Toxicology of Cyanides and Cyanogens

Alan H. Hall Toxicology Consulting and Medical Translating Services, Inc., USA Department of Health & Human Services, Colorado School of Public Health, USA Gary E. Isom Department of Pharmacology and Toxicology, Purdue University, USA Gary A. Rockwood Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense, USA

List of Contributors xv

Foreword xix

1 Acute cyanide toxicity 1
Andrea R. Allen, Lamont Booker, and Gary A. Rockwood

1.1 Introduction 1

1.2 Pharmacokinetic properties of cyanide 2

1.3 Pharmacodynamic properties of cyanide 4

1.4 Acute cyanide toxicity – routes of administration 5

1.5 Neurological and behavioral effects following acute cyanide exposure 12

1.6 Summary 14

References 14

2 Chronic cyanide exposure 21
Jason D. Downey, Kelly A. Basi, Margaret R. DeFreytas, and Gary A. Rockwood

2.1 Introduction 21

2.2 Sources of chronic cyanide exposure 21

2.3 Chronic cyanide exposure in human disease 23

2.4 Experimental models of chronic cyanide exposure 30

2.5 Conclusion 35

References 36

3 Physicochemical properties synthesis applications and transport 41
David E. Thompson and Ilona Petrikovics

3.1 Introduction 41

3.2 Natural sources of cyanide 41

3.3 Isolation and characterization of cyanide 43

3.4 Industrial production of cyanide 44

3.5 Applications and uses of cyanide 46

Acknowledgments 50

References 50

4 Cyanide metabolism and physiological disposition 54
Gary E. Isom, Joseph L. Borowitz, and Alan H. Hall

4.1 Introduction 54

4.2 Metabolism and toxicokinetics 55

4.3 Non-enzymatic detoxification of cyanide 63

4.4 Diseases associated with altered cyanide metabolism 64

4.5 Metabolism and endogenous generation of cyanide 65

References 65

5 Biochemical mechanisms of cyanide toxicity 70
Gary E. Isom and Joseph L. Borowitz

5.1 Introduction 70

5.2 Cytochrome oxidase inhibition and mitochondrial dysfunction 72

5.3 Oxidative stress and inhibition of cellular oxidative defense 75

5.4 Cyanide-induced changes in cellular Ca2+ regulation 76

5.5 Cyanide-induced cell death and post-intoxication lesions 77

5.6 Alteration of intermediary metabolism and lactic acidosis 78

5.7 Conclusion 78

References 79

6 Environmental toxicology of cyanide 82
Samantha L. Malone, Linda L. Pearce, and Jim Peterson

6.1 Introduction 82

6.2 Environmentally relevant chemistry of cyanides 83

6.3 Occupational concerns 87

6.4 Ground/surface water 87

6.5 Exposure to cyanogens through diet 89

6.6 Dietary health hazards 89

6.7 Cassava consumption 90

6.8 Fires and smoke 91

6.9 Conclusion 92

References 93

7 Cyanide in the production of long-term adverse health effects in humans 98
Julie Cliff, Hipolito Nzwalo, and Humberto Muquingue

7.1 Introduction 98

7.2 Long-term adverse health effects 100

7.3 Conclusions 107

References 107

8 Pediatric cyanide poisoning 113
Robert J. Geller

8.1 Introduction 113

8.2 Sources of acute cyanide poisoning in children 114

8.3 Manifestations of acute cyanide poisoning 122

8.4 Cyanide antidotes 124

8.5 Conclusion 126

References 126

9 Sodium nitroprusside in intensive care medicine and issues of cyanide poisoning cyanide poisoning prophylaxis and thiocyanate poisoning 129
Prasad Abraham, Alissa Lockwood, John Patka, Marina Rabinovich, Jennifer Sutherland, and Katleen Chester

