2
Understanding the Problem of Low-Level Exposure to Chemical Warfare Agents

Inhalation dose is a function of both concentration and duration of exposure. An exposure dose is considered to be low level if it is below that which results in an immediate observable adverse health effect or operationally relevant performance decrements in healthy U.S. Department of Defense (DOD) personnel exposed to the agent (DOD 2003). The DOD’s Master Research Plan (Research Plan) focuses primarily on the latter. While various exposure durations are described in the Research Plan, DOD has stated that a temporary or brief, one-time or continuous exposure lasting from minutes to several hours is the scenario most likely to occur and it is of particular importance in the planning of research.

Chemical warfare agents (CWAs) of primary concern in development of the Research Plan are nerve agents (tabun [GA], sarin [GB], soman [GD], cyclosarin [GF], and VX) and the vesicating agent sulfur mustard (HD); however, nerve agents are of immediate concern to DOD. Throughout the Research Plan, the effects of miosis are referred to as the operationally relevant performance decrements of primary importance. The Research Plan does not point to any known potential delayed adverse health effect associated with low-level exposure to CWAs.

As a result of the high prevalence of unexplained illnesses among veterans of Operation Desert Shield/Storm, a presidential advisory committee (PAC) was formed to address the concerns of veterans groups and the public. The PAC examined the potential health outcomes as they related to selected Gulf War risk factors—for example, exposures to



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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents 2 Understanding the Problem of Low-Level Exposure to Chemical Warfare Agents Inhalation dose is a function of both concentration and duration of exposure. An exposure dose is considered to be low level if it is below that which results in an immediate observable adverse health effect or operationally relevant performance decrements in healthy U.S. Department of Defense (DOD) personnel exposed to the agent (DOD 2003). The DOD’s Master Research Plan (Research Plan) focuses primarily on the latter. While various exposure durations are described in the Research Plan, DOD has stated that a temporary or brief, one-time or continuous exposure lasting from minutes to several hours is the scenario most likely to occur and it is of particular importance in the planning of research. Chemical warfare agents (CWAs) of primary concern in development of the Research Plan are nerve agents (tabun [GA], sarin [GB], soman [GD], cyclosarin [GF], and VX) and the vesicating agent sulfur mustard (HD); however, nerve agents are of immediate concern to DOD. Throughout the Research Plan, the effects of miosis are referred to as the operationally relevant performance decrements of primary importance. The Research Plan does not point to any known potential delayed adverse health effect associated with low-level exposure to CWAs. As a result of the high prevalence of unexplained illnesses among veterans of Operation Desert Shield/Storm, a presidential advisory committee (PAC) was formed to address the concerns of veterans groups and the public. The PAC examined the potential health outcomes as they related to selected Gulf War risk factors—for example, exposures to

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents chemical and biological weapons, depleted uranium, infectious diseases, pyridostigmine bromide and so forth. The PAC closely examined the question of adverse health effects after low-level exposure to nerve agents. Their conclusions related to low-level nerve agent exposure were as follows (Presidential Advisory Committee on Gulf War Veterans’ Illnesses 1996): Available scientific evidence does not indicate that long-term, subtle, neuropsychological and neurophysiological effects occur in humans after asymptomatic exposure to nerve agents. There are minimal human and animal research data on low-level exposure to nerve agents. DOD should support additional research on the long-term health effects of low-level exposure to nerve agents. Another reason for DOD to pursue investigations of low-level CWA exposure is based on the military’s need to ensure that current doctrine, materiel, and training are adequate to protect soldiers from the effects of exposure to low levels of nerve agents (GAO 1998). While the Research Plan being considered by the committee also may provide some answers to the concerns of the PAC on Gulf War Veterans Health, the Research Plan, and thus the charge to the committee, is directly related to the issue of current military operational doctrine. The questions to be answered by the research accomplished under the Research Plan address operational and delayed adverse health effects concerns of the military and are not designed to develop occupational exposure criteria for the general population. The directed research in the Research Plan should address the development of best estimates of concentration and duration of nerve agents causing mild human incapacitation. One of the issues for the committee was framed by DOD at one of its presentations in terms of the question, When can warfighters safely remove their protective masks without suffering significant performance decrements (miosis) caused by low-level exposure to nerve agents in the environment? The committee assumes the same information would be useful in determining when it is appropriate to put protective masks on when nerve agents are detected. It was stressed to the committee that the focus of the research effort was operational effectiveness as opposed to force health protection. However, it also was stated in the Research Plan that the potential long-term health effects from acute exposure to low levels of nerve agents are to be a consideration for the committee; likewise, the effects of repeated exposures

