Handbook of Toxicology of Chemical Warfare Agents

Description

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 injuries 36.4.1.4 Mechanistic studies of sulfur mustard toxicity 36.4.1.5 Etiogenesis of the delayed ocular sulfur mustard injury: current theories 36.4.2 Lewisite 36.4.2.1 Toxicokinetics of ocular lewisite injuries 36.4.3 Phosgene oxime 36.5 Nerve agents 36.6 Psychomimetic incapacitating agents 36.7 Blood agents 36.8 Choking agents 36.9 Riot control agents 36.10 Biological toxins 36.10.1 Botulinum neurotoxins (BoNTs) 36.10.2 Ricin 36.10.3 Staphylococcus enterotoxin B (SEB) 36.11 Concluding remarks and future directions Disclaimer References 37 Skeletal muscle 37.1 Introduction 37.2 Behavioral effects 37.3 Cholinergic system 37.3.1 Normal activity of acetylcholinesterase and its molecular forms 37.3.2 Inhibition of acetylcholinesterase and its molecular forms by nerve agents 37.3.3 Butyrylcholinesterase 37.3.4 Choline acetyltransferase 37.3.5 Acetylcholine receptors 37.4 Noncholinergic system 37.4.1 Muscle excitotoxicity 37.4.2 Oxidative/nitrosative stress 37.4.3 High-energy phosphate depletion and myonecrosis 37.5 Muscle activity—electromyography 37.6 Muscle fiber histopathology 37.7 Muscle cytotoxicity biomarkers 37.7.1 Creatine kinase and creatine kinase isoenzymes 37.7.2 Lactate dehydrogenase and lactate dehydrogenase isoenzymes 37.8 Skeletal muscle involvement in tolerance development 37.9 Skeletal muscle involvement in intermediate syndrome 37.10 Prevention/treatment of myopathy 37.11 Acetylcholinesterase reactivators and acetylcholinesterase receptor blockers 37.11.1 N-Methyl-d-aspartate receptor antagonist 37.11.2 Anticonvulsants and anesthetics 37.11.3 Antioxidants, spin-trapping agents, and creatine 37.12 Concluding remarks and future directions Acknowledgment References 38 Dermal toxicity of sulfur mustard 38.1 Introduction 38.2 Background 38.2.1 Military use 38.2.2 Wound repair 38.3 Pathogenesis 38.3.1 Cytotoxicity of sulfur mustard 38.3.1.1 Alkylation of DNA/poly(ADP-ribose) polymerase activation 38.3.1.2 Reactions with glutathione/oxidative stress 38.3.1.3 Reactions with glutathione/calcium homeostasis 38.3.2 Inflammation 38.3.3 Protease activation 38.3.4 Apoptosis 38.3.5 Signal transduction pathways 38.4 Models of dermal sulfur mustard exposure 38.4.1 Introduction 38.4.2 Model systems for screening sulfur mustard 38.4.3 Decontamination 38.4.4 Treatment of blisters 38.5 Therapeutics 38.5.1 Antioxidants 38.5.2 Poly(ADP-ribose) polymerase inhibitors 38.5.3 Proteolytic inhibitors 38.5.4 Steroids, corticosteroids, and glucocorticoids 38.5.5 Nonsteroidal antiinflammatory drugs 38.5.6 Bifunctional compounds 38.5.7 Transient receptor potential ligands 38.5.8 Cooling 38.6 Concluding remarks and future directions References 39 Reproductive toxicity and endocrine disruption of potential chemical warfare agents 39.1 Introduction 39.2 Important definitions and concepts 39.2.1 Chemical warfare agents 39.2.2 Environmental contaminants associated with industrial or agricultural terrorism 39.2.3 Reproduction 39.2.4 Reproductive toxicity 39.2.4.1 Teratogenesis 39.2.4.2 Mechanisms of reproductive toxicity and teratogenesis 39.2.4.3 Reproductive toxicants 39.2.4.4 Teratogens 39.2.4.5 Endocrine disruption 39.2.4.6 Mechanisms of endocrine disruption 39.2.4.7 Endocrine-disrupting chemicals, endocrine disruptors, and hormonally active agents 39.3 The reproductive toxicity of selected toxicants 39.3.1 The reproductive toxicity of riot control agents 39.3.2 The reproductive toxicity of chemical warfare agents 39.3.2.1 Vesicants 39.3.2.1.1 Arsenicals 39.3.2.1.2 Chlorine gas 39.3.2.1.3 Phosgene and phosgene oxime 39.3.2.1.4 Sulfur mustard 39.3.2.2 Inhibitors of protein synthesis 39.3.2.2.1 Ricin 39.3.2.3 Inhibitors of cellular respiration (“blood agents”) 39.3.2.3.1 Hydrogen cyanide and cyanide-related compounds 39.3.2.4 Nerve agents 39.3.2.4.1 Organophosphate nerve agents 39.3.2.5 The reproductive toxicity environmental contaminants resulting from acts of terrorism 39.3.2.6 Ionizing radiation 39.3.2.7 Pesticides and other organic contaminants 39.3.2.7.1 Adverse effects of pesticides and other organic contaminants on male reproductive function 