effects following exposure to nerve agents 8.3.4 Evaluation of other potential effects 8.3.5 Inhalation/ocular toxicity in controlled experiments with human subjects 8.3.5.1 Agent GB 8.3.5.2 Agents VX and Vx 8.3.6 Inhalation/ocular toxicity in laboratory species 8.3.6.1 G-series agents 8.3.6.1.1 Lethal levels 8.3.6.1.2 Sublethal levels 8.3.6.2 Agent VX 8.3.6.2.1 Lethal levels 8.3.6.2.2 Sublethal level 8.4 Risk assessment 8.4.1 Acute exposure guideline levels 8.4.1.1 Application of AEGL values 8.4.2 Estimated oral reference doses 8.4.3 Management of exposure to nerve agents 8.4.4 Critical role of decontamination 8.4.5 Signs and symptoms guiding medical management 8.4.6 Nerve agent antidotes 8.4.7 Ongoing antidote development 8.5 Concluding remarks and future directions Acknowledgments References 9 Russian VX 9.1 Introduction and background 9.2 Monitoring of Russian VX 9.2.1 Ambient monitoring of Russian VX 9.2.2 Biomonitoring of Russian VX 9.3 Mechanisms of action and principles of therapy 9.3.1 Acute intoxication with Russian VX 9.3.2 Delayed effects: chronic and subchronic intoxication with Russian VX 9.3.3 Delayed effects: embryo- and gonadotoxicity, mutagenesis, and carcinogenesis 9.3.4 Principles of therapy 9.4 Toxicometry and hygienic regulations 9.5 Concluding remarks and future research References 10 Novichoks 10.1 Historical overview 10.2 Synthesis 10.3 Physicochemical properties 10.4 Mechanism of action 10.5 Toxicity 10.6 Concluding remarks and future directions Acknowledgment References 11 Blister agents 11.1 Introduction 11.1.1 Sulfur mustards 11.1.2 Nitrogen mustards 11.1.3 Lewisite 11.2 History and background 11.2.1 Sulfur mustards 11.2.2 Nitrogen mustards 11.2.3 Lewisite 11.3 Toxicokinetics 11.3.1 Sulfur mustards 11.3.2 Nitrogen mustards 11.3.3 Lewisite 11.4 Mode of action 11.4.1 Sulfur mustards 11.4.2 Nitrogen mustards 11.4.3 Lewisite 11.5 Toxicity 11.5.1 Sulfur mustard 11.5.2 Nitrogen mustards 11.5.3 Lewisite 11.6 Risk assessment 11.6.1 Sulfur mustards 11.6.1.1 Noncancer 11.6.1.2 Cancer 11.6.2 Nitrogen mustards 11.6.2.1 Noncancer 11.6.2.2 Cancer 11.6.3 Lewisite 11.6.3.1 Noncancer 11.6.3.2 Cancer 11.7 Treatment 11.7.1 Sulfur mustards 11.7.2 Nitrogen mustards 11.7.3 Lewisite 11.8 Concluding remarks and future directions References 12 Riot control agents 12.1 Introduction 12.2 History 12.3 Background 12.3.1 The agents and their physicochemical properties 12.3.1.1 Chloroacetophenone 12.3.1.2 Ortho-chlorobenzylidene malononitrile 12.3.1.3 Dibenz(b,f)-1:4-oxazepine 12.3.1.4 Diphenylaminechlorarsine 12.3.1.5 Oleoresin capsicum 12.3.1.6 Pelargonic acid vanillylamide 12.3.1.7 New potent compounds 12.4 Mechanism of action 12.5 Toxicokinetics 12.5.1 Uptake, distribution, and metabolism of ortho-chlorobenzylidene malononitrile 12.5.2 Uptake, distribution, and metabolism of dibenz(b,f)-1:4-oxazepine 12.5.3 Uptake, distribution, and metabolism of capsaicin 12.6 Toxicity 12.6.1 Ophthalmological effects 12.6.1.1 Ortho-chlorobenzylidene malononitrile 12.6.1.2 Chloroacetophenone 12.6.1.3 Dibenz(b,f)-1:4-oxazepine 12.6.1.4 Capsaicin 12.6.2 Nasal/pharyngeal toxicity 12.6.3 Cardiovascular