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents to low doses of nerve agents are in the committee’s charge. Therefore, a brief review of the literature on this topic is important in understanding the scope of the problem, and it provides a basis for advancement in knowledge. BACKGROUND Four groups of synthetic compounds constitute CWAs: nerve agents (the primary focus of this discussion), vesicants, cyanide, and pulmonary agents. These agents were designed to kill or incapacitate enemy forces, disrupt military operations, and deny terrain to the adversary (Sidell 1992; Chemical Casualty Care Office 1995; Sidell 1997). However, in unscrupulous hands some have been shown to be effective weapons of terror (Yokoyama et al. 1998a,b). CWAs are classified as persistent or nonpersistent. The former include the vesicants and the nerve agent VX. Nonpersistent agents are volatile and do not remain in an open environment for more than a few hours. Among these are phosgene, cyanide, and the G series of nerve agents—GA, GB, GD, and GF. Toxicity follows exposure to CWAs dispersed as solids, liquids, aerosols, or vapor. Most CWAs were designed to be volatile and nonpersistent and are encountered as vapor or gas. The persistence of the agent depends on factors such as temperature, pressure, and wind speed. Thus, for some of the nerve agents—such as GA, GB, GD, and GF, as well as cyanide, phosgene, and chlorine—the primary route of intoxication is through the respiratory tract (Chemical Casualty Care Office 1995; Sidell 1997). The nerve agents VX and thickened GD and the vesicant agent HD are three of the most persistent CWAs; they pose a threat from dermal absorption of liquids or droplets and can pose vapor hazards as well. The nerve agents are organophosphorus compounds and their toxicity is primarily related to inhibition of the enzyme acetylcholinesterase (AChE). The rate constants for inhibition of AChE by nerve agents are several orders of magnitude greater than some of the common organophosphates (OPs), such as diisopropyl fluorophosphate (DFP), paraoxon, and methyl paraoxon (Gray and Dawson 1987). Toxicity of the nerve agents is both concentration and time dependent, with acute effects of nerve agents being elicited at very low vapor concentration-duration combinations causing mild symptoms, such as miosis, rhinorrhea, and bronchospasm (Sidell 1974; Chemical Casualty Care Office 1995). Ex-

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents posure of skin to small-to-moderate amounts of liquid nerve agent causes localized sweating, muscle fasciculation, nausea, vomiting, and lethargy (Sidell 1974; Chemical Casualty Care Office 1995). Large doses of vapor or liquid cause convulsions, loss of consciousness, apnea, paralysis, and death (Sidell 1974; Sidell 1992; Chemical Casualty Care Office 1995). Additionally, after both vapor and liquid agent exposure, there are central nervous system (CNS) effects that vary in intensity and duration. After mild-to-moderate exposure to nerve agent, there may be transient signs such as forgetfulness, inability to concentrate, insomnia, impaired judgment, nightmares, irritability, and depression (Sidell 1974, 1992, 1997). Most research efforts during the past two decades have focused on developing new antidotal interventions (enzyme reactivators and cholinolytics), pretreatments (pyridostigmine bromide), and preventive measures for nerve agent, seizure-induced brain injury (McDonough and Shih 1997). Several recent comprehensive reviews describing the pharmacology of, and general treatment principles for, the major nerve agents have been prepared by Sidell (1997) and Spencer et al. (2000). Numerous recent comprehensive reviews of the health effects of low-level exposure to nerve agents are provided by Sidell and Hurst (1997), Romano et al. (2001), Brown and Brix (1998), Ray (1998), and Moore (1998). TOXICOLOGIC STUDIES For nerve agents, extensive toxicologic studies, including sensitive screening methods, have been conducted in various animal models. The G agents have been screened for mutagenicity or clastogenicity by using in vitro and in vivo assays (Goldman et al. 1987). GB and GD have been found not to be mutagenic. GA was found to be weakly mutagenic in three different assays but not teratogenic in rabbits and rats (Bucci et al. 1992a,b). Evidence of neurotoxicity and neuropathology has been sought in a number of studies using nerve agents. Wide-ranging doses of nerve agents were used in 11 studies; no neuropathy or neurotoxic esterase inhibition was seen with VX or with G agents at lethal doses in rats and rabbits treated with atropine and pralidoxime chloride to ensure survival (LaBorde and Bates 1986). According to Sidell and Hurst (1997), “the syndrome (delayed neurotoxicity) has not been noted in the handful of humans severely exposed to nerve agents or in the hundreds of humans