39.3.2.7.2 Adverse effects of pesticides and other organic contaminants on female reproductive function 39.3.2.7.3 Adverse effects of pesticides and other organic contaminants on embryonic/fetal development 39.3.2.8 Heavy metals 39.3.2.8.1 Adverse effects of heavy metals on male reproductive function 39.3.2.8.2 Adverse effects of heavy metals on female reproductive function 39.3.2.8.3 Adverse effects of heavy metals on embryonic/fetal development 39.4 Conclusion References 40 Liver toxicity of chemical warfare agents 40.1 Introduction 40.2 Structural organization of the liver 40.2.1 Hepatic functional capacity 40.2.2 Hepatic cellular components 40.3 Factors influencing hepatic toxicity 40.3.1 Preferential hepatic uptake 40.3.2 Xenobiotic metabolic bioactivation 40.3.3 Phase II/conjugation reactions 40.3.4 Phase III reactions 40.3.5 Pathologic manifestations of hepatic injury 40.3.5.1 Hepatic steatosis/fatty liver 40.3.5.2 Steatohepatitis 40.3.5.3 Apoptosis versus necrosis 40.3.5.4 Hepatic pigment accumulation 40.3.5.5 Hepatic cholestasis 40.3.5.6 Hepatic fibrosis 40.3.5.7 Cirrhosis 40.3.5.8 Pathomechanisms of hepatic injury 40.3.6 Oxidative stress and free radicals with classic examples 40.3.7 Disruption of calcium homeostasis 40.3.8 Inhibition of mitochondrial function 40.3.9 Autophagy and endoplasmic reticulum stress 40.3.10 Disruption of the cytoskeleton 40.3.10.1 Cholestatic mechanisms 40.3.10.2 Idiosyncratic reactions 40.4 Biological toxins 40.5 Warfare agents affecting the liver 40.5.1 Fungal and plant toxins 40.5.1.1 Microcystins 40.5.1.2 Aflatoxins 40.5.1.3 Ricin 40.5.1.4 Abrin 40.5.2 Bacterial (anthrax) 40.6 Concluding remarks and future directions References 41 Renal system 41.1 Introduction 41.2 Anatomy and physiology 41.2.1 Functional anatomy 41.2.2 Biotransformation 41.3 Toxic responses of the urinary system 41.3.1 Acute renal failure 41.3.2 Chronic renal failure 41.3.3 Patterns of toxic injury 41.3.4 Glomerular injury 41.3.5 Proximal tubular injury 41.3.6 Distal nephron/renal papillary injury 41.3.7 Lower urinary tract 41.4 Toxic effects of chemical warfare agents 41.4.1 Vesicants 41.4.2 Nerve agents 41.4.3 Depleted uranium 41.4.4 Thallium 41.4.5 Ricin 41.4.6 Anthrax toxins 41.4.7 Cyanobacterial toxins 41.4.8 Other agents 41.5 Concluding remarks and future directions References 42 Impact of chemical warfare agents on the immune system 42.1 Introduction 42.2 The immune system 42.2.1 The innate immune system 42.2.2 The adaptive immune system 42.3 Targets of immunotoxicity 42.3.1 Effects on precursor stem cells 42.3.2 Effects on maturation of lymphocytes 42.3.3 Effects on initiation of immune responses 42.3.4 Induction of inflammation and noncognate T–B cooperation 42.4 Exposition of autoantigens and interference with co-stimulatory signals 42.5 Regulation of the immune response 42.6 Immunotoxicity of chemical warfare agents 42.6.1 Nerve agents 42.6.1.1 Immunotoxicity of nerve agents 42.6.2 Blister or vesicant agents 42.6.2.1 Immunotoxicity of blister agents 42.6.3 Choking agents 42.6.3.1 Immunotoxicity of choking agents 42.6.4 Blood agents 42.6.4.1 Immunotoxicity of blood agents 42.7 Concluding remarks and future directions References 43 Health effects of nuclear weapons and releases of radioactive materials 43.1 Introduction 43.2 Conceptual framework 43.3 Nomenclature 43.4 Sources of radiation dose 43.5 Key early events in radiation science 43.6 Historical overview of radiation protection standards 43.7 Discovery of fission changed the world 43.8 The Manhattan Project 43.9 The tolerance dose 43.10 The first nuclear weapons 43.11 Post-World War II nuclear weapons development and testing 43.12 Contemporary nuclear activities 43.13 Blast and thermal effects of nuclear weapons 43.14 Exposures to radioactive materials and radiation dose 43.15 Radiation-induced health effects 43.15.1 Sources of information on radiation effects 43.15.1.1 Overview of key biological mechanisms 43.15.2 Acute radiation syndrome and early effects 43.16 Early radiation effects from internally deposited radionuclides 43.16.1 Radiation-induced cancer in humans from acute exposures 43.16.1.1 Radiation-induced cancer from internally deposited radionuclides 43.17 Linear