toxicity 12.6.4 Respiratory toxicity 12.6.4.1 Ortho-chlorobenzylidene malononitrile 12.6.4.2 Chloroacetophenone 12.6.4.3 Dibenz(b,f)-1:4-oxazepine 12.6.4.4 Capsaicin 12.6.5 Neurologic toxicity 12.6.6 Gastrointestinal toxicity 12.6.7 Dermatological toxicity 12.6.7.1 Ortho-chlorobenzylidene malononitrile 12.6.7.2 Chloroacetophenone 12.6.7.3 Dibenz(b,f)-1:4-oxazepine 12.6.7.4 Capsaicin 12.6.8 Other toxicity 12.6.9 Lethality 12.6.10 Traumatic injuries 12.7 Risk assessment 12.7.1 Identification of intended and unintended effects 12.7.2 Dose response 12.7.3 Exposure assessment 12.7.4 Characterization of the risk and risk management 12.8 Treatment 12.8.1 Eyes 12.8.2 Skin 12.8.3 Respiratory 12.9 Concluding remarks and future directions References 13 Phosgene oxime 13.1 Introduction 13.2 Properties and chemistry 13.3 Exposure and toxicity 13.4 Mechanism of action 13.5 Protection, decontamination, and treatment 13.6 Concluding remarks and future directions Acknowledgment References 14 Psychotomimetic agent BZ (3-quinuclidinyl benzilate) 14.1 Introduction 14.2 Background 14.3 Toxicokinetics and mechanism of action 14.4 Toxicity 14.5 Symptoms 14.6 Risk assessment 14.7 Treatment 14.8 Analytical methods 14.9 Agent BZ in behavioral research 14.10 Concluding remarks and future directions References 15 Fluoroacetate 15.1 Introduction 15.2 Background 15.3 Toxicokinetics 15.3.1 Detoxification 15.3.2 Analytical procedure 15.3.3 Distribution in tissues and elimination 15.4 Mechanism of action 15.4.1 Molecular mechanism of aconitase inhibition 15.4.2 Physiological and biochemical effects of fluoroacetate 15.4.2.1 Effects of fluoroacetate and fluorocitrate on mitochondria and other intracellular organelles 15.4.2.2 Effects of fluoroacetate on isolated cells 15.4.2.3 Biochemical parameters under intoxication with fluoroacetate 15.4.2.4 Effects of fluoroacetate on the cells of the nervous system: interaction of glia and neurons 15.4.3 Physiology of blood vessels under intoxication with fluoroacetate 15.4.4 Body temperature of rats and rabbits under intoxication with fluoroacetate 15.4.5 Electrophysiological studies of fluoroacetate intoxication 15.5 Toxicity and risk assessment 15.6 Treatment 15.7 Concluding remarks and future directions References 16 Strychnine 16.1 Introduction 16.2 Background 16.2.1 Chemistry and physicochemical properties 16.2.2 History 16.2.3 Therapeutic uses 16.3 Pharmacokinetics and toxicokinetics 16.3.1 Absorption, distribution, metabolism, and excretion 16.4 Clinical symptomatology 16.5 Mechanism of action 16.6 Toxicity 16.6.1 Animal toxicity 16.6.2 Human toxicity 16.6.3 Diagnosis 16.7 Risk assessment 16.7.1 Human health hazard 16.7.2 Safety data 16.8 Treatment 16.9 Concluding remarks and future directions References 17 Superwarfarins 17.1 Introduction 17.2 Background 17.2.1 AAPCC data on superwarfarins 17.3 Classification of superwarfarins 17.3.1 4-Hydroxycoumarins 17.3.1.1 Bromadiolone 17.3.1.2 Brodifacoum 17.3.1.3 Coumatetralyl 17.3.1.4 Coumafuryl 17.3.1.5 Difenacoum 17.3.1.6 Warfarin 17.3.2 Indanediones 17.3.2.1 Chlorophacinone 17.3.2.2 Diphacinone 17.4 Toxicokinetics 17.4.1 