Chemical Warfare Toxicology

Franz Worek; John Jenner; Horst Thiermann

BOOK

Chemical Warfare Toxicology

Franz Worek | John Jenner | Horst Thiermann

(2016)

Additional Information

Book Details

ISBN: 978-1-78262-241-3
Edition: 1
Language: English
Pages: 322
Subjects: Medical toxicology
Biochemistry
Biotechnology

Abstract

Despite ongoing efforts to prohibit the production, storage and use of chemical warfare agents recent world events highlight the enduring threat to the population from these agents. Research efforts in various countries have resulted in novel insights into chemical warfare toxicology that has enabled the development of new approaches for the diagnosis and treatment of chemical warfare poisoning. This book provides an up-to-date treatise on the ongoing research into the toxicology of chemical warfare agents, the diagnosis and verification of exposure, and the pre- and post-exposure treatment of poisoning. Focussing on the fundamentals of the toxicology of nerve agents and vesicants, this book will give the reader a comprehensive overview of the many different aspects of chemical warfare agent toxicology. The text will appeal to toxicologists, biochemists and weapons specialists working in industry and academia, and anyone with an interest in chemical warfare toxicology or exposure.
Experts covering the broad range of topics related to CWAs author the chapters of this book. The authors are regarded as authorities in the fields of toxicology and military medicine, presenting state-of-the-art information for academic, clinical and governmental audiences.
David Oliver

