Environmental Toxicology and Pharmacology 26 (2008) 113122

Contents lists available at ScienceDirect

Environmental Toxicology and Pharmacology

Mini-review

Chemical warfare agents

Department of Chemical Engineering, Panjab University, Chandigarh, India Department of Medicine, Government Medical College and Hospital, Chandigarh 160030, India c Department of Respiratory Medicine, Pinderelds General Hospital, Aberford Road, Wakeeld WF1 4DG, UK d Department of Neurology, Army Hospital (Research & Referral), New Delhi, India e Department of Internal Medicine, Post Graduate Institute of Medical Education & Research, Chandigarh, India f City Clinic, MDC, Panchkula 134109, Haryana, India
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Chemical warfare agents (CWAs) are dened as any chemical substance whose toxic properties are utilised to kill, injure or incapacitate an enemy in warfare and associated military operations. Chemical agents have been used in war since times immemorial, but their use reached a peak during World War I. During World War II only the Germans used them in the infamous gas chambers. Since then these have been intermittently used both in war and acts of terrorisms. Many countries have stockpiles of these agents. There has been a legislative effort worldwide to ban the use of CWAs under the chemical weapons convention which came into force in 1997. However the manufacture of these agents cannot be completely prohibited as some of them have potential industrial uses. Moreover despite the remedial measures taken so far and worldwide condemnation, the ease of manufacturing these agents and effectiveness during combat or small scale terrorist operations still make them a powerful weapon to reckon with. These agents are classied according to mechanism of toxicity in humans into blister agents, nerve agents, asphyxiants, choking agents and incapacitating/behavior altering agents. Some of these agents can be as devastating as a nuclear bomb. In addition to immediate injuries caused by chemical agents, some of them are associated with long term morbidities and psychological problems. In this review we will discuss briey about the historical background, properties, manufacture techniques and industrial uses, mechanism of toxicity, clinical features of exposure and pharmacological management of casualties caused by chemical agents. 2008 Elsevier B.V. All rights reserved.

Article history: Received 5 August 2007 Received in revised form 6 March 2008 Accepted 11 March 2008 Available online 18 March 2008 Keywords: Blister agents Nerve agents Asphyxiants Choking agents

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blister agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Sulfur mustards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Nitrogen mustards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 115 115 115 115 115 116 116 116 116 116 116 116

Abbreviations: CWA, chemical warfare agent; WWI, rst world war; WWII, second world war; US, United States (of America); CWC, chemical weapons convention; NATO, North Atlantic Treaty Organisation; SM, sulfur mustard; NM, nitrogen mustard; DNA, de-oxy ribonucleic acid; LD50 , lethal dose in 50%; LCt50 , lethal concentration in 50%; TEPP, tetra-ethyl pyrophosphate; PTSD, post-traumatic stress disorder; FDA, US Food and Drug Administration; 2-PAM Cl, 2-pralidoxime chloride; CK, cyanogen chloride; HCN, hydrogen cyanide; SA, arsine; PS, chloropicrin; CG, phosgene; ARDS, acute respiratory distress syndrome. Corresponding author. Tel.: +91 172 2561355; fax: +91 172 2608488. E-mail address: [email protected] (S. Chauhan). 1382-6689/$ see front matter 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.etap.2008.03.003

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4.

5.

6.

7. 8. 9.

2.2.4. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Lewisite (L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nerve agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asphyxiants/blood agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Cyanogen chloride (CK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Hydrogen cyanide (HCN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Arsine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Choking/pulmonary damaging agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Chlorine (Cl) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Chloropicrin (PS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Phosgene (CG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioural agents/incapacitating agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Mechanism of human toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection of CWAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Destruction of chemical weapons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Chemical warfare is the use of the toxic properties of chemical substances to kill, injure or incapacitate an enemy in warfare and associated military operations. A chemical substance intended for such use in military operations is dened as a chemical warfare agent (CWA). Chemical agents have been used in war since times immemorial. These have been elaborately described in ancient Chinese literature. In 600 B.C. Helleborus roots were used successfully by the Athenians to contaminate water supplies during the siege of Kirrha. Spartans ignited pitch and sulfur to create toxic fumes during the Peloponnesian War in 429 B.C. Thereafter, there have been intermittent use of CWAs in battleelds, but their use reached a peak during World War I (WWI). French were the rst to use ethylbromoacetate in WWI. It was followed by use of o-dianisidine chlorosulphonate, chloroacetate, chlorine, phosgene, hydrogen cyanide, chlorine, diphenylchloroarsine, ethyl- and methyldichloroarsine and sulfur mustard resulting in nearly 10,000 deaths and over a million casualties (Eckert, 1991). CWAs were not used on the eld during World War II (WWII) due to the fear that the enemy possessed more deadly CWAs, except for by the Germans who used them in the infamous gas chambers for mass genocide of Jews. After WWII, CWAs have been used intermittently both in war, as in the IraqIran war, and acts of terrorisms as in the Japanese underground rail station attacks (Okumura et al., 1996). It is estimated that nearly 1,00,000 United States (US) troops may have been exposed to CWAs during operation Desert Storm. There has been a legislative effort worldwide to ban the use of CWAs. The chemical weapons convention (CWC) which came into force in 1997 stated that all member countries must destroy all chemical weapons over a 10-year period, with the treaty providing a leveling out principle that ensures possessors destroy their stockpiles at roughly the same time. More than 170 countries have signed the CWC and 139 have ratied it. The manufacture of some of these agents however cannot be banned because of important industrial uses. These agents also still remain a threat especially from countries that do not possess nuclear technology as these are easy to manufacture, cheap and have devastating effects. Moreover, these can also be used effectively as weapons of small scale terrorist attacks. North Atlantic Treaty Organization (NATO) has classied agents of chemical terrorism as blister agents, nerve agents, asphyxiants, choking agents and incapacitating/behavior altering agents (Table 1). In this review we will discuss briey about the CWAs. The CWAs are classied and their historical perspective, manufacture, mechanisms of toxicity, clinical features on exposure and treatment are discussed. This review is conned to synthetic chemicals only and biological agents are not discussed. 2. Blister agents Blister agent or vesicants are a group of chemicals that cause severe blistering when they come in contact with skin. These may also have systemic effects if absorbed. These agents are not very lethal as far as causing death is concerned but can incapacitate the enemy and overload the already burdened health care services during war time. These include sulfur mustard, nitrogen mustard and lewisite. 2.1. Sulfur mustards Sulfur mustards (SMs), commonly known as mustard gas, are alkylating agents capable of causing short and long term morbidity. Since these had a mustard like odor, these were called sulfur mustard or mustard gas. They were discovered acciden-