Absorption, metabolism, and excretion in laboratory animals and humans 17.5 Mechanism of action 17.6 Toxicity 17.6.1 Clinical effects: signs and symptoms 17.6.1.1 Animal toxicology 17.6.1.2 Pediatric exposures 17.6.1.3 Adult exposures 17.6.1.4 Household pets and farm animal exposures 17.6.1.5 Nontarget wildlife exposures 17.6.1.6 Laboratory/monitoring and general recommendations 17.6.1.7 Analytical methods 17.7 General treatment recommendations 17.7.1 Referral to healthcare facilities 17.7.2 Home observation criteria 17.7.3 Treatment at healthcare facilities 17.7.3.1 Emesis 17.7.3.2 Activated charcoal 17.7.3.3 Gastric lavage 17.7.3.4 Laboratory monitoring 17.8 Concluding remarks and future directions References 18 PCBs, dioxins, and furans: human exposure and health effects 18.1 Introduction 18.2 Historical background 18.3 Human exposure to PCBs, PCDDs, and PCDFs 18.4 Physicochemical properties and global distribution 18.5 Analytical methods 18.6 Mechanism of action and toxicity 18.7 Concluding remarks and future directions References 19 Polycyclic aromatic hydrocarbons: implications for developmental, molecular, and behavioral neurotoxicity 19.1 Introduction 19.2 Background 19.2.1 Epidemiological evidence for the negative effects of PAHs on pregnant women 19.2.2 Conclusion from prospective epidemiology cohort studies 19.2.3 Effects of maternal stress 19.2.4 PAH-DNA adducts 19.2.5 Refinement of our susceptibility-exposure paradigm to assess the effects of in utero exposure to PAH aerosols on neu... 19.2.6 Refinement of our susceptibility-exposure paradigm to assess the effects of in utero exposure to PAH aerosols on beh... 19.3 PAH experimental model systems 19.3.1 Toxicological observations from modeling B(a)P aerosols 19.3.2 In situ generation of “oxidative metabolites” in neocortical tissue from in utero exposure to B(a)P aerosol 19.3.3 Temporal modulation of NMDA-mediated developmental processes as a result of in utero exposure to B(a)P aerosol 19.3.4 Rescue of spatial discrimination deficit phenotypes in brain-Cpr-null offspring subsequent to in utero exposure to B... 19.4 Implications 19.5 Other model systems used for PAH-induced neurotoxicity and role of the microbiome 19.6 Concluding remarks and future directions References 20 Thallium 20.1 Introduction 20.2 Background 20.3 Toxicokinetics 20.4 Mechanism of action 20.5 Toxicity 20.6 Risk assessment 20.7 Treatment 20.8 Concluding remarks and future directions References 21 Arsenicals: toxicity, their use as chemical warfare agents, and possible remedial measures 21.1 Introduction 21.2 Background 21.3 Arsine 21.3.1 Synthesis of arsine 21.3.2 Metabolism of arsine 21.3.2.1 In animals 21.3.2.2 In humans 21.3.3 Mechanism of toxicity 21.3.4 Effects on humans 21.3.4.1 Acute arsine poisoning 21.3.4.2 Immediate effects 21.3.4.3 Late effects 21.3.4.4 Long-term exposure 21.3.5 Diagnostic tests 21.4 Organic arsenicals 21.4.1 Mechanism of toxicity 21.4.2 Symptoms 21.5 Methyldichloroarsine 21.6 Dlphenylchloroarsine 21.6.1 Structure 21.6.2 Effects of dlphenylchloroarsine 21.7 Ethyldichloroarsine 21.7.1 Structure 21.7.2 Effects of ethyldichloroarsine 