Toxicology of Cyanides and Cyanogens

Name: Toxicology of Cyanides and Cyanogens | Experimental, Applied and Clinical Aspects
Brand: Wiley-Blackwell
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Experimental, Applied and Clinical Aspects

Alan H. Hall Gary E. Isom Gary A. Rockwood(Herausgeber*in)

Wiley-Blackwell (Verlag)

Erschienen am 13. Oktober 2015

368 Seiten

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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

Chapter 1
Acute cyanide toxicity

Andrea R. Allen,, Lamont Booker, and Gary A. Rockwood

Disclaimer: the views expressed in this chapter are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government.

At a Glance

Cyanide intoxication can result from diet, fires, alternative and standard medical treatments, industrial exposure, and intentional exposure (e.g., suicide, homicide, terrorism).
Cyanide blocks the oxidative respiration pathway, impeding oxygen usage within tissues; the major metabolic pathway results in the formation of less toxic thiocyanate.
Across species, long-term effects of cyanide post-exposure include a range of behavioral and neurological dysfunction, such as Parkinsonism.
Antidotal treatments for acute cyanide toxicity may significantly reduce adverse sequelae and provide a better quality of life post-exposure.

1.1 Introduction

Cyanide (CN) is a potent toxicant with rapid onset of histotoxic anoxia through inhibition of mitochondrial oxidative phosphorylation (Way, 1984), inhibition of oxidative metabolism (cytochrome C oxidase (CcOX) inhibition), and alteration of critical cellular ion homeostasis (Gunasekar et al., 1996). CN exists in a variety of forms, including gaseous hydrogen cyanide (HCN), water-soluble potassium (K) and sodium (Na) salts, poorly water-soluble mercury (Hg), copper (Cu), gold (Au), and silver (Ag) CN salts (Leybell et al., 2011). Cyanogens, which are glycosides of sugar and CN-containing aglycon (Makkar et al., 2007), include complex nitrile-containing compounds that can generate free CN of toxicological significance (Rao et al., 2013). Within the liver, the enzyme rhodanese catalyzes the conversion of CN to thiocyanate (SCN), which is normally excreted through the kidneys. CN can bind to both the oxidized and reduced forms of CcOX, but it possesses a greater affinity for the oxidized form (Van Buuren et al., 1972).

Cyanogenic compounds, such as amygdalin, can be found in certain plants, particularly in the seeds and pits of members of the genus Prunus, which includes apricot pits, peach pits, cherry pits, apple seeds, and almond husks (Shepherd & Velez, 2008). Other sources of CN exposure include exposure from industrial products and processes. Worldwide industrial consumption of CN is estimated to be 1.5 million tons per year, and occupational exposures account for a significant number of CN poisonings (Cummings, 2004). CN is typically used as a poison (e.g., used during World War II in concentration camps; used as a chemical for pest control). CN is an ingredient in some jewelry cleaners, photographic solutions, metal polish, and is also a by-product of the manufacture of some synthetic products such as nylon, rayon, polyurethane foam, and insulation (Hamel, 2011). In industrialized countries, the most common cause of CN poisoning is fires (Megarbane et al., 2003). Toxicologic evaluation of passengers following the explosion in 1985 of a Boeing 737 during take-off in Manchester, England, revealed that 20% of the 137 victims who escaped had dangerously elevated blood levels of carbon monoxide, while 90% had dangerously elevated levels of CN (Walsh & Eckstein, 2004; Jameson, 1995). Lastly, CN exposure can also occur via acts of terrorism, murder, and suicide.

The intentional and unintentional use, or threat of use, of CN in domestic and foreign incidents has occurred in recent years. These include the 1995 Tokyo subway attack (Sauter & Keim, 2001), the 2002 recovery of stored CN in Paris, France, linked to Al-Qaeda operatives (Cloud, 2004), and the 2004 discovery by US forces of "cookbooks" on how to make HCN. Some recent threats include images of a "chemical laboratory" in a house in Fallujah, Iraq, that was allegedly used by terrorists linked to Abu Musab al-Zarqawi (Gertz, 2004), contamination of smokeless tobacco products with CN from a local merchant (Lenart et al., 2010), and the 2012 London Olympic threat to distribute CN-adulterated lotions (Bromund et al., 2012; Ritz, 2012). The Centers for Disease Control and Prevention (CDC) and the Occupational Safety and Health Administration (OSHA) developed regulations for CN and set permissible exposure limits at 10 ppm and 4.7 ppm, respectively (www.cdc.gov/niosh; www.osha.gov). Because of the rapidly debilitating actions of CN, it is necessary to quickly diagnose the level of exposure and provide supportive treatment to counteract the effects from CN intoxication.