nonthreshold models 43.18 Current radiation protection guidance 43.19 Summary 43.20 Personal perspective 43.21 Dedication References 44 Clinical and cellular aspects of traumatic brain injury 44.1 Introduction 44.2 Traumatic brain injury mouse models 44.3 Clinical manifestations and management of traumatic brain injury 44.3.1 Classifying traumatic brain injury using the Glasgow Coma Scale 44.3.2 Coma recovery scale to track meaningful changes with severe traumatic brain injury 44.3.3 Intracranial pressure 44.3.4 Primary and secondary brain injury 44.3.5 Immediate care 44.3.6 Surgical management 44.3.7 Targeted therapies to prevent secondary injury 44.4 Maintenance of adequate cerebral perfusion improves outcome after traumatic brain injury 44.4.1 Other targeted therapies 44.4.2 Opportunities for rehabilitation and recovery posttraumatic brain injury 44.5 Cognitive impairments 44.5.1 Neuronal loss 44.5.2 Synapse loss 44.5.3 Seizures 44.6 Cellular mechanisms of primary and secondary injuries 44.6.1 Necrosis 44.6.2 Apoptosis 44.6.2.1 Glutamate dysregulation and excitotoxicity 44.6.2.2 Oxidative stress 44.6.2.3 Cell-cycle reentry 44.7 Potential mechanisms of synaptic impairment 44.8 Pathological hallmarks of Alzheimer’s disease in traumatic brain injury 44.8.1 Alzheimer’s disease: Aβ and tau 44.8.2 Aβ in traumatic brain injury 44.8.3 Tau in traumatic brain injury 44.9 Concluding remarks and future directions References 45 Neurological effects and mechanisms of blast overpressure injury 45.1 Introduction 45.2 Blast waves and mechanisms of injury 45.2.1 Pressure waves 45.2.2 Mechanism of primary injury 45.3 Clinical features of traumatic brain injury 45.3.1 Common clinical features of traumatic brain injury 45.3.2 Distinct clinical features of blast traumatic brain injury 45.3.2.1 Blast lung 45.3.2.2 Hearing loss, tinnitus, and visual impairments 45.3.2.3 Postconcussive syndrome and posttraumatic stress disorder 45.4 Human neuropathology of blast traumatic brain injury 45.4.1 Neuropathological features of blast traumatic brain injury 45.4.2 Clinical management 45.5 Animal models of blast traumatic brain injury 45.6 Biomarkers of blast injury 45.6.1 Serum and cerebrospinal fluid protein biomarkers 45.6.1.1 Biomarkers of neuronal injury 45.6.1.2 Biomarkers of glial injury 45.6.1.3 Biomarkers of inflammation 45.6.1.4 MicroRNA biomarkers 45.7 Concluding remarks and future directions References 46 Genomics and proteomics in brain complexity in relation to chemically induced posttraumatic stress disorder 46.1 Introduction 46.2 The effect of posttraumatic stress disorder on different regions of brain 46.3 The hypothalamic–pituitary–adrenal axis 46.4 Hippocampus 46.5 Amygdala 46.6 Cortex 46.7 Understanding posttraumatic stress disorder: the genomics and proteomics way 46.8 Applications of genomic and transcriptomics methods 46.9 Role of noncoding RNAs and epigenetics in posttraumatic stress disorder 46.10 Toxic chemical exposure and human diseases 46.11 Genomic applications: understanding the relationship between posttraumatic stress disorder and chemical toxicity 46.12 Proteomics 46.13 Neuroproteomics: proteomics applications in neuroscience 46.14 Proteomics approaches to understand natural and chemical toxicity-induced posttraumatic stress disorder 46.15 Concluding remarks and future directions Acknowledgment References 47 Excitotoxicity, oxidative stress, and neuronal injury 47.1 Introduction 47.2 Excitotoxicity and oxidative injury 47.3 Lipid peroxidation and in vivo markers of oxidative damage 47.4 Anti-AChE-induced seizures, oxidative injury, and neurodegeneration 47.5 Oxidative damage and dendritic degeneration following KA-induced excitotoxicity 47.6 Suppression of seizure-induced oxidative injury and neurodegeneration 47.6.1 Antioxidants 47.6.2 N-methyl-d-aspartate receptor antagonist (memantine) 47.7 Concluding remarks and future directions Acknowledgment References 48 Blood–brain barrier damage and dysfunction by chemical toxicity 48.1 Introduction 48.2 Structure and function of the BBB 48.3 In vivo and in vitro models to study the BBB 48.3.1 In vivo model 48.3.2 In vitro models 48.4 Gender differences in the BBB 48.5 The BBB in young and adult