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents with mild to moderate effects from nerve agents.” However, more recently, a number of studies have been reviewed that indicate exposure to nerve agents under normal and stressful conditions can inhibit neurotoxic esterase (Somani and Husain 2001). OTHER ANIMAL STUDIES Because high doses generally are selected by investigators to elicit observable effects, there are relatively few studies on the effect of low-level exposure to CWAs. Studies have been performed with long-term exposure to symptomatic nonlethal doses of nerve agents (G agents and VX). With the exception of one study using GA in rats, there were no persistent changes in histopathology, hematology, clinical chemistry, or other biochemical parameters (Shih et al. 1994). It should be noted that neuropathology observed following exposure to OP nerve agents is typically thought to be the result of seizures and convulsions following high-dose exposure; thus, single or repeated low-level exposure would not be expected to lead to neuropathological changes. Attenuation of hormonal responses to physiologic or pharmacologic challenge was observed in a single study 2 weeks after an acute symptomatic dose of GD, possibly attributable to suppression of diurnal hormonal cycles (Kant et al. 1991). In another study, rhesus monkeys were implanted with cortical and depth electrodes and injected with agent GB in one of two dosage schedules: a single high dose (5 micrograms per kilograms [µg/kg] of body weight, intravenously) that elicited seizures or low doses (1 µg/kg, intramuscularly) once per week for 10 weeks that caused no clinical effects (Burchfiel et al. 1976). Electroencephalograms (EEGs) were recorded before exposure, 24 hours after exposure, and 1 year after exposure. The animals from both dosage schedules had increases in high-frequency beta activity but were otherwise healthy. No long-term behavioral effects were noted. HUMAN EXPOSURES For ethical and practical reasons, it is not possible to perform the types of human research studies that would directly answer the questions of concern regarding CWAs over a wide range of exposures. The only

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents human data likely to be available are the results of historical studies (of somewhat limited value for deriving dose-response relationships because analytical and clinical methods were inferior to current methods) or natural experiments (accidental or malicious releases), which generally lack precise estimates of exposure. Suggested below are several ways the value of existing (and future) human data may be optimized. Accidental Human Exposures A source of potentially valuable data could be obtained from epidemiologic studies of pesticide-exposed workers, particularly those in underdeveloped countries where personal protection and exposure controls are less sophisticated. While recognizing that those agents do not share all the specific toxicologic properties of the nerve agents, there is sufficient similarity of toxicologic mechanisms that such studies would provide numerous clinical observations that could usefully serve as a means to validate the relevance of animal findings. Over the past 50 years, hundreds of industrial and laboratory workers have been accidentally exposed to both asymptomatic and symptomatic levels of nerve agents. The strongest evidence in humans of a possible long-term effect of exposure to nerve agents is from studies reporting changes in EEGs. No single study or set of studies exactly addresses the acute and long-term changes in EEG activity produced by nerve agents. Also, virtually all the animal EEG studies of nerve agent exposure have focused on the effects of high-dose exposure and the mechanisms and treatment of more serious toxic effects induced by these exposures. The first study to suggest long-term EEG effects after nerve agent exposure was by Metcalf and Holmes (1969), who described their findings from a group of workers at a GB production plant. Exposed workers had higher-voltage EEGs with more pronounced alpha rhythm and bursts of slow waves during drowsiness. The individuals also had a high incidence of “narcoleptic” sleep patterns, presumably corresponding to early REM (rapid eye movement) sleep. Yanno and Musiichuk (1997) published a summary of 209 acute accidental poisonings from Russian nerve agent production facilities. Most, if not all, of the exposures were symptomatic, and a significant proportion of the cohort required hospitalization after their exposure. The resulting adverse health outcomes of the exposures included sleep