Acute toxicity can be defined as the antagonistic effects resulting from a single exposure to a chemical substance or repeated exposures within a short period of time ( h) (Andrew, 2009). The clinical features of acute CN poisoning are variable, and the major determinants of severity and mortality are the source of exposure (CN or CN compound), the route and magnitude of exposure (amount and duration), and the effects and the time of any treatments that may have been tried (Yen et al., 1995). Acute CN toxicity can take place through ingestion, membrane absorption, and inhalation. Since there are no pathognomonic clinical signs and symptoms for its toxicity, it is pertinent to acquire a full patient or epidemiologic history and consider the diagnosis in cases of unexplained sudden collapse or acidosis (Nnoli et al., 2013). In a clinical environment, CN toxicity can occur after treatment with sodium nitroprusside, which is often used in pediatric intensive care units (Baek et al., 2010) for its strongly antihypertensive properties (Moffett & Price, 2008) and various pharmacokinetic advantages (Gilboa & Urizar, 1983) of rapid distribution and short half-life. Early diagnosis for acute CN toxicity is challenging because of the multitude of symptoms associated with CN intoxication (i.e., lightheadedness, nausea, pulmonary edema, restlessness, etc.). Unfortunately, instantaneous detection of CN exposure in deployed operations fields for first responders and the military is currently not available, and CN exposure often presents a narrow therapeutic window of treatment. This chapter will explore the pharmacokinetic/pharmacodynamic properties of CN, the effects of acute CN toxicity in various experimental models, and the chronic neurodegenerative implications as a result of acute CN toxicity.

1.2 Pharmacokinetic properties of cyanide

1.2.1 Absorption

The pharmacokinetic properties of CN can vary depending on the general composition of the CN (i.e., KCN, NaCN, CuCN, AgCN, and HCN) and route of exposure. CN can be rapidly lethal as a result of its fast absorption and distribution into tissues and the bloodstream, binding to metalloenzymes and rendering them inactive (Solomonson, 1981). The chemical composition of CN is one property that greatly influences the rate of absorption. The Henderson Hasselbach equation describes the ratio of ionized versus unionized at a particular pH, or vice versa. Smaller, neutral, non-ionized compounds are favored for absorption across biological membranes. Since KCN and NaCN are water soluble, they readily undergo dissolution and are absorbed in the stomach after ingestion, although the presence of food in the stomach slows the absorption of CN and potentially delays the onset of toxicity. With the pKa of for HCN, passive diffusion will be less efficient at alkaline pHs. Dermal absorption of the ionized solution is unfavorable. In a clinical and in a laboratory setting, HCN in contrast to NaCN and KCN has a faster onset of toxicity because both NaCN and KCN must first be converted to HCN in the body or skin unless equilibrium shifts to blood from stomach (Ballantyne, 1987; Curry & LoVecchio, 2001). HCN exists as a non-ionized molecule and thus can diffuse across the lipid membrane. Additionally, HCN has the lowest molecular weight in comparison to other forms of CN, enabling it to simply diffuse readily across the membrane. Gettler and Baine (1938) studied the effects of dose and absorption rate in dogs. Three dogs were administered lethal doses of HCN via gavage, and the difference between the dose of CN given and the portion of CN remaining in the stomach and intestines was determined to represent the total amount absorbed. This difference can be attributed to enterohepatic recirculation of compounds that have phase II metabolism, where a drug is absorbed from the gastrointestinal tract (GI), goes to the liver and is passed into the bile, and then is re-secreted into the GI through the bile. Dogs were administered 20 mg, 50 mg, or 100 mg HCN, and all subsequently died within 2.5 hours. The absorbed fraction was determined to be 72%, 24%, and 17% respectively, suggesting that zero-order kinetics is independent of the CN concentration (Gettler & Baine, 1938). In another study Sousa et al. (2003) assessed the absorption rate of CN in rats and pigs given 1.2 mg/kg KCN via gavage. Blood CN concentrations in rats reached a peak after 15 min (0.15 mg/100 ml) whereas in pigs the blood CN concentrations reached a peak within 30 min (0.23 mg/100 ml). Irrespective of the route of exposure, species, or impeding factors such as the presence of food in the stomach, CN absorption into the bloodstream occurs within seconds to minutes after exposure (Sousa et al., 2003).

1.2.2 Distribution

CN is rapidly distributed throughout the body after absorption (Ahmed & Farooqui, 1982; Djerad et al., 2001). Subsequently, tissues with the highest oxygen demand (i.e., brain, heart, liver, kidney, and stomach) are the most drastically affected...

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