21.8 Lewisite 21.8.1 Background 21.8.2 Mechanism of action and toxicokinetics 21.8.3 Clinical and pathological findings 21.9 Inorganic arsenic 21.9.1 Sources and uses 21.9.1.1 Uses 21.9.1.2 Exposure 21.9.2 Toxicokinetics 21.9.3 Biochemical and toxic effects 21.9.3.1 Hematopoietic 21.9.3.2 Skin (dermal) 21.9.3.3 Hepatic 21.9.3.4 Gastrointestinal 21.9.3.5 Respiratory 21.9.3.6 Cardiovascular 21.9.3.7 Reproductive and developmental 21.9.3.8 Neurological 21.9.3.9 Diabetes mellitus 21.9.4 Mechanisms of toxicity 21.9.4.1 Oxidative stress 21.9.5 Diagnosis 21.9.5.1 Clinical features 21.9.5.2 Other biomarkers 21.9.5.3 Treatment 21.9.6 Chelating agents and chelation therapy 21.9.6.1 2,3-Dimercaprol (dimercaprol; British antilewisite) 21.9.6.1.1 Drawbacks 21.9.6.2 Meso 2,3-dimercaptosuccinic acid 21.9.6.2.1 Drawbacks 21.9.6.3 Sodium 2,3-dimercaptopropane-1-sulfonate 21.9.6.3.1 Drawbacks 21.9.6.4 Monoesters of meso 2,3-dimercaptosuccinic acid 21.9.7 Monoisoamyl DMSA 21.9.7.1 Drawbacks 21.9.7.2 Role of antioxidants 21.10 Combination treatment 21.11 Concluding remarks and future directions References 22 Chlorine 22.1 Introduction 22.2 History of use and human exposure 22.3 Absorption, distribution, metabolism, and excretion 22.4 Mechanistic studies 22.5 Toxicity 22.5.1 Human studies 22.5.2 Laboratory animal studies 22.6 Risk assessment 22.7 Treatment 22.8 Concluding remarks and future directions References 23 Phosgene 23.1 Introduction 23.2 Background 23.3 Toxicokinetics 23.4 Mechanism of action 23.5 Toxicity 23.5.1 Human 23.5.1.1 Noncancer 23.5.1.2 Cancer 23.5.2 Animal 23.5.2.1 Noncancer 23.5.2.2 Animal cancer 23.6 Risk assessment 23.7 Treatment 23.8 Concluding remarks and future directions References 24 Carbon monoxide: can’t see, can’t smell, body looks red but they are dead 24.1 Introduction 24.2 Historical background 24.3 Epidemiological considerations 24.4 Physicochemical properties of carbon monoxide 24.5 Sources of carbon monoxide 24.5.1 External sources of carbon monoxide 24.5.2 Endogenous sources of carbon monoxide 24.6 Methods for carbon monoxide measurement 24.7 Measurement of blood carbon monoxide 24.8 Ambient air carbon monoxide 24.9 Home detectors 24.10 Carbon monoxide in expired breath 24.11 Toxicokinetics and toxicodynamics 24.11.1 Absorption, distribution, and elimination of carbon monoxide 24.12 Mechanism of toxicity 24.12.1 Classical mode of action 24.12.2 Electrocardiographic/heart rhythm effects 24.12.3 Cardiac hemodynamic effects 24.12.4 Cardiomegaly 24.12.5 Other cardiac effects 24.12.6 Effects on cerebral blood flow 24.13 Effects on brain metabolism 24.14 Redox and reoxygenation/reperfusion injuries in the brain 24.15 The catecholamine crisis hypothesis 24.16 Other possible mechanisms of central nervous system toxicity 24.17 Toxicity of carbon monoxide 24.17.1 Factors affecting susceptibility to poisoning 24.17.2 Combined exposures to carbon monoxide, cyanides, and other toxicological gases in battlefield and military circumst... 