Testing for and Identifying Health Effects of Exposure to Nerve Agents*

Nerve agents are extremely toxic compounds that were designed specifically to kill or incapacitate. Sarin and cyclosarin (the agents of concern in the Persian Gulf) are organophosphates that permanently inhibit acetylcholinesterase. This results in an accumulation of acetycholine at the cholinergic synapses, causing continued stimulation of the affected organ. The toxic effects of poisoning depend largely on the intensity of exposure. The effects range from miosis, or pinpoint pupils, and blurred vision at lower concentrations, to involuntary defecation, nausea, vomiting, muscular twitching, weakness and convulsions, and death at somewhat higher concentrations.

Experimental studies on the long-term effects of sarin on animals and humans have produced inconclusive results. In 1982, the National Research Council conducted a study examining long-term or delayed adverse health effects of 15 anticholinesterases tested on about 1,400 military volunteers during the 1960s and 1970s. That panel concluded that "although no evidence has been developed (to date) that any of the anticholinesterase test compounds surveyed carries long-range adverse human health effects in the doses used, the panel is unable to rule out the possibility that some anti-ChE [cholinesterase] agents produced long-term adverse health effects in some individuals. Exposures to low doses of OP [organophosphate] compounds have been reported (but not confirmed) to produce subtle changes in EEG, sleep pattern, and behavior that lasts for at least a year." (NRC, 1982:33).

*  

The material in this section is based, in part, upon presentations and discussion by Kent Anger, Ph.D.; Arthur Asbury, M.D.; David Cornblath, M.D.; Bhupendra Doctor, M.D.; Eva Feldman, M.D.; Lt. Col. Robert Gum, M.D.; David Janowsky, M.D.; Richard Johnson, M.D.; Robert MacPhail, Ph.D.; Peter Spencer, Ph.D.; and Roberta White, Ph.D.



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--> Testing for and Identifying Health Effects of Exposure to Nerve Agents* Nerve agents are extremely toxic compounds that were designed specifically to kill or incapacitate. Sarin and cyclosarin (the agents of concern in the Persian Gulf) are organophosphates that permanently inhibit acetylcholinesterase. This results in an accumulation of acetycholine at the cholinergic synapses, causing continued stimulation of the affected organ. The toxic effects of poisoning depend largely on the intensity of exposure. The effects range from miosis, or pinpoint pupils, and blurred vision at lower concentrations, to involuntary defecation, nausea, vomiting, muscular twitching, weakness and convulsions, and death at somewhat higher concentrations. Experimental studies on the long-term effects of sarin on animals and humans have produced inconclusive results. In 1982, the National Research Council conducted a study examining long-term or delayed adverse health effects of 15 anticholinesterases tested on about 1,400 military volunteers during the 1960s and 1970s. That panel concluded that "although no evidence has been developed (to date) that any of the anticholinesterase test compounds surveyed carries long-range adverse human health effects in the doses used, the panel is unable to rule out the possibility that some anti-ChE [cholinesterase] agents produced long-term adverse health effects in some individuals. Exposures to low doses of OP [organophosphate] compounds have been reported (but not confirmed) to produce subtle changes in EEG, sleep pattern, and behavior that lasts for at least a year." (NRC, 1982:33). *   The material in this section is based, in part, upon presentations and discussion by Kent Anger, Ph.D.; Arthur Asbury, M.D.; David Cornblath, M.D.; Bhupendra Doctor, M.D.; Eva Feldman, M.D.; Lt. Col. Robert Gum, M.D.; David Janowsky, M.D.; Richard Johnson, M.D.; Robert MacPhail, Ph.D.; Peter Spencer, Ph.D.; and Roberta White, Ph.D.

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--> Lack of knowledge regarding who might have been exposed to nerve agents and at what level is impeding researchers attempting to answer questions about health effects. The extent and frequency of exposure of troops to nerve agents in the Persian Gulf is still being investigated. Concerns about exposure were heightened by the announcement that troops in the vicinity of Khamisiyah on March 10, 1991, may have been exposed to sarin or cyclosarin when US military personnel destroyed a munitions dump. It is not known whether or to what extent personnel were exposed. In addition, the military is investigating other potential exposures to nerve agents in the Persian Gulf. Without definitive information on the intensity and frequency of exposures, interpretation of research results is problematic. Research on exposure to organophosphate pesticides, some of the most acutely toxic and potentially lethal pesticides in use today, may provide information useful to those studying the effects of sarin and cyclosarin because these types of pesticides and nerve agents both inhibit cholinesterase. Acute symptoms of poisoning from these OP pesticides can be as severe as those found with any nerve agent, but the long-term neurobehavioral health effects in the absence of acute clinical effects at the time of exposure are still debated A study of individuals occupationally exposed to organophosphate pesticides examined workers without acute, clinical symptoms, but with blood measurements that showed depressed cholinesterase levels. Neurobehavioral tests were used in the study but no residual neurologic health effects were documented in this population (Ames et al., 1995). Detection, over time, of organophosphate nerve agents in the blood is impossible because such agents are completely detoxified by a set of enzymes in the body. Therefore, measuring the presence of nerve agents in the blood over time is not a practical approach for determining whether an exposure occurred. In addition, there is no surrogate marker of exposure. Another important issue is the use of pyridostigmine bromide (PB) pills which were distributed to soldiers deployed to the Persian Gulf. Pyridostigmine bromide is a carbamate that also inhibits acetylcholinesterase. Unlike sarin and cyclosarin, however, PB binds temporarily with acetylcholinesterase. The DoD's intent, therefore, was for troops threatened with exposure to chemical warfare agents to take the pills so the PB could bind temporarily with their acetylcholinesterase, leaving little available for the nerve agents to act on. Any acute clinical response to PB would be short-lived, unlike responses to sarin and cyclosarin, thereby saving the life of the exposed victim. Acute, short-term effects of PB can include respiratory problems, nausea, and diarrhea. As is the case with sarin and cyclosarin, there has been little research into the long-term health effects of PB used in healthy individuals exposed to low levels of nerve agents. Long-term health effects of low level nerve agent exposure have not been shown to exist. However, it might be hypothesized that such health effects, if they exist, might relate to inhibition of acetylcholinesterase and be manifested as