Section Title	Page	Action	Price
Cover	Cover
Chemical Warfare Toxicology Volume 1: Fundamental Aspects	i
Preface	vii
References to Material in the National Archives	ix
Contents	xi
Chapter 1 - Development, Historical Use and Properties of Chemical Warfare Agents	1
1.1 Introduction	1
1.2 Brief History of CW	2
1.2.1 Prior to 1914	2
1.2.2 The 1914–18 War (WWI)	2
1.2.2.1 Overview	2
1.2.2.2 Irritants	3
1.2.2.3 Chlorine	3
1.2.2.4 Phosgene	3
1.2.2.5 Sulfur Mustard	4
1.2.2.6 Other Agents	4
1.2.3 The Inter-War Years	4
1.2.4 The 1939–1945 War (WWII)	5
1.2.5 Post WWII and the Cold War Years	6
1.2.6 The Middle East	7
1.2.7 Terrorism	8
1.2.8 Chemical Weapons Convention	8
1.3 Classification, Properties and Modes of Use of CW Agents	9
1.3.1 Classification	9
1.3.2 Physicochemical Properties	9
1.3.2.1 Gaseous and Liquid Agents	9
1.3.2.2 Solid Agents	11
1.3.3 Ease of Production	12
1.4 Main Classes of Chemical Agents	12
1.4.1 Lung Injurants (Choking Agents)	12
1.4.1.1 Chlorine	12
1.4.1.2 Phosgene and Diphosgene	13
1.4.1.3 Perfluoroisobutene	13
1.4.2 Blood Agents	13
1.4.2.1 Hydrogen Cyanide	13
1.4.2.2 Cyanogen Chloride	14
1.4.3 Vesicants (Blister Agents)	14
1.4.3.1 Sulfur Mustard	14
1.4.3.2 Nitrogen Mustards	15
1.4.3.3 Lewisite	16
1.4.4 Nerve Agents	16
1.4.4.1 Tabun and DFP	16
1.4.4.2 Sarin, Soman, Cyclosarin and 2-Methyl GF	17
1.4.4.3 V Agents	18
1.4.4.4 Other Nerve Agents	18
1.4.5 Riot Control Agents	19
1.4.6 Incapacitants	20
1.4.7 Future Developments	22
References	23
Chapter 2 - Toxicology of Vesicants	29
2.1 Introduction	29
2.2 Sulfur Mustard	30
2.2.1 Mechanism of Action	30
2.2.1.1 Chemical Reactivity	30
2.2.1.2 Alterations to DNA	31
2.2.1.3 Alterations to Other Cellular Components and Processes	32
2.2.2 Toxicokinetics, Metabolism and Distribution	32
2.2.2.1 Studies in Animals	33
2.2.2.1.1\rDermal.Cullumbine46 used a histological stain that formed an insoluble black complex with free SM, but not with degradation prod...	33
2.2.2.1.2\rInhalation.SM is readily absorbed across the respiratory tract, including across the nasal membrane.49 Langenberg et al.50 showe...	33
2.2.2.1.3\rOther Routes.Radioactivity appears in the kidney, lung and liver after intravenous administration of radiolabelled SM to the rab...	33
2.2.2.2 Studies in Humans	34
2.2.2.2.1 Dermal.Renshaw† reported that >80% of SM applied to the skin evaporates if the application site is left unoccluded,58 a...	34
2.2.2.2.2\rOther Routes of Exposure.No systematic studies describe the kinetics of SM following other routes of exposure in humans. In part...	34
2.2.2.3 In vitro Studies	36
2.2.3 Acute Toxicity	36
2.2.3.1 Studies in Animals	36
2.2.3.1.1\rOral Exposure.There are few reports on the oral toxicity of SM. In one study, the oral lethal dose, 50% (LD50) of SM [administer...	36
2.2.3.1.2\rDermal Exposure.Since the first research efforts in 1917–1918, a large range of animal species have been exposed to SM liquid an...	37
Lethality.Dacre and Goldman72 reported the percutaneous LD50 of SM to be 9 mg kg−1 in the rat, 92 mg kg−1 in the mouse, 20 mg kg...	37
Sublethal Pathology.Venkateswaran et al.74 investigated the systemic effects of sublethal percutaneous doses of SM (3.88, 7.75 o...	37
2.2.3.1.3\rInhalation	38
Pathology.An early study described the pathology of SM effects on the lungs in detail.75 Three groups of dogs responded in diffe...	38
Lethality by Inhalation.There are very few quantitative determinations of the lethality of SM after inhalation exposure. Box and...	39
2.2.3.2 Exposures of Humans	40
2.2.3.2.1\rDermal.The acute dermal effects of SM are a primary irritancy reaction and are covered in detail in Section 2.4	40
2.2.3.2.2\rInhalation.There are no non-anecdotal reports of acute effects in humans by the inhalation route. The following is an account of...	40
First World War.In a 1922, a clinical study of 83 “pensioners” with recognised disability due to gas poisoning during WWI was pe...	42
Second World War.There were no battlefield exposures to SM during combat in WWII. However, an example of the effects of an acute...	42
Iran–Iraq War.Over 100000 medical casualties were reported from the Iran–Iraq War with symptoms related to SM exposure. Of 61 vi...	43
2.2.4 Irritation and Corrosiveness	44
2.2.4.1 Studies in Animals	44
2.2.4.1.1\rDermal.Early studies97 described similar pathology of liquid SM on the skins of rabbits, guinea pigs and cats. Within 2 hours of...	44