24.17.3 Acute toxicity 24.17.4 Delayed (interval) manifestations of acute toxicity 24.18 Typical anatomic pathology findings 24.19 Treatment of carbon monoxide overdose 24.19.1 Oxygen 24.19.2 Targeted temperature management 24.19.3 Sympatholytics and sedation 24.19.4 Allopurinol and N-acetylcysteine 24.19.5 Insulin 24.20 Acceptable exposure levels within the military context 24.21 Defensive measures 24.22 Concluding remarks and future directions References 25 Acute cyanide toxicity and its treatment: the body is dead and may be red but does not stay red for long 25.1 Introduction: basic terminology and a brief and tragic history of the use and misuse of cyanide 25.2 Sources of exposure 25.3 Toxic levels of cyanide 25.4 Detection and estimation of cyanide 25.5 Toxicokinetics of cyanide 25.5.1 Absorption 25.5.2 Distribution 25.5.3 Elimination 25.6 Mechanism of action 25.7 Diagnosis and clinical features of cyanide poisoning 25.8 Treatment of cyanide poisoning 25.8.1 Antidotal therapy 25.8.2 Methemoglobin inducers 25.8.3 Amyl nitrite 25.8.4 Sodium nitrite 25.8.5 4-Dimethylaminophenol 25.8.6 Sulfur donors 25.8.7 Cobalt compounds 25.8.8 Dicobalt edetate (Kelocyanor) 25.8.9 Hydroxocobalamin (Cyanokit) 25.8.10 Supportive therapy 25.9 Concluding remarks and future directions References 26 Methyl isocyanate: the Bhopal gas 26.1 Introduction 26.2 The making of a disaster 26.3 Chemistry and toxicokinetics of isocyanates 26.3.1 Chemistry of isocyanates 26.3.1.1 Synthesis of methyl isocyanate 26.3.1.2 Physicochemical reactions with methyl isocyanate 26.3.1.3 Quantification of methyl isocyanate 26.4 Mechanism of death following exposure to methyl isocyanate 26.5 The cyanide controversy 26.6 Toxicity of isocyanates 26.7 Toxicity of methyl isocyanate 26.7.1 Toxicity of methyl isocyanate in animal models 26.7.1.1 Mortality 26.7.1.2 Pulmonary toxicity 26.7.1.3 Ocular toxicity 26.7.1.4 Reproductive toxicity 26.7.1.5 Immunotoxicity, genotoxicity, and carcinogenic effects 26.7.1.6 Other toxic effects 26.7.2 Toxicity in humans 26.7.2.1 Acute toxicity Nonlethal effects Fatal effects 26.7.2.2 Subacute and chronic toxicity 26.7.2.2.1 Pulmonary complications 26.7.2.2.2 Ocular toxicity 26.7.2.2.3 Reproductive toxicity 26.7.2.2.4 Genotoxicity 26.7.2.2.5 Carcinogenicity 26.7.2.2.6 Immunotoxicity 26.7.2.2.7 Neurotoxicity and psychological effects 26.7.2.2.8 Other toxic effects 26.8 Treatment 26.9 Toxic potential of methyl isocyanate beyond the Bhopal disaster 26.10 Benzyl chlorines and other chemicals at Bhopal 26.11 Concluding remarks and future directions Acknowledgments References 27 Other toxic chemicals as potential chemical warfare agents 27.1 Introduction 27.2 General 27.2.1 Chemical weapons convention: article II, definitions and criteria 27.3 Specific agents 27.3.1 Carbamates 27.3.2 Dioxin 27.3.3 Bicyclic phosphates 27.3.4 Perfluoroisobutene 27.3.5 Organophosphates 27.3.6 Toxins 27.3.6.1 Aziridines 27.3.6.2 Tremorine 27.3.6.3 Imino-β,β-dipropionitrile 27.3.7 Bioregulators 27.3.7.1 Angiotensins 27.3.7.2 Bombesin 27.3.7.3 Bradykinin 27.3.7.4 Endorphins 27.3.7.5 Endothelins 27.3.7.6 Enkephalins 27.3.7.7 Histamine-releasing factor 27.3.7.8 Neuropeptide Y 27.3.7.9 Neurotensin 27.3.7.10 Oxytocin 27.3.7.11 Somatostatin 27.3.7.12 Substance P 27.3.7.13 