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents disturbances and memory loss. CNS symptoms were most persistent in those individuals poisoned by GD. The widely cited work of Duffy et al. (1979) describes EEG changes found in a group of 77 workers accidentally exposed to GB, showing signs and symptoms of exposure and AChE inhibition greater than 25%. Of the 77, 41 workers had more than three exposures. EEGs from this group were compared with those of a control group from the general population. Subtle but statistically significant increases in EEG beta-band activity over the controls were observed for 1-6 years after exposure in the GB group. Individuals exposed to GB were reported to have more and longer periods of REM sleep than the general population. However, the control group in this study also had changes in their sleep patterns that differed from the general population. The 77 workers exposed to agent GB reported no adverse health effects and no behavioral changes. The significance of the alterations in EEG patterns is uncertain because no behavioral effects can be attributed to them. Rengstorff (1994) evaluated acute effects of GB on vision in two men accidentally exposed to it. While miosis was evident, no changes in visual acuity were noted. On June 27, 1994, a presumed terrorist attack with GB took place in a residential area of the city of Matsumoto, Japan. About 600 residents and rescue staff were clinically affected; 58 were admitted to hospitals, and seven died (Morita et al. 1995; Yokoyama et al. 1998a,b). Signs and symptoms of exposure included ocular pain, darkness of visual field, nausea, vomiting, headache, rhinorrhea, narrowing of visual fields, sore throat, fatigue, and dyspnea (Nakajima et al. 1998). Two patients had abnormal EEGs (Okudera 2002). Red blood cell AChE inhibition was documented and all examined subjects recovered within 3 months. However, “subclinical miosis” and extremity dysesthesias (reported as “neuropathy”) were present in some individuals up to 30 days after exposure. Visual complaints, termed “asthenopia,” were present at the outset, more frequent at 4 months, and extant in some individuals 1 year after exposure. A 3-year follow-up study of the exposed population revealed persistence of symptoms among those with lower AChE activity (Nakajima et al. 1999). Additional information on possible persistent effects after symptomatic exposure to agent GB comes from studies of victims of the Tokyo subway attack on March 20, 1995. Eighteen victims were examined by computerized posturography 6-8 months after the poisoning. Their plasma cholinesterase activities were 13-95 (mean 68.2) international units per liter (IU/L) for females and 19-131 (mean 75.9) IU/L for males.

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Romberg quotients for the low-frequency sway in the anterior-posterior direction for females and low-frequency sway and length of sway in the mediolateral direction for males were significantly related to the logarithm of cholinesterase activity. It was suggested that a delayed effect on the vestibulocerebellar system was induced by acute GB poisoning, with females possibly more sensitive than males (Yokoyama et al. 1998). Another follow-up study found P 300 and visual evoked potential (P 100) latencies to be significantly prolonged in GB-exposed persons compared with matched controls (Murata et al. 1997). One subject developed neuropathy with pathological evidence of nerve fiber degeneration at death 15 months after exposure (Himuro et al. 1998). Studies on Human Volunteers Between 1958 and 1975, the U.S. Army undertook a human volunteer study to investigate the immediate and short-term effects of various classes of chemicals with warfare potential. The studies were conducted under the auspices of the soldier-volunteer test program of the Army Chemical Center, Aberdeen Proving Ground (formerly Edgewood Arsenal), Maryland. Subjects (n = 4,826) received one or more of 254 chemicals in five classes, including nerve agents. In the early 1960s, 1,406 healthy soldier volunteers, mostly 20-25 years of age, were tested with single or multiple doses of one or more of 15 anticholinesterases, including the OP esters GB (n = 246), GA (n = 26), GD (n = 83), GF (n = 21), VX (n = 740), and DFP (n = 11). Some OP treated subjects were given antidotes. The doses used in these experiments were equal to or less than 1.5 ED50 (the dose of agent that causes early signs of incapacitation [miosis] in 50% of exposed individuals). While the quality of medical care and observation fell far short of current standards, data were collected on red blood cell cholinesterase values, symptoms, and signs. Available data suggest that the rate of cholinesterase depression is related to the presence or absence of clinical manifestations. A small number of subjects treated with anticholinesterase chemicals appeared to be unexpectedly sensitive given their unusual reactions during testing. The medical records for two of these subjects were available for review by a National Research Council (NRC) committee (NRC 1982). The committee recommends that efforts be made to obtain a complete data set for these individuals to determine whether the information included can be used to illuminate the basis for susceptibility.