Table 1 Classication of chemical warfare agents 1. Blister agent Sulfur mustard Nitrogen mustard Lewisite 2. Nerve gases G series Tabun Sarin Soman V series VE VX VG VM 3. Choking agent Chlorine Chloropicrin Phosgene 4. Asphyxiants Cyanogen chloride Hydrogen cyanide Arsine 5. Behavioral altering agent

tally in 1822. Guthrie in the United Kingdom and Niemann in Germany synthesized, 2,2-dichlorodiethylsulde, also known as sulfur mustard (SM) in 1860. In 1917, the German forces used SM for the rst time in battleeld. It accounted for about 70% of the million-plus gas related casualties in WWI. Several varieties and mixtures of SMs have been employed (HD, H, HT, HL, HQ). The NATO codenamed SM as H which stood for Germans or Hunns. The letter D in HD indicated that it was a distilled product of SM or H. 2.1.1. Manufacture Chemically mustard gas is a -chloro thioether with the formula C4 H8 Cl2 S. The Germans produced SM using the Meyer process. This involved reacting ethylene with hypochlorous acid followed by sodium sulde, forming , -dihydroxy-methyl sulde. Further heating with hydrochloric acid produced SM. In the US, the Levenstein process was used in which ethylene was reacted with sulfur monochloride. Another process used in the US involved the reaction between ethylene oxide and hydrogen sulde to form bis-(2-hydroxyethyl)-thioether, which on further reaction with hydrochloric acid forms SM. Under the CWC the stockpiles of SM are required to be destroyed by 2007. The various methods for destruction include hightemperature incineration, plasma treatment and electrochemical reduction, hydrolysis and oxidation and reacting sulfur dissolved in ethylenediamine with SM (Menger and Elrington, 1990; Ganesan et al., 2005). 2.1.2. Properties Sulfur mustard is not a gas but a pale yellow, oily liquid of specic gravity of 1.27 that vaporizes at 25 C and decomposes at 217.5 C. Hence it is a liquid in cold and damp environments and easily vaporizes in warm dry environments. It is heavier than air with a density 5.6 times that of air. It has an odor of mustard in the impure form but the pure form is colorless and odorless. It is sparingly soluble in water and soluble in fat, fat solvents, and other common organic solvents. It penetrates ordinary clothes easily in the vaporized form. 2.1.3. Uses It has no industrial use at present.

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2.1.4. Mechanism of human toxicity SMs are alkylating agents. They damage all exposed epithelial surfaces, both in aerosol and liquid form. These effects appear within 212 h after exposure, depending on the exposure dose. The exact mechanism of its toxicity is yet to be elucidated. Most authors believe that it dissolves aqueous media, such as sweat, rapidly forming extremely reactive cyclic ethylene sulfonium ions. These reactive ions react with deoxyribonucleic acid (DNA) in rapidly dividing cells leading to cellular death and inammatory reactions (Papirmeister et al., 1985). An alternative theory suggests that it depletes the cell of Glutathione which leads to oxidative damage and cell death (Gross et al., 1993). 2.1.5. Clinical features Exposure to SM results in high morbidity and psychological impact but low mortality. The mortality rate with sulfur mustard is estimated to be 25%. The lethal dose of HD to cause death in 50% of persons exposed (LD50 ) is estimated to be 100 mg/kg and lethal concentration of vapor/aerosol to cause death in 50% of exposed persons (LCt50 ) is 15,000 mg min/mm3 (Raber et al., 2001). Most often exposed surfaces i.e. skin, airways, and eyes suffer the brunt of the damage. Irritation of the eyes followed by conjunctivitis, photophobia, blepharospasm, pain, and corneal damage, which can lead to perforation, is seen after exposure of the eyes. Glaucoma may develop later as a result of scarring. Dermatological manifestations are akin to second degree burns, StevenJohnsons syndrome or toxic epidermal necrolysis. Contact with skin can manifest as painful erythema, vesicles or bullae containing a transudative straw colored uid. As the uid is a transudate it does lead to as much protein loss as would be expected with burns of a similar nature. Inhalation of SM leads to irritation of the nose, epistaxis, pharyngeal pain, laryngitis, voice changes, cough and dyspnea. Terminally, there may be necrosis of airways with hemorrhagic edema, pseudomembrane formation and obstruction of the bronchi. Systemic absorption from ingestion affects the gastrointestinal tract (nausea and vomiting lasting up to 24 h), central nervous system (seizures, behavioral abnormalities and psychological problems) and also causes bone marrow suppression. Pseudomembrane formation and laryngospasm are the major cause of death in the rst 24 h. Secondary bacterial pneumonia may cause mortality between the third and fth days. Bone marrow suppression which peaks in 721 days is a cause of delayed mortality. Late complications which do occur after exposure to SM include ulcerative keratitis, chronic bronchitis, pulmonary brosis, hypo or hyperpigmentation of skin and psychological problems. In a study involving 500 soldiers who were exposed to SM during the IranIraq war (19831988) showed that all of them developed either pulmonary or ocular complications 15 years after the war (Mohammad et al., 2004). Chronic low grade exposure also results in morbidity (chronic conjunctivitis with impaired vision, nasal polyps, anorexia, vomiting weight loss, irritability, bladder carcinoma and leukemia). 2.1.6. Treatment There is no specic antidote. Supportive treatment remains the mainstay. Removal of exposed persons by well protected rescuers is of prime importance. Thereafter removal of all clothing and giving a through bath helps in decontamination. Clothing removed should be packed in plastic bags. Topical cortisone may be of benet in erythematous skin lesion. Larger bullae require unroong with saline irrigation and application of antibiotics (silver sulfadiazine or modied Dakins solution) over denuded areas. Management of large areas of skin involvement is similar to burns patient requiring supportive measures but with special regard to uids as these patients are prone to pulmonary edema. Irrigation, topical antibiotic and steroids are required for exposure to