Vasopressin 27.3.8 Thyroid-stimulating hormone 27.4 Nonlethal weapons 27.4.1 Genetic and ethnic weapons 27.5 Concluding remarks and future directions Acknowledgment References 28 Ricin 28.1 Introduction 28.2 History of biological weapons 28.3 The weaponization of biological agents 28.4 The family of ribosome-inactivating proteins 28.5 The ricin toxin structure and biosynthesis 28.6 The cellular internalization of ricin 28.7 N-Glycosidase activity of ricin 28.8 Signs and symptoms of ricin exposure 28.9 Field-forward biological agent detection 28.9.1 Immunoassays 28.9.2 DNA-based assays: polymerase chain reaction 28.10 Concluding remarks and future directions References 29 Botulinum toxin 29.1 Introduction 29.2 Historical aspects 29.3 Background 29.3.1 Toxin structure and molecular function 29.3.1.1 Function of heavy and light chains 29.3.1.2 Accessory proteins of the progenitor toxin complex 29.3.2 Overview of botulinum neurotoxin action 29.3.3 Clinical forms of botulism in humans and animals 29.3.4 Infectious forms of botulism 29.3.4.1 Infant botulism 29.3.4.2 Wound botulism 29.3.4.3 Child or adult botulism from intestinal colonization 29.3.5 Noninfectious forms of botulism 29.3.5.1 Foodborne botulism 29.3.5.2 Inhalational 29.3.5.3 Inadvertent systemic botulism 29.3.6 Human intoxication 29.4 Epidemiology 29.4.1 Foodborne botulism 29.5 Pathogenesis 29.5.1 Overview of pathogenesis 29.5.2 Toxin stability 29.5.2.1 Biological stability of the toxins in the gastrointestinal tract 29.5.3 Oral intoxication: toxin absorption from the gastrointestinal tract 29.5.3.1 Role of progenitor toxin accessory proteins 29.5.3.2 Role of enterocytes 29.5.4 Respiratory intoxication 29.5.4.1 Toxin absorption from the respiratory tract 29.5.5 Toxin binding and uptake into target tissues 29.6 Toxicokinetics 29.6.1 Foodborne toxicity 29.6.1.1 Toxin persistence in the circulation and transit to target tissues 29.6.2 Inhalation toxicity 29.6.2.1 Toxin persistence in the circulation and transit to target tissues 29.7 Mechanism of action 29.7.1 Heavy chain 29.7.2 Light chain 29.8 Toxicity 29.8.1 Lethality 29.8.2 Oral toxicity 29.8.3 Inhalation toxicity 29.8.4 Clinical toxicity 29.8.4.1 Foodborne botulism 29.8.4.2 Infant botulism 29.9 Risk assessment 29.10 Treatment 29.10.1 Antitoxin 29.10.2 Treatment for infant botulism 29.10.3 Vaccines 29.11 Concluding remarks and future directions 29.11.1 Development of animal model test systems 29.11.1.1 Inadequacies of current animal model test systems 29.11.1.2 Advantages of the mouse hemidiaphragm assay References 30 Onchidal and fasciculins 30.1 Introduction 30.2 Background 30.2.1 Onchidal 30.2.2 Fasciculin 30.3 Mechanism of action and biological effects 30.3.1 Onchidal 30.3.2 Fasciculin 30.4 Experimental and human toxicity 30.4.1 Experimental 30.4.2 Human 30.5 Computational toxicology assessment 30.6 Treatment 30.7 Concluding remarks and future directions 30.8 Disclosures Acknowledgments References 31 Cyanobacterial (blue-green algae) toxins 31.1 Introduction 31.2 Hepatotoxins 31.2.1 Microcystins and nodularins 31.2.1.1 Introduction 31.2.1.2 Chemistry 31.2.1.3 Toxic