brains 48.6 Transport of molecules across the BBB 48.7 Effects of toxic agents on the BBB 48.7.1 Anticholinesterase organophosphate nerve agents 48.7.2 Oxime reactivators of AChE inhibited by OPs and the BBB 48.7.3 NMDAR antagonist memantine and the BBB 48.7.4 Drugs of abuse-induced BBB damage 48.7.5 Metals 48.8 Bacterial toxin-induced BBB damage 48.9 GWI and the BBB 48.10 Effects of blasts on the BBB 48.11 Excitotoxicity, stress, and the BBB 48.12 Brain barriers and CNS diseases 48.13 Melatonin and the BBB 48.14 Concluding remarks and future directions Acknowledgment References 49 The effects of organophosphates in the early stages of human skeletal muscle regeneration 49.1 Introduction 49.2 Regeneration process in human skeletal muscle 49.3 Noncholinergic effects of DFP in regenerating human skeletal muscle 49.3.1 The effect of DFP on IL-6 secretion from myoblasts and myotubes 49.3.2 Heat shock proteins in human myoblasts and myotubes after treatment with DFP 49.3.3 Response of human myoblasts to hypoxia 49.3.4 The effects of DFP on the NRE activity in human myoblasts 49.4 Expression and role of AChE in human myoblasts 49.4.1 Recovery of AChE mRNA expression and AChE activity after gene silencing of AChE and after exposure to DFP 49.4.2 The role of AChE in myoblast apoptosis 49.5 Concluding remarks and future directions Acknowledgments References 50 Experimental modeling for delayed effects of organophosphates 50.1 Introduction and background 50.2 Experimental procedures 50.3 Toxicological data 50.4 Biochemical data 50.4.1 Cholinesterases 50.4.2 Carboxylesterase 50.4.3 Carbohydrate and fat metabolism 50.4.4 Liver and kidney damage 50.5 Concluding remarks and future directions Funding References 51 Alternative animal toxicity testing of chemical warfare agents 51.1 Introduction 51.2 Brief history of chemical warfare use 51.3 Top five chemical warfare agents 51.4 The concept of 3Rs 51.5 International cooperation on alternative test methods 51.6 Alternatives to animal testing of chemical warfare agents 51.7 Animal efficacy rule 51.8 Human-on-a-chip 51.8.1 New predictive models of toxicity 51.9 Concluding remarks and future directions References 52 Toxicokinetic aspects of nerve agents and vesicants 52.1 Introduction 52.2 Overview of the invasion processes of CWAs 52.2.1 Percutaneous uptake by contact with skin 52.2.1.1 Epidermis 52.2.1.2 Dermis 52.2.2 Respiratory uptake by inhalation 52.2.2.1 Airways and absorption 52.2.2.2 Absorption in the upper respiratory tract 52.2.2.3 Absorption in the middle respiratory tract 52.2.2.4 Absorption in the alveoli 52.2.2.5 Nose-only exposure model for controlled respiratory uptake in animal studies in vivo 52.2.3 Gastrointestinal uptake by ingestion 52.2.4 Uptake by intravenous injection 52.3 Nerve agents 52.3.1 OPCs as nerve agents 52.3.2 Physicochemical properties 52.3.2.1 Water solubility 52.3.2.2 Octanol:water partition coefficient 52.3.2.3 Hydrolysis 52.3.2.4 Chirality 52.3.3 Toxicity 52.3.4 Inhibition of AChE 52.3.5 Additional targets with potential clinical relevance 52.3.6 Elemental steps of nerve agent toxicokinetics 52.3.6.1 Invasion 52.3.6.2 Distribution 52.3.6.3 Biotransformation and elimination 52.3.7 Enzymatic hydrolysis 52.3.7.1 Phosphotriesterases 52.3.7.2 Nonmammalian enzymes 52.3.8 Nonproteinaceous scavengers and hydrolyzing compounds 52.3.9 Formation of protein adducts 52.3.9.1 Carboxylesterase 52.3.9.2 Acetyl monoalkylglycerol ether hydrolase 52.3.9.3 Acetylcholinesterase 52.3.9.4 Butyrylcholinesterase 52.3.9.5 Albumin 52.3.9.6 Keratins 52.3.9.7 Ubiquitin 52.3.9.8 Additional proteins 52.3.10 Muscarinic receptors 52.3.11 Excretion 52.3.12 Concentration–time profiles of nerve agents in blood after various routes of administration 52.3.12.1 Intravenous uptake 52.3.12.2 Subcutaneous uptake 52.3.12.3 Percutaneous uptake 52.3.12.4 Respiratory uptake (nose-only model) 52.3.13 Mathematical simulation for prediction of nerve agent toxicokinetics 52.3.14 Bioanalytical techniques relevant to toxicokinetics 52.3.14.1 Determination of nerve agents 52.3.14.2 Detection of enzyme and protein adducts of nerve agents 52.4 Vesicants 52.4.1 Sulfur mustard 52.4.1.1 Overview of sulfur mustard 52.4.1.2 Toxicity of