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--> neurological problems (e.g., peripheral sensory neuropathies) and as psychiatric problems (e.g., alterations in mood, cognition or behavior). Persons who may have been exposed to nerve agents could, therefore, be examined for both junctional myopathies and peripheral neuropathies. Junctional myopathy is normally associated with life-threatening respiratory muscle damage, not with acute anticholinesterase effects. Organophosphate-induced junctional myopathies are thought to be caused by excessive acetylcholine activity at the neuromuscular junction, whereas peripheral neuropathies are thought to be caused by inhibition of an enzyme known as neuropathy target esterase. Toxic insults can damage nerve axons, resulting in subsequent loss of nerve fiber and the development of neuropathy. Symptoms of neuropathy include numbness, tingling, and prickling sensations with differing degrees of intensity and duration. Signs of neuropathy include mild loss of vibration at toes, decreased ankle reflexes early on, and sensory loss later. A conventional neuropathy diagnosis begins with a careful patient history, followed by a characterization of the symptoms and electrophysiological tests. These tests traditionally involve nerve conduction studies and quantitative sensory testing. Severe neuropathy may extend to the central nervous system, leading to more critical problems. An accurate, etiologic diagnosis of a neuropathy cannot be based on symptoms alone. A simple, reliable neuropathy diagnosis requires a neurologist, a set of noninvasive diagnostic instruments including a thorough patient history questionnaire; clinical examination questions about sensory, motor, and autonomical functions; and simple nerve conduction and quantitative sensory tests. In addition, physicians must consider other possible etiologies of neuropathy in patients, including inherited problems, paraneoplastic syndromes, immune-mediated neuropathy, infectious vectors including HIV status, diabetes, alcohol use, and the use of therapeutic drugs. In routine clinical practice, the first choice in diagnosing a neuropathy would be to perform a routine neurological examination. If the results were normal, one would end the investigation. If the results were abnormal, or if controlled scientific research was being conducted on a potential, undefined, subclinical, or preclinical-type syndrome, one would then perform quantitative sensory testing and nerve or skin biopsies. Other important health effects that should be examined include psychological or psychiatric changes or problems. There are well-known, useful neurobehavioral tests for neurotoxicity that are reliable (i.e., the results are replicable), valid in the sense that they detect established effects seen at higher concentrations as well as at low concentration exposure, and are specific for certain chemical classes and not for others. These neurobehavioral tests for neurotoxicity are the same tests as are used in neurological evaluations of other conditions. Neuropsychological tests are generally classified into domains of function. The domains most commonly applied include motor skills, general

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--> intelligence and academic abilities, attention, executive function, verbal and language abilities, visuospatial skills, memory (anterograde, retrograde), and personality and affect. In order to apply neuropsychological tests to clinical assessment, the technique used must allow the clinician first to document brain damage attributable to neurotoxicant exposure (from subtle to severe) and second, to feel comfortable attributing any observed deficits to neurotoxicant exposure rather than some other cause. It is important to explicitly rule out other potential causes of impairment such as age, education, smoking, alcohol use, developmental disorders, psychiatric disorders, neurological disorders, and motivational states in which persons consciously or unconsciously sabotage their own test performance. A recent study of Oregon veterans investigated psychosocial, neuropsychological, and neurobehavioral elements to determine objective memory and attention impairment. The population-based study used questionnaires as well as clinical examinations to identify behavioral, psychosocial, and performance disorders. Results indicate that neurobehavioral tests can identify veterans with objective deficits in attention or memory and cognitive processes (Anger, 1996, Unpublished presentation). Whether these objective deficits result in clinical impairments has not yet been documented. In addition, although neurotoxic chemical exposure is one possible explanation for these outcomes, other possibilities exist.