eyes. Chemical pneumonitis, characterized by productive cough, dyspnea and fever, occurs within 1224 h of inhalation. Infection generally occurs on the third to fth day, signaled by an increased fever, pulmonary inltrates, and an increase in sputum production with a change in color. Formation of pseudomembrane necessitates breoptic bronchoscopy. Bronchodilators and glucocorticoids are of benet for bronchospasm. Bone marrow suppression beginning on the 3rd day and peaking at 714 days requires granulocyte colony-stimulating factor, transfusion support or even bone marrow transplants. Recent research has shown some benecial effects of vanilloid compounds and N-acetylcysteine in animal trials. 2.2. Nitrogen mustards Nitrogen mustards (NMs) are alkylating agents, like SMs. These have also been classied under blister agents by NATO and are nitrogen analogues of SMs. They are commonly known by their military designations i.e. HN-1 (bis(2-chloroethyl) ethylamine), HN-2 (bis(2-chloroethyl) methylamine), and HN-3 ( ). These were produced in 1920s and 1930s as potential CWAs. During WWII, nearly 100 tons of HN-1 was produced by the US and 2000 tons of HN-3 by Germany, but these were never used. HN-1 was originally used for treatment of warts but later found itself in category of CWAs. HN-2 and HN-3 were specically produced as CWAs. 2.2.1. Properties HN-1 (bis(2-chloroethyl) ethylamine) has the chemical formula C6 H13 Cl2 N It has a faint, shy or musty odor. It is sparingly soluble in water but miscible with acetone and other organic solvents and decomposes at temperatures greater than 194 C. HN-2(bis(2chloroethyl) methylamine) has the chemical formula C5 H11 Cl2 N. It has a fruity odor at high concentrations and a soapy odor at low concentrations. HN-3 (tris(2-chloroethyl) amine) has the chemical formula C6 H12 Cl3 N. It is odorless when pure but has been reported to have a bitter almond odor. It is the most stable of the nitrogen mustards but decomposes at temperatures greater than 256 C. It has a much lower vapor pressure than HN-1 or HN-2 and is insoluble in water. 2.2.2. Uses HN-1, 2 and 3 have no utility except as a CWA. 2.2.3. Mechanism of human toxicity These are alkylating agents and damage the DNA in dividing cells like the SMs (Papirmeister et al., 1985; Gross et al., 1993). 2.2.4. Clinical features Typically, signs and symptoms of NM exposure do not occur immediately. The onset of symptoms may be up to several hours after exposure to the agent. The concentration of the agent exposed to would determine how soon symptoms occur after contact. These agents, like SMs, affect the skin, eyes, respiratory tract and gastrointestinal tract. Like SMs, systemic absorption can lead to bone marrow suppression and central nervous system effects. 2.2.5. Treatment As no specic antidote exists for NM exposure, management is supportive and on similar lines as that of SMs. 2.3. Lewisite (L) This agent is classied as a blistering agent. It was developed as a potential CWA during WWI, but by the time it was synthesized the war had ended. During WWII it was found to be less effective

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as compared to SM and therefore was not stockpiled. It also gets hydrolysed in humid environment; there by rendering it less effective in operational conditions. Though it has never been used in warfare, it is classied as a potential CWA. 2.3.1. Manufacture Synthesis can be carried out by reacting arsenic trichloride with acetylene in the presence of a hydrochloric acid solution of mercuric chloride. 2.3.2. Properties Lewisite chemically is C2 H2 AsCl3 (2-chloroethenyldichloroarsine). It is usually a mixture of the isomers 2-chlorovinylarsonous dichloride, bis(2-chloroethenyl) arsinous dichloride and tris(2chlorovinyl) arsine. It has a density of 1.89 g/cm3 with melting and boiling points of 18 and 190 C respectively. It hydrolyses in water to form hydrochloric acid, and in contact with alkaline solutions can form poisonous trisodium arsenate. 2.3.3. Uses It was used initially as antifreeze for mustard gas or to penetrate protective clothing in special situations by the US. However it was declared obsolete in 1950s and it has no present industrial use. 2.3.4. Mechanism of human toxicity It can easily penetrate ordinary clothing and even rubber. It is a powerful blistering agent and damages the surfaces it comes in contact with. Since it also contains arsenic, some features of arsenic toxicity can also develop. 2.3.5. Clinical features The LD50 of L is estimated to be 30 mg/kg and LCt50 is 100,000 mg min/mm3 for dermatological manifestations (Raber et al., 2001). Signs and symptoms are similar to other blistering agent. In addition, refractory hypotension known as Lewisite shock, can develop in persons exposed to L. Bone marrow suppression is not a feature of toxicity. 2.3.6. Treatment Removal of casualties by well protected staff from area of contamination is most important followed by removal of clothing and a liberal bath. In addition to supportive treatment, a specic antidote British anti-Lewisite (dimercaprol, BAL) is used for systemic or severe toxicity. It is a chelating agent which has proved to be very effective and is widely used (Eagle et al., 1946; Oeheme, 1972). Other chelating agents available include sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3 dimercaptosuccinic acid (DMSA) and the mono and dialkylesters of DMSA. All of them are derivatives of BAL. DMPS and DMSA can be given both intravenous as well as orally and are believed to be possibly more effective. 3. Nerve agents These are organophosphorus compounds which inhibit the enzyme acetylcholinesterase. Cholinesterase inhibitors have been used in the treatment of human diseases, the control of insect pests, and more notoriously as CWAs and weapons of terrorism. Commonly known as nerve agents, these are the deadliest of CWAs. These agents have both chemical names as well as 2letter NATO codes. These are categorized as G series agents: GB (Sarin), GD (Soman), GA (Tabun), GF and V Series agents: VE, VG, VM and VX, the letter G representing the country of origin Germany and letter V possibly denoting Venomous. Historically earliest recorded use of cholinesterase inhibitors was by