sulfur mustard 52.4.1.3 Invasion 52.4.1.3.1 Percutaneous absorption 52.4.1.3.2 Respiratory absorption 52.4.1.4 Distribution 52.4.1.5 Biotransformation 52.4.1.6 Elimination 52.4.2 Lewisite 52.4.2.1 Overview of lewisite 52.4.2.2 Toxicity of lewisite 52.4.2.3 Invasion 52.4.2.3.1 Percutaneous absorption 52.4.2.3.2 Respiratory absorption 52.4.2.4 Distribution 52.4.2.5 Biotransformation 52.4.2.6 Elimination 52.4.2.7 Bioanalytical techniques for quantification of vesicants 52.4.2.7.1 Determination of vesicants and direct biotransformation products 52.4.2.7.2 Detection of DNA and protein adducts of vesicants 52.5 Concluding remarks and future directions References 53 Toxicokinetics and toxicodynamics of DFP 53.1 Introduction 53.1.1 DFP synonyms and scientific publications 53.1.2 Research field of the use of DFP 53.2 Physicochemical properties and chemical identification of DFP 53.2.1 Chemical structure, identity, and analogy with other nerve agents 53.2.2 Physicochemical properties 53.3 History of DFP synthesis and its relationship with the development of warfare nerve agents 53.4 Toxicokinetic and biotransformation of DFP and studies on DFPase 53.4.1 Absorption, distribution, and toxicokinetic studies 53.4.1.1 Distribution after exposure by inhalation 53.4.1.2 Distribution after intravenous administration 53.4.1.3 Skin penetration 53.4.1.4 Physiologically based pharmacokinetic/pharmacodynamic studies 53.4.2 Biotransformation of DFP: phosphotriesterases, paraoxonase, DFPPase 53.4.2.1 Detoxification of DFP by binding to proteins 53.4.2.2 The role of albumin in the detoxification of DFP 53.5 Acute toxicity of DFP and interaction with AChE 53.5.1 In vitro studies on cholinesterase inhibition 53.5.2 Experimental animal studies on cholinesterase inhibition and acute toxicity 53.5.3 Studies in man 53.6 DFP in studies on neurotoxicity and therapy with reactivators 53.6.1 Neuropharmacological studies of the cholinergic system 53.6.2 Neurobehavior and neurodevelopment 53.6.3 Therapy against anticholinesterase toxicity 53.6.4 DFP in other biological studies 53.7 Interaction of DFP with other esterases 53.7.1 Serine proteases and albumin: role of tyrosine residues 53.7.2 Inhibition of soluble PVases of peripheral nerve by DFP 53.7.3 DFP- and OP-induced delayed neuropathy and neuropathy target esterase 53.7.3.1 Phosphorylation site identified by radiolabeled DFP 53.7.3.2 The target site identified as an esterase: neuropathy target esterase 53.7.3.3 Protection and induction of neuropathy: the role of the aging reaction 53.7.3.4 Testing delayed neuropathy 53.7.3.5 Molecular and genomic characterization of NTE and its role in embryonic development 53.8 Concluding remarks and future directions References Chemical databases Patents Bibliographic references 54 Physiologically based pharmacokinetic modeling of chemical warfare agents 54.1 Introduction 54.2 Development of PBPK models 54.3 Need for improved measures of CWNA exposure—the use of PBPK analysis of data 54.4 Relationship between regenerated sarin and AChE activity and its use as a dose surrogate 54.5 General PBPK model structure 54.6 PBPK simulation of cholinesterase inhibition and regenerated GB 54.7 Concluding remarks and future directions References 55 Biotransformation of warfare nerve agents 55.1 Introduction 55.2 Chemical aspects of biotransformation of nerve agents 55.3 Esterases involved in the metabolism of warfare nerve agents 55.3.1 A-esterases 55.3.1.1 Toxicological relevance of A-esterases 55.3.2 B-esterases 55.3.2.1 Serum cholinesterase 55.3.2.2 Carboxylesterases (EC 3.1.1.1) 55.3.2.3 The relationship between CarbE activity and toxicity of warfare nerve agents 55.3.2.4 The role of CarbE in detoxification of OP 55.3.2.5 Prolidase (EC 3.4.13.9) 55.4 Lipase 55.5 Protein binding 55.6 Concluding remarks and future directions References 56 Laboratory analysis of chemical warfare agents, adducts, and metabolites in biomedical samples 56.1 Introduction 56.2 Nerve agents 56.2.1 Analysis of intact nerve agents 56.2.2 Verification of exposure to nerve agents 56.3 Sulfur mustard and lewisite 56.4 Concluding remarks and future directions References 57 On-site detection of chemical warfare agents 57.1 Introduction 