Neurological aspects of chemical terrorism

This review describes the neurological aspects of chemical terrorism with a focus on the civilian perspective. This review defines chemical threats as highly toxic chemicals that could be used in a terrorist attack, or those that could be released at toxic levels from transportation vehicles and storage facilities during an accident or natural disaster. Chemical threats can be categorized based on the target tissues and types of primary acute effects they produce (Table). Probably the most easily recognizable chemical terrorism threats are the traditional chemical warfare agents (CWAs) developed during the first and second World Wars. These include the organophosphorus (OP) nerve agents, such as sarin and VX, and the mustard blister agents. As a consequence of previous state-sponsored CWA programs, several stockpiles remain around the world. Sulfur mustard and OP nerve agents were used against Iraqi Kurdish villages in the late 1980s, and more recently, the OP nerve agents were used by the Japanese cult organization Aum Shinrikyo in two separate attacks against civilians in Japan. The United States also produces and uses more than 80,000 chemicals, many of which are highly toxic and lethal at relatively low doses. Chemical agents in this broad category include the toxic industrial chemicals (TICs) manufactured and stored in large volume at industrial facilities and transported across the nation for various uses. Whereas the threat from CWAs is mitigated by restricted access, difficulty in synthesis of purified agent, and international treaties against their use, the TICs are not regulated as strictly, and many chemicals are readily available or stored in large enough amounts to pose a serious threat to human health if released by accident, natural disaster, or a deliberate act of terror. One of the most deadly industrial accidents occurred in Bhopal, India, where methyl isocyanate was released from an industrial storage tank killing 5,000 people and injuring thousands more, some with long-term effects. More recent fatal accidents involving large-scale chlorine gas releases during transportation in the United States have brought national attention to the hazards associated with TICs. Organophosphorus Nerve Agents The OP nerve agents belong to a chemically diverse group of organic compounds that have in common at least one carbon atom bound to a phosphorous atom. They are sometimes referred to as nerve gases because of the high volatility of some of the specific agents, but in fact, they are clear, colorless liquids at room temperature. The OP nerve agents were derived from OP pesticides during World Ward II by the Nazis to be used as CWAs against the allied forces. Traditional OP nerve agents fall into two groups, the Gand the V-series, based on their chemical and physical properties. The G-series nerve agents (GA, tabun; GB, sarin; GD, soman; and others) are volatile liquids at room temperature that can be deadly when inhaled as a vapor or from percutaneous exposure to the vapor. V-series agents (VX and others) have a consistency similar to oil and do not evaporate rapidly. V-series agents can remain on clothing and other surfaces for a long time, and they pose a greater risk from dermal exposure or by ingestion. Agents in the V-series are approximately 10to 100-fold more toxic than those in the G-series. OP nerve agents inhibit the catalytic function of acetylcholinesterase (EC 3.1.1.7; AChE) by phosphorylating the esteratic site of the enzyme. This removes the capacity of the enzyme to catalyze its endogenous substrate acetylcholine (ACh). As a consequence, the hydrolysis of ACh is prevented, leading to accumulation of ACh in the synaptic cleft and overstimulation and subsequent desensitization of muscarinic and nicotinic ACh receptors at cholinergic synapses in the brain, glands, and skeletal and smooth muscles. The OP nerve agents are more toxic than the related OP pesticides still in use today, and they bind irreversibly to AChE and interact at several other molecular sites at low doses. They are lethal at minute doses. For example, the median lethal dose (LD50) of VX for a 70kg person is only 10mg. The acute effects of OP nerve agents and pesticides are well characterized and include a progression from miosis, excessive secretions, and muscle fasciculation to epileptic seizures, muscle