native tribesmen of Western Africa. They used Calabar bean as an ordeal poison in witchcraft. An extract of Calabar bean was later used for various medicinal purposes and the active principle physostigmine was isolated in 1864 (Fraser, 1863). Wurtz in 1854 synthesized the rst organophosphate compound, tetraethyl pyrophosphate (TEPP). In 1937 Gerhard Schrader developed the general formula for all organophosphorus compounds and manufactured GB and GA. This was followed rapidly by development of other agents. It is estimated that Germany manufactured about 12,000 tons of these nerve agents during WWII. However, Germany restrained from their use in the battleeld. The nerve agents GA and GB were rst used on the battleeld by Iraq against Iran during the rst Persian Gulf war and again against the Kurdish rebels (Dingeman and Jupa, 1987; Barnaby, 1988). In 1995, the Japanese cult Aum Shinrikyo used GB in terrorist attacks in Tokyo resulting in 12 deaths (Okumura et al., 1996; Yokoyama et al., 1996). 3.1. Manufacture Many nerve gases require chemical technologies similar to those used for production of agricultural insecticides. VX is produced by the Transester Process, where phosphorus trichloride is methylated to produce methyl phosphorous dichloride. This compound is reacted with ethanol to form a diester and then trans-esteried to produce an intermediate which is then reacted with sulfur to form VX. 3.2. Properties All nerve agents are liquid at standard temperature and pressure. Their high volatility makes them a powerful weapon. The term nerve gas itself is a misnomer. This arises from a misunderstanding as chlorine and phosgene, which were the rst CWAs used in WWI, were true gases at standard temperature and pressure. Popular accounts tend to refer to subsequently developed CWAs as poison gas or nerve gas. GA (ethyl N,N-dimethylphosphoramidocyanidate) is chemically C5 H11 N2 O2 P and is a colorless to brown liquid, with a faintly fruity odor. It evaporates twice as fast as mustard gas making it a powerful CWA. GB (2-(uoro-methyl-phosphoryl)oxypropane) is chemically C4 H10 FO2 P. It is a clear colorless and odorless liquid and with a boiling point of 158 C, it is one of the most volatile agents. It evaporates at the same rate as water and 36 times faster than GA. A lethal dose of GB in humans is about 0.5 mg making it 500 times more deadly than cyanide. VX (O-ethylS-[2(diisopropylamino)ethyl]methylphosphonothiolate) is chemically C11 H26 NO2 PS. VX is the least volatile agent with consistency of motor oil. They can persist in the ground for as long as 24 h. This persistence and higher lipophilicity make VX 100150 times more toxic than GB in cases of delayed evacuation. 3.3. Uses Besides as CWAs, organophosphorus compounds are widely used as insecticides in agriculture. 3.4. Mechanism of human toxicity These agents inhibit the enzyme acetylcholinesterase at cholinergic synapses, thereby inhibiting degradation of acetylcholine. Accumulation of the released neurotransmitter acetylcholine, causes end-organ overstimulation, recognized as cholinergic crisis. In addition VX can induce acute lung injury.

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3.5. Clinical features The LD50 of GA, GB, GD and VX in humans is estimated to be 24.3, 14.3, 5 and 0.14 mg/kg and the LCt50 is 400, 100, 50 and 10 mg min/mm3 respectively (Menger and Elrington, 1990; Raber et al., 2001). Exposure can be either to vapors or liquid, the former being more likely in a war scenario. The onset of symptoms from time of exposure generally occurs within minutes if inhaled but can vary from 30 min to 2 days with liquid exposure. Exposure of a person to nerve agent vapor affects the eye (miosis) due to papillary muscle contraction described by Tokyo subway victims as the world going black, causes increase in secretions from various glands (manifesting as rhinorrhea, salivation, bronchorrhea), contraction of bronchial smooth muscle resulting in bronchospasm and impaired ventilation of the lungs leading to hypoxia and death. This is commonly termed as the patient drowning in his own secretions. Gastrointestinal tract exposure results in abdominal cramping and pain, nausea, vomiting, and diarrhea. Other organs affected include the heart (increased or decreased heart rate, hypo or hypertension), exocrine glands (increased sweating), muscles (fasciculations, twitching and paralysis), and brain (loss of consciousness, seizures, and central apnea). Death is due to respiratory failure due to a combination of bronchorrhea, bronchospasm, respiratory muscle paralysis and central apnea. Neuropsychiatric sequelae in non-dose dependant fashion have been described (Murata et al., 1997; McDonough, 2002; Hatta et al., 1996). This syndrome overlaps with post-traumatic stress disorder (PTSD) and in some patients it may actually be a true PTSD. Other delayed manifestations that have been observed include organophosphorus induced neuropathy (not seen with VX) and intermediate syndrome. Intermediate syndrome has been well described in organo phosphate insecticide toxicity. It is characterized by muscular weakness and occurs after apparent recovery from the acute cholinergic syndrome and reects prolonged action of acetyl choline on nicotinic receptors. Also a delayed neurobehavioural syndrome has been described in a small proportion of nerve agent survivors. Other than nerve agents, cyanides can potentially cause a person to suddenly fall, lose consciousness and develop seizures. Miosis, a typical feature of nerve agent toxicity is not seen with cyanide poisoning. Absence of secretions favors cyanide exposure. In cyanide poisoning a classical cherry red color of the skin is seen. Amongst laboratory tests a raised anion gap metabolic acidosis is typical of cyanide poisoning. Cholinesterase levels may not be helpful as the range is very variable. Sometimes it may be difcult to differentiate between the two and in such a scenario treatment should be instituted for both. 3.6. Treatment Acute nerve agent poisoning is treated by decontamination, respiratory support, and specic antidotes. Decontamination of a vapor is theoretically not necessary, but vapors can be trapped in clothes and therefore removal of all clothes and decontamination of skin using copious amount of water or sodium hypochlorite solution is mandatory. A skin decontamination kit approved by FDA containing activated charcoal impregnated with ion exchange resins (Ambergard) is also available. Atropine rapidly reverses cholinergic overload at muscarinic synapses and is the antidote of choice. US military personnel are given MARK I kits, which contain 2 mg atropine in an auto injector form for use intramuscularly. The eld-loading dose is 2, 4, or 6 mg, with retreatment every 510 min until the patients secretions are dry. Oximes reactivate cholinesterase and restore normal enzyme function (Quinby, 1964). The US has approved and elded 2-pralidoxime chloride (2-PAM