57.2 Properties of chemical warfare agents 57.3 Concept of on-site detection 57.4 The present situation of detection technology 57.4.1 Classical manual method 57.4.2 Photometric method 57.4.3 Ion mobility spectrometry method 57.4.4 Vibrational spectroscopy 57.4.5 Gas chromatography 57.4.6 Mass spectrometry 57.4.7 Other sensor technologies 57.5 Comparison of existing on-site detection technologies 57.6 Development of new on-site detection technologies 57.7 Concluding remarks and future directions References 58 Neuropathy target esterase as a biomarker and biosensor of delayed neuropathic agents 58.1 Introduction 58.2 Organophosphorus compounds 58.2.1 Conventional nerve agents versus delayed neuropathic agents 58.2.2 Organophosphorus compounds of pentavalent versus trivalent phosphorus 58.3 Organophosphorus compound–induced delayed neurotoxicity 58.4 Neuropathy target esterase 58.4.1 Definition of neuropathy target esterase and its potential normal or pathogenic roles 58.4.2 Role of neuropathy target esterase in organophosphorus compound–induced delayed neurotoxicity 58.5 Kinetics of organophosphorus inhibitor–serine hydrolase interactions 58.5.1 Introduction 58.5.2 Inhibition 58.5.3 Reactivation 58.5.4 Aging 58.5.5 Relative inhibitory potency 58.6 Biomarkers 58.6.1 Introduction 58.6.2 Enzymological measurements of neuropathy target esterase inhibition and aging 58.6.3 Identification of neuropathy target esterase–organophosphorus conjugates using mass spectrometry 58.7 Biosensors 58.7.1 Nanostructured electrochemical biosensors to measure enzyme activity 58.7.2 Electrochemical biosensor arrays for high-throughput analysis 58.7.3 Assembly of electrochemical biosensor interfaces for serine hydrolases 58.7.4 Electrochemical measurements of serine esterase activity 58.8 Concluding remarks and future directions References 59 The cross-linking action of organophosphorus poisons; Implications for chronic neurotoxicity 59.1 Introduction 59.2 Chemical reactions of organophosphorus poisons 59.3 Cross-linking mechanism 59.4 Mass spectrometry identifies cross-linked peptides 59.5 The consequences of treating tubulin with chlorpyrifos oxon 59.6 Implications for neurotoxicity 59.7 Zero-length cross-links between lysine and glutamic acid or lysine and aspartic acid 59.8 Concluding remarks References 60 Monitoring of blood cholinesterase activity in workers exposed to nerve agents 60.1 Introduction 60.2 Determination of cholinesterases 60.3 Factors influencing the activity of cholinesterases 60.4 Diagnosis of organophosphorus compound poisoning 60.5 Monitoring of blood cholinesterase activity in workers exposed to nerve agents 60.5.1 Introduction 60.5.2 Methods for determination 60.5.3 Correlation among methods 60.5.4 Subjects 60.5.5 Statistical analysis 60.5.6 Results and discussion 60.6 Concluding remarks Acknowledgments References 61 Potential agents that can cause contamination of animal feedingstuff and terror 61.1 Introduction 61.1.1 Agricultural food ecosystem and terror 61.2 Mycotoxins and toxigenic fungi 61.2.1 Background 61.2.2 Applications of biotechnology 61.2.3 Fungal biocontrol agents 61.2.4 Economic losses from the use of fungi and mycotoxins as weapons 61.2.5 Terrorism using mycotoxin-contaminated feedingstuff 61.2.6 Residues in edible tissues 61.3 Microbial toxins 61.3.1 Botulism toxin 61.3.1.1 Background 61.3.1.2 Mechanism of action 61.3.1.3 Potential production and use 61.4 Plant toxins 61.4.1 Toxins in seeds 61.4.2 Castor beans (ricin) 61.4.2.1 Background 61.4.2.2 Weaponization of ricin 61.4.2.3 Toxicity and mechanism of action 61.4.2.4 Analytical methods 61.4.2.5 Clinical and pathological findings 61.4.3 Other plant source type 2 RIPs 61.5 Rapidly acting and easily available substances 61.5.1 Cyanide 61.5.1.1 Mechanism of action 61.5.2 Insecticides and drugs 61.6 Persistent organic compounds 61.6.1 Background 61.6.2 Potential economics of terror attacks using persistent organic pollutants 61.7 Heavy metals and metalloids 61.7.1 Lead 61.7.2 Arsenic 61.8 Concluding remarks and future directions References 62 Chemical warfare agents and risks to animal health 62.1 Introduction 62.2 Chemical warfare agents 62.2.1 Chlorine gas 62.2.1.1 Clinical