9.1 Introduction 129

9.2 History 129

9.3 Mechanism of action 130

9.4 Metabolism 130

9.5 Evidence for CN− toxicity associated with SNP 132

9.6 Incidence of CN− toxicity 134

9.7 Challenges associated with CN−monitoring 140

9.8 Safe use of SNP – clinical monitoring 141

9.9 Prevention and treatment of CN−toxicity 142

9.10 Conclusions 146

9.11 Disclosure 146

References 146

10 Smoke inhalation 151
Alan H. Hall and Stephen W. Borron

10.1 Introduction 151

10.2 Cyanide in smoke inhalation 152

10.3 Plasma lactate levels as a screening assay 154

10.4 Exhaled breath cyanide meters 154

10.5 Cobinamide colorimetric quantitative/qualitative blood cyanide measurements 154

10.6 Additional information 154

References 156

11 Occupational exposure to cyanide 158
Tee L. Guidotti

11.1 Introduction 158

11.2 Firefighters 159

11.3 Hazmat and counter-terrorism 161

11.4 Other occupations 162

11.5 Illicit operations using cyanide 163

References 164

12 Cyanogenic aliphatic nitriles 166
Stephen W. Borron

12.1 Overview 166

12.2 Toxicology 166

12.3 Case reports of human toxicity of specific nitriles 172

12.4 Antidotal treatment 178

12.5 Summary 179

Acknowledgments 179

References 179

13 The special case of acrylonitrile (CH2=CH–C≡N) 181
Dana B. Mirkin

13.1 Introduction – clinical vignettes 181

13.2 Physical and chemical properties 182

13.3 History – preparation – manufacture 182

13.4 Occurrence 183

13.5 Compounds and uses 183

13.6 Hazardous exposures 184

13.7 Toxicokinetics 184

13.8 Mode of action 185

13.9 Clinical effects 186

13.10 Diagnosis – toxicity 189

13.11 Treatment – antidote 190

13.12 Biological monitoring 191

13.13 Exposure limits 191

References 192

14 Cyanide in chemical warfare and terrorism 195
René Pita

14.1 Cyanides as chemical warfare agents 195

14.2 Cyanide and chemical terrorism 200

14.3 Conclusions 206

References 206

15 Cyanide-induced neural dysfunction and neurodegeneration 209
Gary E. Isom and Joseph L. Borowitz

15.1 Introduction 209

15.2 Cyanide exposure and manifestations of toxicity 210

15.3 Cyanide-induced histotoxic hypoxia and metabolic dysfunction 210

15.4 Neurochemical actions of cyanide in the nervous system 212

15.5 Cyanide-induced brain injury and neurodegeneration 214

15.6 Endogenous cyanide generation in CNS 215

15.7 Cyanide-induced neurological disorders 216

15.8 Conclusion 220

References 220

16 Cyanides and cardiotoxicity 224
J.-L. Fortin, T. Desmettre, P. Luporsi, and G. Capellier

16.1 Introduction 224

16.2 Physiopathology 224

16.3 Clinical aspects 226

16.4 Treatment 228

16.5 Conclusion 230

References 230

17 Respiratory effects of cyanide 232
A. Eisenkraft, A. Falk, and Y. Bentur

17.1 Background 232

17.2 Mechanisms of the respiratory effects of cyanide 233

17.3 Clinical manifestations and animal studies 238

17.4 Management of cyanide poisoning and its respiratory effects 241

17.5 Conclusion 245

References 245

18 The analysis of cyanide in biological samples 249
Brian A. Logue and Brendan L. Mitchell

18.1 Introduction 249

18.2 Biological matrices 249

18.3 Sample storage 251

18.4 Sample preparation 251

18.5 Spectroscopy 252

18.6 Gas chromatography 254

18.7 High-performance liquid chromatography 256

18.8 Capillary electrophoresis 257

18.9 Electrochemical methods 258

18.10 Sensors 258

18.11 Cyanide metabolites 260

18.12 Insights on cyanide analysis 260

References 260

19 Postmortem pathological and biochemical diagnosis of cyanide poisoning 268
Daniel Lugassy and Lewis Nelson

19.1 Introduction 268