Cl). MARK I kits in addition to atropine also contain auto injectors of 600 mg of 2-PAM Cl. Initial eld loading doses are 600, 1200, or 1800 mg. The usual recommendation is 1000 mg through slow intravenous drip over 2030 min, with no more than 2000 mg over a period of 11.5 h. Nerve agent-induced seizures respond only to benzodiazepines. Midazolam is the fastest acting and most effective. However under eld conditions, diazepam is equally effective. It is distributed amongst the forces as 10-mg injectors for intramuscular use (McDonough et al., 1999, 2000). To counteract rapidly acting agents such as GD, the US military evaluated the use of pyridostigmine bromide, which was approved by the FDA, for wartime use. It is to be used only prophylactically before exposure in a dose of 30 mg every eight hourly and not after the exposure. It binds reversibly with cholinesterase thereby preventing more deadly GD to bind to the receptors. This gives time for other antidotes to act which are given after exposure. It was given to 250,000300,000 American troops in a daily dose of 90 mg for a maximum of 7 days in the Gulf War, as a pretreatment against potential Iraqi attacks with the nerve gas Soman (Cerasoli et al., 2005). However, still uncertainties prevail about its efcacy. Recently researchers have developed bioscavangers, which are either a human cholinesterase molecule or an altered human cholinesterase which would bind and detoxify nerve agent entering a patients circulation so that it would not be able to reach the tissues. These include plasma-derived butyrylcholinesterase and recombinant butyrylcholinesterase (Huang et al., 2007). Furthermore for neuroprotection, several drugs including ketamine and HU-211 have shown promising results in clinical trials. 4. Asphyxiants/blood agents Asphyxiants are substances that cause tissue hypoxia. These are classied as either simple or chemical. Simple asphyxiants (e.g., methane and nitrogen) physically displace oxygen in inspired air, resulting in oxygen deciency and hypoxemia. Chemical asphyxiants like cyanides interfere with oxygen transport at cellular level causing tissue hypoxia, anaerobic metabolism and lactic acidosis. The important chemical asphyxiants used as CWAs include cyanogen chloride (CK), hydrogen cyanide (HCN), arsine (SA). 4.1. Cyanogen chloride (CK) Cyanogen chloride, also known as chlorine cyanide, chlorocyan, or cyanochloride was used during WWI by the French, who called it Mauguinite. Two properties made it an effective CWA: Firstly CK could penetrate the masks of that time. The mask breaking properties of cyanogen chloride lead to its mass production (around 11,000 tons) by the US. Secondly, it was not inammable and therefore did not burn up during the burster charge. After WWII, CK rapidly fell out of favor being replaced by faster acting nerve agents. 4.1.1. Manufacture CK is produced as a byproduct when bleach-containing decontaminants are used for decomposition of the nerve agent GA. 4.1.2. Properties Cyanogen chloride is chemically ClCN. It is a colorless vapor at normal temperatures with a boiling point of 13.8 C. It has a pungent biting, pepper-like odor. 4.1.3. Uses Cyanogen chloride is used in industry for synthesis of herbicides, ore rening, and as a metal cleaner.