signs 62.2.1.2 Kinetics 62.2.1.3 Decontamination and treatment 62.2.1.4 Species susceptibility 62.2.2 Phosgene 62.2.2.1 Clinical signs 62.2.2.2 Kinetics 62.2.2.3 Decontamination and treatment 62.2.2.4 Species susceptibility 62.2.3 Mustard gas 62.2.3.1 Clinical signs 62.2.3.2 Kinetics 62.2.3.3 Decontamination and treatment 62.2.3.4 Species susceptibility 62.2.4 Lewisite 62.2.4.1 Clinical signs 62.2.4.2 Kinetics 62.2.4.3 Decontamination and treatment 62.2.4.4 Species susceptibility 62.2.5 Phosgene oxime 62.2.5.1 Clinical signs 62.2.5.2 Kinetics 62.2.5.3 Decontamination and treatment 62.2.5.4 Species susceptibility 62.2.6 Cyanide and hydrogen cyanide 62.2.6.1 Clinical signs 62.2.6.2 Kinetics 62.2.6.3 Decontamination and treatment 62.2.6.4 Species susceptibility 62.2.7 Military nerve agents 62.2.7.1 Clinical signs 62.2.7.2 Kinetics 62.2.7.3 Decontamination and treatment 62.2.7.4 Species susceptibility 62.2.8 3-Quinuclidinyl benzilate 62.2.8.1 Clinical signs 62.2.8.2 Kinetics 62.2.8.3 Decontamination and treatment 62.2.8.4 Species susceptibility 62.2.9 RCAs (lacrimators) 62.2.9.1 Clinical signs 62.2.9.2 Kinetics 62.2.9.3 Decontamination and treatment 62.2.9.4 Species susceptibility 62.2.10 Ricin and abrin (toxalbumins) 62.2.10.1 Clinical signs 62.2.10.2 Kinetics 62.2.10.3 Decontamination and treatment 62.2.10.4 Species susceptibility 62.3 Concluding remarks and future directions References 63 Threats to wildlife by chemical and warfare agents 63.1 Introduction 63.2 Infrastructure and potential widespread chemical contamination 63.3 Pyroterrorism and wildlife 63.4 Candidate chemical agents 63.4.1 Background 63.4.1.1 Tetramethylenedisulfotetramine 63.4.1.1.1 Background 63.4.1.1.2 Mechanism of action 63.4.1.1.3 Pathology and detection 63.4.1.2 Sodium monofluoroacetate and sodium fluoroacetamide 63.4.1.2.1 Background 63.4.1.2.2 Toxicology of sodium monofluoroacetate 63.4.1.2.3 Clinical signs of intoxication 63.4.1.2.4 Pathology and forensic chemistry 63.4.1.3 Cyanide 63.4.1.3.1 Background 63.4.1.3.2 Toxicology 63.5 Selected pesticides 63.5.1 Background 63.5.2 Incidents of intoxication 63.6 Castor bean (Ricinus communis) 63.6.1 Background 63.6.2 Toxicology and pathology 63.6.3 Water baits 63.7 Concluding remarks and future directions References 64 Pharmacological prophylaxis against nerve agent poisoning: experimental studies and practical implications 64.1 Introduction 64.2 Protection of acetylcholinesterase against inhibition 64.3 Scavengers 64.4 Prophylaxis with current antidotes 64.5 Prophylactic use of other drugs 64.6 Concluding remarks and future directions Acknowledgment References 65 Prophylactic and therapeutic measures in nerve agents poisonings 65.1 Introduction 65.2 Prophylaxis against intoxication with nerve agents 65.2.1 Use of acetylcholinesterase inhibitors in prophylaxis of poisoning with nerve agents 65.2.1.1 Physostigmine 65.2.1.2 Neostigmine 65.2.1.3 Pyridostigmine 65.2.2 Prophylactic use of oximes 65.2.3 Use of N-methyl-d-aspartate-receptor-blocking drugs in prophylaxis against organophosphorus compounds 65.2.4 Adverse effects of prophylatic regimens 65.2.5 Bioscavengers against nerve agents 65.3 Treatment of intoxication with nerve agents 65.3.1 Anticholinergics 65.3.2 Acetylcholinesterase reactivators 65.3.3 Anticonvulsants 65.3.3.1 Benzodiazepines 65.3.3.2 Glutamate receptor antagonists 65.3.3.3 Time- and dose-dependency of administration of drugs for prevention and treatment of nerve agent-induced convulsions 65.3.3.4 Autoinjectors 65.4 Concluding remarks and further directions References 66 Physiologically based pharmacokinetic/pharmacodynamic modeling of countermeasures to nerve agents 66.1 Introduction 66.2 Background 66.3 Current countermeasures 66.4 Novel countermeasures 66.5 PBPK/PD modeling 66.6 Development of PBPK/PD models 66.7 Experimental and QSAR methodologies to predict blood and tissue partition coefficients 66.8 Interaction PBPK/PD model for NAs and countermeasures 66.9 Health effects assessment and countermeasure optimization 66.10 Concluding remarks and future directions References 67 Research on medical countermeasures for chemical attacks on civilians 67.1 Introduction 67.2 Medical countermeasures used in civilian