2.2.4.1.2\rInhalation.Vijayaraghavan et al.83 investigated the effects of the inhalation of SM on breathing patterns in groups of four mice...	45
2.2.4.1.3\rOcular.Warthin103 compared clinical descriptions of SM induced eye lesions in humans with the pathology of experimental lesions ...	46
2.2.4.2 Studies in Humans	46
2.2.4.2.1\rDermal.SM produces a dose dependent primary irritant response, erythema, oedema and vesication/desquamation when it comes into c...	47
2.2.4.2.2\rOcular Effects.There are two key studies in human volunteers that quantify the effects of SM vapour on human eyes.106,107 Human ...	48
2.2.5 Sensitisation	48
2.2.5.1 Studies in Animals	48
2.2.5.2 Studies and Exposures in Humans	49
2.2.6 Repeated Dose Toxicity	49
2.2.6.1 Studies in Animals	49
2.2.6.1.1\rOral.Sasser et al.118 dosed male and female Sprague–Dawley rats (12 of each gender per dose group) with SM dissolved in sesame o...	49
2.2.6.1.2\rInhalation.McNamara et al.80 studied 6 dogs, 12 rabbits, 30 guinea pigs, 140 rats and 140 A/J mice, housed in a chamber and cont...	50
2.2.6.2 Studies in Humans	51
2.2.7 Mutagenicity	52
2.2.7.1 DNA Damage In vitro	52
2.2.7.2 Mutagenicity Studies In vitro	53
2.2.7.3 Mutagenicity Studies in Drosophila	53
2.2.7.4 In vivo Studies in Mammals	53
2.2.7.5 Studies in Humans	53
2.2.8 Carcinogenicity	54
2.2.8.1 Studies in Animals	54
2.2.8.1.1\rOral.Sasser et al.119 dosed male and female Sprague–Dawley rats as described in Section 2.6.1.1 at doses of 0 (control), 0.003, ...	54
2.2.8.1.2\rInhalation.Heston139 showed that exposure to SM vapour increased the incidence of pulmonary tumours in mice from an incidence of...	54
2.2.8.1.3\rOther Routes of Exposure.Heston141 described studies of the incidence of pulmonary tumours in mice treated intravenously with ni...	55
2.2.8.2 Studies in Humans	56
2.2.8.3 Conclusions for Carcinogenicity	57
2.2.9 Toxicity for Reproduction	58
2.2.9.1 Studies in Animals	58
2.2.9.1.1\rDevelopmental Toxicity.Rommereim and Hackett152 administered oral doses of SM at 0–2 mg kg−1 on gestation days 6–15 inclusive (r...	58
2.2.9.1.2\rFertility.In a 42 week two generation study in the rat,119 groups of 27 females and 20 males/group/generation were treated by ga...	58
2.2.9.2 Studies in Humans	59
2.2.10 Summary of SM Toxicology	60
2.3 Lewisite	60
2.3.1 Toxicokinetics	61
2.3.2 Acute Toxicity	62
2.3.2.1 Studies in Animals	62
2.3.2.2 Studies in Humans	64
2.3.3 Ocular Toxicity	65
2.3.4 Repeated Dose Toxicity	66
2.3.5 Mutagenicity	67
2.3.6 Toxicity for Reproduction	67
2.3.7 Summary of L Toxicology	68
2.4 Conclusions	68
Acknowledgements	69
References	69
Chapter 3 - Toxicology of Organophosphorus Nerve Agents	81
3.1 Introduction	81
3.2 General Substance Information	82
3.2.1 Physicochemical Properties	82
3.2.2 History	83
3.2.3 Uses	86
3.3 Hazard Characterization of Nerve Agents	86
3.3.1 Acute Effects of Nerve Agent Exposure	87
3.3.2 Historical Nerve Agent Toxicity Studies	88
3.3.2.1 Systemic Toxicity Studies	89
3.3.2.2 Vapour Exposures	93
3.3.2.3 Penetration of Skin and Clothing by Liquid Agents	98
3.3.3 Other Effects of Nerve Agent Exposure	100
3.3.4 Delayed and Long Term Effects of Nerve Agent Exposure	101
3.3.5 Effects of Low Level Nerve Agent Exposure	102
3.4 Human Estimates of Nerve Agent Toxicity	104
3.5 Summary	104
References	107
Chapter 4 - Toxicology and Treatment of Phosgene Induced Lung Injury	117
4.1 Introduction	117
4.2 Properties	119
4.2.1 Odour	119
4.2.2 Pathophysiology	119
4.2.2.1 Initial Reflex Syndrome	120
4.2.2.2 Clinical Latent Phase	121
4.2.2.3 Clinical Oedema Phase	122
4.3 History of Use	123
4.3.1 Warfare	123
4.3.2 Occupational/Accidental Exposures	124
4.4 Haber’s Law	125
4.5 Tolerance	127
4.6 Mechanisms of Phosgene Injury	128
4.7 Therapeutic Research Approaches	130
4.7.1 In vitro Studies	131
4.7.2 Small Animal In vivo Studies	134
4.7.3 Large Animal In vivo Studies	136
4.8 Recent Advances	141
4.8.1 Potential Future Therapeutic Options	143
4.8.1.1 Stem Cells	145
4.8.1.2 Growth Factors	145
4.9 Conclusions	146
Acknowledgements	147
References	147
Chapter 5 - Human Exposures to Sulfur Mustard	154
5.1 Introduction	154
5.2 Toxic Effects of SM in Humans	155
5.2.1 Effects on the Eyes	155
5.2.2 Effects on the Skin	158
5.2.2.1 Vapour	160
5.2.2.1.1\rExposure of the Forearm.Several groups have attempted to establish the threshold Ct for erythema in humans. The first systematic...	160
5.2.2.1.2\rWhole Body Exposures	161
Chamber Trials.In a series of chamber exposures carried out in India in 194240, men were exposed to Cts of SM from 40.9 to 176 m...	161