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4.1.4. Mechanism of human toxicity Cyanide interferes with aerobic respiration at a cellular level by forming a reversible complex with the cytochrome oxidase enzyme system (Singh et al., 1989). This enzyme is responsible for oxygen utilization and cell respiration. The resultant inhibition of cytrochrome oxidase enzyme results in inability to utilize oxygen and accumulation of lactic acid and cell death from tissue anoxia. An airborne concentration of 270 ppm is immediately fatal. 4.1.5. Clinical features Onset is usually rapid with deaths occurring in less than 10 min. Inhalation in low concentration causes breathlessness, headache, dizziness, anxiety, palpitations, mydriasis, blurring of vision, nausea and drowsiness. Exposure to high concentrations produces hyperventilation, followed by loss of consciousness, convulsions, xed and dilated pupils. High concentrations result in death from respiratory and/or cardiac arrest within minutes without any symptoms. Despite hypoxia, there is no cyanosis. Instead the color of skin turns cherry red (Salkowski and Penney, 1994; Johnson and Mellors, 1988). Cyanides should be suspected in areas of mass fatalities, especially when the characteristic symptoms of nerve agent intoxication are absent. Other clues would be persistent hypotension, metabolic acidosis, normal arterial oxygenation, and excessive venous oxygenation (Johnson and Mellors, 1988). 4.1.6. Treatment Adequate protection by wearing protective impermeable clothing with breathing apparatus and evacuating staff must be ensured before rescuers attempt to aid casualties. Skin decontamination should be carried out using a rinse-wipe-rinse technique with a dilute detergent solution. Besides supportive management, three specic antidotes are available and include nitrites, dicobalt edentate and hydroxycobalamine/thiosulfate. Ten milliliters of 3% sodium nitrite is given intravenously over 520 min. Amyl nitrite (one 0.2 ml ampoule inhaled over 0.51 min) can be used in case intravenous access is a problem followed by sodium thiosulfate which is given as 25 ml of a 50% solution intravenous over 10 min (Kulig, 1991). Nitrites convert hemoglobin to methhemoglobin. Methhemoglobin binds to cyanides more avidly as compared to cytochrome oxidase and thus preventing the toxicity. Sodium thiosulfate removes cyanide from methhemoglobin by forming sodium thiocyanate which is removed from the body and methhemoglobin is converted back to hemoglobin. Dicobalt edetate given in doses of 300600 mg intravenously over 25 min is equally effective in cases of severe cyanide poisoning, but its use is limited by severe cardiovascular side effects (Braitberg and Vanderpyl, 2000). Hydroxycobalamine/thiosulfate is emerging as the drug of choice as it has minimal adverse effects (Mushett et al., 1952; Borron et al., 2007). It has been recently approved by the FDA. There is no head to head comparison between the three antidotes, but considering the safety prole and overall efcacy, hydroxycobalamine is the drug of choice. In cases of poisoning with cyanides, it is of the utmost importance that counter measures are immediately introduced. For this reason, a medical antidote (PAPP, para-aminopropiophenone) for use as a pretreatment is under evaluation (Steven et al., 1992). 4.2. Hydrogen cyanide (HCN) HCN is also known as hydrocyanic acid or prussic acid. Liquid hydrocyanic acid was rst produced by Scheele in 1782. In WWI French forces used this in large quantities but it proved to be less effective as compared to other CWAs because of its tendency to rapidly evaporate. However, under the brand name Zyklon-B it was perhaps most infamously employed by the Nazi regime in mid-20th

century as a method of mass extermination and again in 1980s in the IranIraq war against the Kurds. It is highly toxic and in sufcient concentrations it rapidly leads to death. 4.2.1. Manufacture HCN can be produced by reaction of ammonia and methane in the presence of oxygen at about 1200 C over a platinum catalyst or in absence of oxygen by heating formamide. Small amounts of HCN can be produced in a laboratory by the addition of acids to cyanide salts of alkali metals. 4.2.2. Properties It is a colorless or pale blue, highly volatile liquid that boils slightly above room temperature at 25.70 C. High volatility probably makes HCN difcult to use in warfare since there are problems in achieving sufciently high concentrations outdoors. HCN has a faint, bitter, almond-like odor. 4.2.3. Uses HCN is a precursor to many chemical compounds ranging from polymers to plastics. It is used in the pharmaceutical industry and also for fumigation of ships and buildings. 4.2.4. Mechanism of human toxicity Is same as that of CK. 4.2.5. Clinical features The most important route of poisoning is through inhalation, though they can be absorbed through the skin also. Signs and symptoms are similar to those seen after exposure to CK. Lethal concentration of HCN is 270 ppm for 68 min, 181 ppm for 10 min and 135 ppm for 30 min. 4.2.6. Treatment Is on the same lines as for CK. 4.3. Arsine Arsine (arsenic hydride, arsenic trihydride, arseniuretted hydrogen, arsenous hydride, hydrogen arsenide) is the most toxic form of arsenic. During the WWII it was extensively studied as a CWA, but its low toxicity prevented it from being used in war. However, it still remains a potential threat of small scale terrorist attacks and is included in the NATOs list of CWAs. Although arsine itself has not been used as a CWA, several arsine-derived organoarsenic compounds have been developed and used as CWAs, including lewisite (beta-chlorovinyldichloroarsine), adamsite (diphenylaminearsine), Clark I (diphenylchlorarsine), and Clark II (diphenylcyanoarsine). 4.3.1. Manufacture It is prepared by the reaction of arsenic chloride (AsCl3 ) with NaBH4 and also by reaction of Zn3 As2 with hydrogen ion. 4.3.2. Properties The gas is colorless, almost odorless, and 2.5 times denser than air. It is highly inammable. It is shipped as a liqueed compressed gas. It is soluble in water (200 ml/l) and in many organic solvents as well. This compound is generally regarded as stable. 4.3.3. Uses Arsine may be released in metal rening processes. It is used as a doping agent in microelectronics and is also used in the manufacturing of organic chemicals and lead storage batteries. It has