effects 31.2.1.4 Mechanism of action 31.2.1.5 Chemical warfare potential 31.2.2 Cylindrospermopsin 31.2.2.1 Introduction 31.2.2.2 Chemistry 31.2.2.3 Toxic effects 31.2.2.4 Mechanism of action 31.2.2.5 Chemical warfare potential 31.3 Neurotoxins 31.3.1 Anatoxin-a 31.3.1.1 Introduction 31.3.1.2 Chemistry 31.3.1.3 Toxic effects 31.3.1.4 Mechanism of action 31.3.1.5 Chemical warfare potential 31.3.2 Anatoxin-a(s) 31.3.2.1 Introduction 31.3.2.2 Chemistry 31.3.2.3 Toxic effects 31.3.2.4 Mechanism of action 31.3.2.5 Chemical warfare potential 31.3.3 Saxitoxins 31.3.3.1 Introduction 31.3.3.2 Chemistry 31.3.3.3 Toxic effects 31.3.3.4 Mechanism of action 31.3.3.5 Chemical warfare potential 31.4 Concluding remarks and future directions References 32 Chemical warfare agents and the nervous system 32.1 Introduction 32.2 Overview of the nervous system 32.2.1 Special features of neurons and high energy demand 32.2.2 Blood–brain barrier 32.3 Types of neurotoxicity 32.4 Selected chemical warfare agents that affect the nervous system 32.4.1 Organophosphorus nerve agents 32.4.2 Cyanides 32.4.3 Sulfur mustard 32.4.4 3-Quinuclidinyl benzilate 32.5 Concluding remarks and future directions References 33 Behavioral toxicity of nerve agents 33.1 Introduction 33.2 The methods used to evaluate the behavioral effects of nerve agents 33.2.1 Functional observatory battery 33.2.2 Performance on the RAM task 33.2.3 Acoustic startle response and prepulse inhibition 33.2.4 Performance on the Y-maze 33.2.5 Performance on the T-maze 33.2.6 Performance on the Morris water maze 33.2.7 Performance on the passive avoidance test 33.2.8 Performance on the Barnes maze 33.3 Long-term behavioral effects of acute high-level exposure to nerve agents 33.4 Chronic behavioral effects of single or repeated low-level exposure to nerve agents 33.5 Concluding remarks and future directions References 34 The respiratory toxicity of chemical warfare agents 34.1 Introduction 34.2 History of chemical warfare agents use 34.3 The respiratory system 34.4 Pulmonary agents 34.4.1 Arsine 34.4.1.1 Exposure physiology 34.4.1.2 Exposure biochemistry 34.4.1.3 Exposure histopathology 34.4.2 Chlorine 34.4.2.1 Exposure physiology 34.4.2.2 Exposure biochemistry 34.4.2.3 Exposure histopathology 34.4.3 Phosgene 34.4.3.1 Exposure physiology 34.4.3.2 Exposure biochemistry 34.4.3.3 Exposure histology 34.4.4 Nerve agents 34.4.4.1 Volatile agents 34.4.4.2 Exposure physiology 34.4.4.3 Exposure biochemistry 34.4.4.4 Exposure histopathology 34.4.5 Nonvolatile agents 34.4.5.1 Exposure physiology 34.4.5.2 Exposure biochemistry 34.4.5.3 Exposure histopathology 34.4.6 Cyanides 34.4.6.1 Exposure physiology 34.4.6.2 Exposure biochemistry 34.4.6.3 Exposure histopathology 34.4.7 Riot control agents 34.4.7.1 2-Chlorobenzylidene malononitrile 34.4.7.1.1 Exposure physiology 34.4.7.1.2 Exposure biochemistry 34.4.7.1.3 Exposure histopathology 34.4.7.2 Dibenz (b,f)−1:4-oxazepine (CR) 34.4.7.2.1 Exposure physiology 34.4.7.2.2 Exposure biochemistry 34.4.7.2.3 Exposure histopathology 34.4.7.3 10-Chloro-5,10-diphenylaminochlorarsine (DM-adamsite) 34.4.7.3.1 Exposure physiology 34.4.7.3.2 