19.2 Cyanide pathology and antemortem presentation 268

19.3 Exposures 269

19.4 Autopsy features 269

19.5 Biochemical analysis 271

19.6 Risk to autopsy staff 273

References 274

Further reading 275

20 Medicolegal and forensic factors in cyanide poisoning 276
Jorn Chi-Chung Yu and Ashraf Mozayani

20.1 Introduction 276

20.2 Forensic practice for the investigation of cyanide poisoning 277

20.3 Discussion 278

20.4 Conclusion 280

References 280

21 Brief overview of mechanisms of cyanide antagonism and cyanide antidotes in current clinical use 283
Alan H. Hall

21.1 Introduction 283

21.2 Methemoglobin inducers 283

21.3 Sulfur donors 285

21.4 Direct cyanide chelating agents 285

21.5 Conclusion 286

References 286

22 Cyanide antidotes in clinical use: 4-dimethylaminophenol (4-DMAP) 288
Alan H. Hall

22.1 Introduction 288

22.2 Mechanism of action 288

22.3 Experimental data 289

22.4 Published clinical data 289

22.5 Adverse/side effects 290

22.6 Conclusions 291

References 291

23 Cyanide antidotes in clinical use: dicobalt EDTA (Kelocyanor®) 292
Alan H. Hall

23.1 Introduction 292

23.2 Mechanism of action 292

23.3 Experimental data 293

23.4 Published clinical data 293

23.5 Adverse/side effects 294

23.6 Conclusions 294

References 294

24 Amyl nitrite sodium nitrite and sodium thiosulfate 296
Richard J. Geller

24.1 History and chemistry 296

24.2 Theoretical bases for use/mechanism of action 297

24.3 Pharmacokinetics 299

24.4 How supplied 299

24.5 Indication and dosing of intravenous antidotes 300

24.6 Adverse effects 301

24.7 Conclusions 301

References 301

25 Cyanide antidotes in current clinical use: hydroxocobalamin 304
Alan H. Hall and Stephen W. Borron

25.1 Background and historical perspective 304

25.2 Pharmacology 305

25.3 Experimental animal studies 306

25.4 Human experience 306

25.5 Dosage and route of administration 306

25.6 Adverse effects 306

25.7 Laboratory interferences 307

25.8 Comparison with other antidotes 307

25.9 Conclusion 307

References 307

26 Cyanide antidotes in development and new methods to monitor cyanide toxicity 309
Matthew Brenner, Sari Mahon-Brenner, Steven E. Patterson, Gary A. Rockwood, and Gerry R. Boss

26.1 Introduction 309

26.2 Cobinamide and sulfanegen 310

26.3 Other cyanide antidotes in development 313

26.4 New research methods to diagnose and monitor cyanide poisoning and therapy 313

26.5 Conclusions 316

References 316

27 Recent perspectives on alpha-ketoglutarate 317
R. Bhattacharya

27.1 Introduction 317

27.2 Cyanide toxicity and its treatment 318

27.3 A-KG as a cyanide antidote 318

27.4 The need for an oral antidote 321

27.5 A-KG as an oral antidote 321

27.6 Some key functions of A-KG 323

27.7 Efficacy of A-KG against other toxins 324

27.8 Role of A-KG as a nutritional supplement 324

27.9 Conclusion 325

Acknowledgments 325

References 325

28 Azide poisonings 330
Thomas L. Kurt and Wendy Klein-Schwartz

28.1 Introduction 330

28.2 Lack of cyanide antidote efficacy 331

28.3 Uses of sodium azide 331

28.4 Review of reported sodium azide human poisoning cases 331

28.5 Human experimental exposures to sodium azide and hydrazoic acid 332

28.6 Signs and symptoms 332

28.7 Fatal cases 332

28.8 Historical perspective 333

28.9 Mechanism(s) of action 333

28.10 Autopsy findings 333

28.11 Other outcomes 333

28.12 Occupational health issues 333

28.13 Occupational/environmental exposure limits/recommendations 334

28.14 Laboratory evaluation 334

28.15 Conclusion 334

Acknowledgments 334

Conflict of interest 334

References 334

Index 337