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applications in the semiconductor industry, and is used in the synthesis of organoarsenic compounds. 4.3.4. Mechanism of human toxicity Inhaled arsine gas causes rapid destruction of red blood cells leading to hypoxia and renal failure. Mechanism is believed to be nonspecic disruption of ion gradients, leading to cell membrane instability and lysis of red blood cells (Graham et al., 1946; PullenJames and Woods, 2006). 4.3.5. Clinical features It has delayed onset of action with a latent period up to 24 h. The symptoms are due to rapid destruction of red blood cells (hemolysis). These include abdominal pain, hematuria (red urine), and jaundice. Nonspecic symptoms like fever, chills, confusion, dizziness, vomiting and cramping may be present. Discoloration of conjunctivae (red, orange, brown, or brassy) and jaundice is seen. In severe cases patient may be passing red or cola colored urine and may develop acute renal failure or acute respiratory distress syndrome (Pullen-James and Woods, 2006). 4.3.6. Treatment Properly protected personnel should remove the victim from continued exposure to arsine. There is no specic antidote. Victims should be administered high ow oxygen. Exchange transfusion should be used in cases of severe hemolysis. Forced alkaline diuresis may prevent development of renal failure. In patients with established renal failure, hemodialysis should be instituted (PullenJames and Woods, 2006). 5. Choking/pulmonary damaging agents Lung toxicants are the general class of gases that are toxic to the human lung when inhaled, resulting in an inammatory response. This manifests as pulmonary edema, reduced pulmonary compliance and altered gas exchange. The CWAs under this category include chlorine, chloropicrin (PS), phosgene (CG) and diphosgenenitrogen oxides. 5.1. Chlorine (Cl) Chlorine in gaseous form is poisonous. Chlorine was discovered in 1774 by the Swedish chemist Carl Wilhelm Scheele. Chlorine was given its current name in 1810. Faced with a shortage of ammunition, Germany used chlorine as a CWA during WWI without much success, but this opened the path for large scale manufacture of CWAs both by Germany and the allies. However at present it a common chemical agent of considerable commercial use. 5.1.1. Manufacture It can be manufactured by a number of processes. Deacon process involves the direct oxidation of hydrogen chloride with oxygen or air at 400 C to form chlorine using CuCl2 as a catalyst. Due to the extremely corrosive reaction mixture, industrial use of this method was difcult. Chlorine is now manufactured by electrolysis of a sodium chloride solution (brine). The production of chlorine results in the byproducts caustic soda (sodium hydroxide, NaOH) and hydrogen gas (H2 ). These two products, as well as chlorine are highly reactive. There are three industrial methods for the extraction of chlorine by electrolysis namely mercury cell electrolysis, diaphragm cell electrolysis and membrane cell electrolysis. 5.1.2. Properties Chlorine gas is pressurized and cooled so that it can be stored in the liquid form. When liquid chlorine is released, it quickly turns

into a gas with yellowgreen color and with an irritating odor. It is heavier than air, there by tending to accumulate in low lying areas. 5.1.3. Uses Chlorine is most commonly used as a bleaching agent in the paper and cloth industry. It is also used to make pesticides, rubber and solvents. Amongst the household uses it is used as a disinfectant in drinking water and in the swimming pool. It is also used to treat industrial waste and sewage. 5.1.4. Mechanism of human toxicity When chlorine gas comes into contact with moist tissues such as the eyes, throat, and lungs, hydrochloric and hypochlorous acid is produced. Hypochlorous acid degenerates into hydrochloric acid and nascent oxygen. Both hydrochloric acid and nascent oxygen damages the lung tissue resulting in an inammatory response that damages the alveolar-capillary membrane of the human lung. This manifests as pulmonary edema, reduced pulmonary compliance, and altered gas exchange. 5.1.5. Clinical features These depend upon site of exposure and concentration of gas. Immediately after exposure patients complains of chest tightness, burning sensation in the nose, throat and eyes, redness and blisters on the skin similar to frostbite. Breathlessness and acute lung injury (ARDS) occurs within 24 h of exposure (Da and Blanc, 1993). 5.1.6. Treatment Removing the causalities from the site by well protected personnel. There is no specic antidote. Measures include removal of all clothing and providing supportive medical care. 5.2. Chloropicrin (PS) PS vapor is highly poisonous when inhaled. It was used in WWI as a CWA with different names. It was called PS by the British, Aquinite by the French, and Klop (green cross) by the Germans. After WWII, its use as CWA is obsolete. 5.2.1. Manufacture PS is prepared by the reaction of picric acid with calcium hypochlorite or by the addition of nitrogen to chlorinated hydrocarbons or by chlorinating nitromethane. 5.2.2. Properties Chloropicrin (tri-chloro(nitro)methane) is chemically CCl3 NO2 . It is an oily, colorless and a faintly yellow liquid which decomposes at 112 C to yield phosgene and nitrosyl chloride. It is more toxic than chlorine but less than phosgene. 5.2.3. Uses Industrial uses include organic synthesis, in fumigants, in fungicides and insecticides, and for the extermination of rats. Chloropicrin is also used for fumigation and to sterilize soil and seed. 5.2.4. Mechanism of human toxicity Is the same as that of chlorine. 5.2.5. Clinical features Three periods of trichlornitromethane intoxication have been described which are irritation, latent (average 25 h) and development of pulmonary edema (Asauliuk, 1990). However if inhaled in high concentrations, the latent period may not be present. Some authors have also described low grade rhabdomyolysis associated

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with its inhalation (Prudhomme et al., 1999). Because of its relative inertness and the small size of its molecule, chloropicrin penetrates gas mask lters causing vomiting. This makes the victim remove the gas mask. For this reason, it is often mixed with other chemical weapons. 5.2.6. Treatment Is along the same lines as following exposure to chlorine. 5.3. Phosgene (CG) CG was rst synthesized by Davy in 1812. It was developed into a CWA by Haber. Since it was more lethal than chlorine, it was used by Germany in 1915 during WWI resulting in 1069 casualties and 120 deaths. Subsequently allied forces also used it. It accounted for 85% of war causalities during WWI. Besides being a CWA, CG has extensive industrial uses. Nearly 1 ton is produced annually by the US alone. 5.3.1. Manufacture CG is not a natural compound. It is manufactured industrially by passing puried carbon monoxide and chlorine gas through a bed of catalyst (porous carbon) at temperatures between 50 and 150 C. Above 200 C, phosgene decomposes back into carbon monoxide and chlorine. Also chloroform upon ultraviolet radiation in the presence of oxygen slowly converts into phosgene via a radical reaction. It is also produced as a byproduct during thermal decomposition of chlorinated hydrocarbons. 5.3.2. Properties It is stored as a liquid under low temperatures and pressures with a boiling point of 8.2 C. Therefore at room temperatures CG is a poisonous gas. It forms a colorless or a white to pale yellow cloud with a pleasant odor of newly mown hay but at higher concentrations it gives an offensive odor. It is 3.5 times heavier than air and tends to accumulate in low lying areas. 5.3.3. Uses Since WWII, CG has found extensive industrial uses. It is widely used in chemical industries such as pharmaceuticals, dyes, pesticides and polyurethane for foam rubber products. 5.3.4. Mechanism of human toxicity Is same as that of chlorine. 5.3.5. Clinical features Following exposure, coughing, burning sensation in the throat and eyes, choking and breathlessness develops. This is followed by a symptom free period which varies from 2 to 48 h followed by acute lung injury (Nelson, 2002). Acute lung injury is precipitated by exercise as was frequently reported in the WWI. In persons who remain asymptomatic and whose lungs appear clear on chest lms obtained 8 h after exposure acute lung injury is unlikely to develop. 5.3.6. Treatment Removing the casualties from the site by well protected personnel. Removal of clothing and liberal bath in soap water helps to decontaminate. Exposure to CG may cause acute lung injury as late as 48 h. There is no antidote. Treatment is symptomatic and supportive. The role of steroids is not proven (Diller, 1985). Exposed people should be observed for up to 48 h. If the patient survives for more than 48 h, the prognosis is excellent (Evison et al., 2002). In experimental studies, N-acetylcysteine and Ibuprofen has shown promising results in phosgene induced lung injury.