chemical incidents 67.3 Research needs for civilian medical countermeasures 67.4 Research at the National Institutes of Health in the United States 67.5 Contract core facilities 67.6 Scope of research 67.7 Research on medical countermeasures for civilian chemical threats 67.8 Concluding remarks and future directions References 68 Pyridinium oximes in the treatment of poisoning with organophosphorus compounds 68.1 Introduction 68.2 Interaction of cholinesterases with organophosphorus inhibitors 68.3 Clinical aspects of acute organophosphorus poisoning 68.4 Antidotes in the treatment of organophosphorus poisoning 68.4.1 Atropine 68.4.2 Diazepam 68.4.3 Oximes 68.5 Pyridinium oximes in the management of poisoning with warfare nerve agents 68.5.1 Pralidoxime (PAM-2) 68.5.2 Trimedoxime (TMB-4) 68.5.3 Obidoxime (LüH-6, toxogonin) 68.5.4 Asoxime (HI-6) 68.5.5 HLö-7 68.5.6 Methoxime (MMB-4) 68.6 Pyridinium oximes in the management of poisoning with organophosphorus pesticides 68.7 Concluding remarks and future directions References 69 Novel cholinesterase reactivators 69.1 Introduction 69.2 OP AChE inhibitors 69.3 Acetylcholinesterase (AChE; EC 3.1.1.7) 69.4 Antidotes for AChE inhibited by OP compounds 69.5 Design and synthesis of new AChE and BChE reactivators 69.6 Uncharged non-oxime reactivators 69.7 Uncharged oxime reactivators 69.8 Mono- or double-charged oxime reactivators 69.9 In vitro evaluation of selected AChE reactivators 69.10 The structure–activity relationship and discussion 69.11 Recent trends in the development of new AChE reactivators and future directions 69.12 Concluding remarks and future directions Acknowledgments References 70 Paraoxonase (PON1), detoxification of nerve agents, and modulation of their toxicity 70.1 Introduction 70.2 PON1 polymorphisms: defining PON1 status 70.3 PON1 and the toxicity of OP insecticides 70.4 PON1 and the toxicity of nerve agents 70.5 PON1 as a therapeutic agent 70.6 Concluding remarks and future directions Acknowledgment References 71 The role of carboxylesterases in therapeutic interventions of nerve agent poisoning 71.1 Introduction 71.2 Enzymology of carboxylesterase 71.3 Carboxylesterase reactivation 71.4 Source and induction of carboxylesterase activity 71.5 Carboxylesterases as scavengers of nerve agents 71.6 Toxicity of nerve agents and carboxylesterase 71.7 Carboxylesterase inhibitors 71.8 Carboxylesterase and prophylactic/therapeutic interventions 71.9 Stoichiometric and catalytic scavengers of organophosphorus compounds 71.10 Concluding remarks and future directions References 72 Catalytic bioscavengers: the second generation of bioscavenger-based medical countermeasures Abbreviations 72.1 Introduction 72.2 Stoichiometric scavengers 72.3 Pseudocatalytic bioscavengers 72.4 Catalytic scavengers 72.5 Requirements 72.6 Potential enzymes 72.6.1 Phosphotriesterases 72.6.1.1 Bacterial phosphotriesterases 72.6.1.2 Human paraoxonase 72.6.2 Other enzymes 72.6.2.1 Other mammalian phosphotriesterases 72.6.2.2 Oxidases 72.6.3 Engineered cholinesterases and carboxylesterases 72.6.3.1 Inhibition of cholinesterases by organophosphates 72.6.3.2 Proton transfer wires 72.6.3.3 Mechanism of aging 72.6.3.4 Spontaneous reactivation 72.6.3.5 New routes of reactivation 72.7 Concluding remarks and future directions Acknowledgment References 73 Rapid decontamination of chemical warfare agents from skin Abbreviations 73.1 Background: the nature of human skin 73.2 Background: nerve agents 73.3 Background: vesicating agents (distilled sulfur mustard, HD; impure sulfur mustard, H; Lewisite, L) 73.4 Model systems to measure absorption, removal, and decontamination 73.4.1 Rats 73.4.2 Guinea pigs 73.4.3 Swine 73.5 Decontamination requirements 73.6 Decontamination schemes 73.6.1 Classical liquid: sodium hypochlorite (bleach) 73.6.2 Powder decontamination material: M291 SDK (Fig. 73.1) 73.6.3 Liquid decontamination material: Sandia foam (Fig. 73.2) 73.6.4 Liquid decontamination material: Diphotérine 73.6.5 Liquid and sponges: Reactive Skin Decontamination Lotion (Fig. 73.3) 73.6.6 Polyurethane sponge (Fig. 73.4) 73.6.7 Immobilized enzyme badges (Gordon et al., 2002) 73.7 Concluding remarks and future directions References Index