5.2.2.1.3\rQuantification of Skin Burns.There have been a number of attempts to devise methods of quantifying skin burns in terms of severi...	163
5.2.2.2 Effects of Increased Temperature on SM Injury	163
5.2.2.3 Effects of RH on SM Injury	164
5.2.2.4 Analytical Considerations	165
5.2.2.5 Clothing	166
5.2.2.5.1\rSystemic Poisoning after Vapour Exposure of the Skin.After the vapour exposures reported by Heinen et al.41 described above, no ...	167
5.2.2.6 Liquid	167
5.2.2.6.1\rPotency of SM on Human Skin and Sensitisation by Previous Exposure.In an early study, 302 workers at the UK defence establishmen...	169
5.2.2.6.2\rSensitisation.The observation from early studies that individuals who had been previously exposed to SM were more sensitive than...	172
5.3 Conclusions	173
References	175
Chapter 6 - Long-Term Effects of the Chemical Warfare Agent Sulfur Mustard	179
6.1 Introduction	179
6.2 Sulfur Mustard	180
6.2.1 Cutaneous Injury	181
6.2.2 Ocular Injury	183
6.2.3 Pulmonary Injury	185
6.2.4 Cancers	186
References	187
Chapter 7 - Toxicokinetics of Sulfur Mustard	191
7.1 Introduction	191
7.2 Experimental	193
7.2.1 Analytical Procedures	193
7.2.2 Animal Models	194
7.3 Toxicokinetics of Sulfur Mustard	195
7.3.1 Intravenous Toxicokinetics of Sulfur Mustard	195
7.3.1.1 Rat	196
7.3.1.2 Hairless Guinea Pig	197
7.3.1.3 Pig	199
7.3.1.4 Marmoset	199
7.3.2 Subcutaneous Toxicokinetics of Sulfur Mustard	200
7.3.2.1 Pig	200
7.3.3 Inhalation Toxicokinetics of Sulfur Mustard	201
7.3.3.1 Rat	201
7.3.3.2 Hairless Guinea Pig	202
7.3.3.3 Marmoset	203
7.3.4 Percutaneous Toxicokinetics of Sulfur Mustard	204
7.3.4.1 Pig	204
7.3.4.2 Hairless Guinea Pig	204
7.4 The Influence of Scavengers on the Toxicokinetics of Sulfur Mustard	206
7.5 Toxicokinetics of Sulfur Mustard in Humans	207
7.6 Conclusions	209
References	210
Chapter 8 - Modeling Organophosphorus Chemical Warfare Nerve Agents: A Physiologically Based Pharmacokinetic–Pharmacodynamic (PBPK-PD) Model of VX	213
8.1 Introduction	214
8.2 Materials and Methods	215
8.2.1 PBPK Model Structure	215
8.2.1.1 Routes	217
8.2.1.2 Endpoints	218
8.2.2 Model Parameters	218
8.2.2.1 Physiological Parameters	218
8.2.2.2 Chemical Specific Parameters	222
8.2.2.3 Pharmacodynamic Parameters	222
8.2.2.4 Dosing Parameters	222
8.2.3 Data Used for Model Parameterization and Validation	222
8.2.3.1 Intravenous Data	223
8.2.3.2 Subcutaneous Data	223
8.2.3.3 Dermal Data	223
8.2.4 Sensitivity Analyses	223
8.3 Results	224
8.3.1 Simulations	224
8.3.1.1 Data for Fitting	224
8.3.1.2 Data for Validation	224
8.3.2 Sensitivity Analyses	225
8.3.2.1 Sensitivity Analyses for the Intravenous Route	227
8.3.2.2 Sensitivity Analyses for the Subcutaneous Route	229
8.3.2.3 Sensitivity Analyses for the Dermal Route	230
8.4 Discussion	231
8.4.1 PBPK Model Structure	231
8.4.2 Model Parameters	251
8.4.3 Simulations	253
8.4.4 Sensitivity Analyses	254
8.5 Conclusions	258
Acknowledgements	258
References	259
Chapter 9 - Allometric Modeling of Mammalian Cyanogen Chloride Inhalation Lethality	264
9.1 Introduction	264
9.2 Statistical Background	265
9.2.1 Allometric Modeling and IH Toxicology	266
9.2.2 IH Dose–Response Statistics and the Toxic Load	268
9.2.3 Probit Analysis Models Used for Fitting Response Data	269
9.2.5 Healthy Subpopulation Versus General Population in Toxicity Sensitivity	271
9.3 CK: Properties and Characteristics	272
9.4 CK IH Toxicology	273
9.4.1 General Toxicology	274
9.4.2 Acute Human Toxicity	274
9.4.3 Acute Mammalian Toxicity	275
9.5 Previous Human Lethality Estimates for CK IH Toxicity	282
9.5.1 UK: Porton (Unofficial)	282
9.5.2 UK: Health Safety Executive	282
9.6 Data Analysis and Results	283
9.6.1 Data Reduction	283
9.6.1.1 Calculation and Collection of Nominal LD50s	283
9.6.1.2 Dataset Management for Probit Analysis	283
9.6.2 PS Estimation	284
9.6.3 Linear Regression Analysis	286
9.6.4 Allometric Scaling of Mammalian CK Lethality	288
9.6.5 TLE and Time–Concentration Relationship	290
9.6.6 Human Lethality Estimates for CK IH	291
9.6.7 Human Severe Effect Estimates for CK IH	291
9.6.8 Comparison of Estimates: Present Chapter with Previous Work	293
9.6.9 Comparison of CK and AC Human Lethality Estimates	294
9.6.10 Comparison of CK and AC Mammalian Lethality	295
9.7 Discussion and Conclusions	298
References	298
Subject Index	307

Chemical Warfare Toxicology

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