6. Behavioural agents/incapacitating agents Following WWII, the US military investigated a wide range of possible nonlethal, psychobehavioural chemical incapacitating agents. These included lysergic acid diethylamide (LSD-25), ketamine, fentanyl, carfentanil and several glycolate anticholinergics. The only agent classied as CWA is 3-quinuclidinyl benzilate, an anticholinergic compound. It is codenamed as BZ by NATO. It is alleged that BZ was stockpiled by Iraq in large quantities, code named Agent 15. It is also believed that BZ was the chemical warfare agent used to subdue terrorists in Moscow on 26 October 2002, though the exact nature of the gas still remains unknown. It is estimated that out of 127 deaths, BZ was responsible for 123 deaths. 6.1. Manufacture It is manufactured by reacting methyl benzilate with 3quinuclidinol in an inert anhydrous aliphatic hydrocarbon solvent in the presence of 715 mol% of metallic sodium based on the methyl benzilate. 6.2. Properties BZ is odorless gas. It can persist for three to four weeks in moist air. It is extremely persistent in soil and water and on most surfaces. 6.3. Uses There are no known uses except as CWA. 6.4. Mechanism of human toxicity BZ is a competitive inhibitor of the neurotransmitter acetylcholine. The organs primarily affected are those innervated by parasympathetic nerves. These include the central nervous system, eye, heart, respiratory system, skin, gastrointestinal tract, and urinary bladder. Sweat glands though innervated by the sympathetic nervous system, are also affected. 6.5. Clinical features The LCt50 is estimated to be around 380040,000 mg min/m3 . It affects the central and peripheral nervous system. The central effects include restlessness, hallucinations, confusion, agitation, tremor, ataxia, stupor, and coma. In the periphery it affects the eye (dilatation of pupil causing photophobia and impairment of near vision), increase in heart rate, nausea, vomiting, ushing, dryness of skin, mouth and throat, urinary retention and hyperthermia. The clinical course is divided into four phases: Phase 1: (04 h after exposure), characterized by parasympathetic blockade and mild CNS effects Phase 2: (420 h after exposure), characterized by stupor with ataxia and hyperthermia Phase 3: (2096 h after exposure), in which overt delirium is seen but often uctuates from moment to moment. Phase 4: characterized by paranoia, deep sleep, reawakening, crawling or climbing automatisms, and eventual reorientation 6.6. Treatment No specic antidote has been found to reverse the action of QNB denitively. Physostigmine, a cholinergic agent, has not been found to be very efcacious in BZ poisoning. Supportive care remains the

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best therapy. However, if the exposed patient is markedly agitated, benzodiazepines can be administered. 7. Detection of CWAs As a countermeasure against CWA use, detection and identication are very important. The detection of CWAs can be difcult as they are frequently rapidly degraded and hence difcult to detect. It may be useful to look for their metabolites and degradation products. Any system developed should be accurate with low false positive and negative alarms, especially in the context of a complex battleeld environment. Detection equipment such as gas detection tubes and ion mobility spectrometers are used for on-site detection. Common techniques used for detection include atmospheric pressure and chemical ionization (APCI) and ame photometric detection. There are several commercially available alarm units which are known by their acronyms and include GID3, RAID1, M90, CHASE and AP2CV. 8. Destruction of chemical weapons Under the CWC, the stockpiles of all CWAs are to be destroyed. This poses a great challenge including the high cost of destruction, safety of the staff involved as well as of the neighboring population and environmental, legal and political factors. Previously the most common disposal methods for CWAs were land burial, sea dumping, detonation and open-pit burning. All these methods posed great threat to the environment as well as to the health of unsuspecting population residing in the vicinity. At present, two technologies are adopted for destroying CWAs: incineration and chemical degradation. Under the incineration process, CWAs are taken to the demilitarization facility, where the chemical agent is removed from the munitions or bulk containers by automated equipment. This puts the workers at the demilitarization plant at a very low risk of exposure. Chemical degradation is done using chemicals, namely alkalis and oxidants, which reduce and often negate the toxicity of chemical agents. 9. Conclusion The use of CWAs still remains a potential threat despite the CWC prohibiting their use. They are relatively easy to manufacture with a potential to cause signicant morbidity and mortality. These agents can, and have been effectively used in warfare in small scale operations and terrorist attacks. Knowledge about these agents is very important to plan a response in an emergency. If timely protective action is taken and exposed persons treated immediately, the mortality and morbidity can be considerably reduced. International treaties such as the CWC should help to control proliferation of chemical weapons along with the safe destruction of existing ones. References
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