Exposure biochemistry 34.4.7.3.3 Exposure histopathology 34.4.7.4 Oleoresin of capsicum (OC—pepper spray) 34.4.7.4.1 Exposure physiology 34.4.7.4.2 Exposure biochemistry 34.4.7.4.3 Exposure histopathology 34.4.7.5 Chloropicrin (PS) 34.4.7.5.1 Exposure physiology 34.4.7.5.2 Exposure biochemistry 34.4.7.5.3 Exposure histopathology 34.4.7.6 1-Chloroacetophenone (CN) 34.4.7.6.1 Exposure physiology 34.4.7.6.2 Exposure biochemistry 34.4.7.6.3 Exposure histopathology 34.4.8 DA and DC 34.4.9 Vesicating agents 34.4.9.1 Sulfur mustard—bis-(2-chloroethyl) sulfide (HD) 34.4.9.1.1 Exposure physiology 34.4.9.1.2 Exposure biochemistry 34.4.9.1.3 Exposure histopathology 34.4.9.2 Lewisite—b-chlorovinyldichloroarsine (agent L) 34.4.9.2.1 Exposure physiology 34.4.9.2.2 Exposure biochemistry 34.4.9.2.3 Exposure histopathology 34.5 Concluding remarks and future directions Acknowledgments References 35 The cardiovascular system as a target of chemical warfare agents 35.1 Introduction 35.1.1 Potential indicators 35.1.1.1 Troponin level changes (cTnT/cTnI) 35.1.1.2 Creatine kinase and lactate dehydrogenases, markers of tissue damage 35.1.1.3 Brain natriuretic peptide 35.1.1.4 C-reactive protein 35.1.1.5 Parathyroid hormone 35.1.1.6 Ischemia-modified albumin 35.1.2 Hazard models 35.2 Background 35.2.1 Cardiac anatomy 35.2.2 Innervation of the heart 35.2.3 Neuropeptides 35.2.4 Energetics of the heart 35.2.5 Electrophysiology 35.3 Signatures of cardiac toxicity 35.3.1 The electrocardiogram as a diagnostic tool for poisoning 35.3.1.1 Recorded morphological changes on the electrocardiogram 35.3.1.2 Long QT 35.3.2 Biochemical markers of tissue injury 35.3.2.1 Conventional biomarkers 35.3.2.2 miRNA 35.4 Indices of the toxicity of warfare agents 35.4.1 Classes of warfare agents 35.4.2 Background 35.4.3 Signatures of toxicity 35.4.4 Nerve agents 35.4.4.1 Mechanism of action 35.4.5 Electrocardiographic signature of organophosphates 35.4.5.1 Toxic effects of organophosphates on the heart 35.5 Specific warfare agents of concern regarding the heart 35.5.1 Currently the most widely used agents rely on organophosphate compounds 35.5.1.1 VX 35.5.1.2 Tabun 35.5.1.3 Sarin 35.5.1.4 Soman 35.5.1.5 Novichok 35.5.2 Antidotes for organophosphate nerve agents 35.5.3 Cyanide 35.5.3.1 Toxicity 35.5.3.2 Antidotes for cyanide poisoning 35.6 Other terror agents 35.6.1 Arsenic 35.6.2 Ricin 35.7 Therapeutics under development 35.8 Concluding remarks and future directions 35.8.1 Current concerns 35.8.2 Potential future scenarios 35.9 A new approach References 36 Ocular toxicity of chemical warfare agents 36.1 Introduction 36.2 Background 36.2.1 The structure of the eye 36.2.2 Effects of ocular structure on regenerative capacities 36.2.3 Importance of neurological function to vision 36.3 Ocular toxicities of specific chemical warfare agents 36.3.1 Selection of agents discussed 36.4 Vesicants (Group 1) 36.4.1 The mustard gases 36.4.1.1 Toxicokinetics of the acute ocular mustard injury in human victims 36.4.1.2 Evidence for a delayed ocular mustard injury in human victims 36.4.1.3 Toxicokinetics of the acute and late-onset ocular mustard