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents In 1980, the U.S. Army requested that the Committee on Toxicology of the NRC conduct a study of the possible chronic adverse health effects on the above group of servicemen who had been exposed to chemical agents under experimental conditions. The committee’s first report (NRC 1982) found no evi-dence to support a finding of adverse long-term or delayed health effects after exposure to nerve agents. However, this report was unable to rule out the possibility that some anticholinesterase agents produced long-term adverse health effects in some individuals. The report deferred to the outcome of a follow-up morbidity study to shed further light on this issue. In the follow-up study (NRC 1985), a questionnaire was sent to subjects of the earlier studies to assess the current health status of more than 4,000 subjects voluntarily exposed to chemical agents during 1958-1975. The long-term health effects of greatest interest included (1) increased cancer risk and (2) adverse mental, neurologic, hepatic, and reproductive effects. Results indicated that subjects who received nerve agents, as a group, did not differ from controls who received no chemical treatment, but mortality was lower than expected in the exposed population; this reduction in mortality could be due to healthy worker effect. The committee recommends that data from the previous studies on the effects of CWAs on military personnel be reevaluated because the follow-up period was not long enough. The committee recognizes that there were problems with these experiments but nevertheless considers them to be a potentially useful source with respect to end points of importance in humans. In a follow-up study, Page (2003) conducted a telephone survey of 4,022 military volunteers for a 1955-1975 program of experimental exposures to chemical agents at Edgewood, Maryland. The current health of those exposed to anticholinesterase agents was compared with that of men exposed to no active chemicals (no chemical test) and to two or more other types of chemical agents (other chemical tests). The survey posed questions about general health and about neurological and psychological deficits. There were only two statistically significant differences: volunteers in anticholinesterase agent tests reported fewer attention problems than those in other chemical tests and greater sleep disturbance than those in no chemical tests. In contrast, volunteers who reported exposure to civilian or military chemical agents outside of their participation in the Edgewood program reported many statistically significant adverse neurological and psychological effects, regardless of their experimental exposure. In this study, the health effects of self-reported, nonexperimental

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents exposure, which are subject to recall bias, were greater than the health effects of experimental exposure. Summary of Studies on Human Volunteers As published by the U.S. Department of Health and Human Services in the Federal Register on March 15, 1988, it was stated that “Questions related to the nerve agents proved relatively easy to resolve. The information bases are fairly complete, and there appears to be little risk either of adverse health effects from long-term exposure to low doses or of delayed health effects from acute exposures.” Furthermore, the NRC was confident that its analyses of the Army human volunteer subjects program would have had the power to detect major adverse health consequences had they been present; however, minor or subtle effects could have gone undetected. Until 1991, with the appearance of unexplained illnesses in returning Gulf War veterans, there was little additional debate about the findings. CHEMICAL WARFARE EXPOSURE SCENARIO It is important that the research being carried out by DOD be considered in the context of the potential exposure of military personnel. As discussed in the Research Plan, DOD has developed hypothetical scenarios that feature military personnel being exposed to CWAs. The operational conditions in the developed scenarios are intended to address the impact of CWA exposures on military operations and to guide future doctrine and research. The operational assumptions include a fit and healthy military force with knowledge of the threat posed by CWAs and the availability of all defense measures against CWAs. The risk in these scenarios is considered to balance between operational efficiency and personnel safety. The scenario conditions are as follows: The commander of an infantry unit is directed to capture a well-defended enemy position over a period of 24 hours. The mission is in support of a full-scale contingency, and intelligence indicates a high threat level for the use of CWAs. CWAs may

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents have been deployed previously on the battlefield with persistent CWAs such as VX, thickened GD, or HD by the enemy to slow a potential advance. Action to take the enemy position might damage existing stores of CWAs and cause their release. The U.S. Forces have available all currently fielded CWA defensive measures. Because of the high ambient temperature (95°F to 100°F), soldiers are directed to wear chemical protective overgarments but not masks and gloves. For making course-of-action decisions, the following questions need to be addressed: Will the possibility of CWAs being deployed by the enemy prevent accomplishment of the mission? What is the highest vapor concentration to which an unmasked soldier can be continuously exposed over a 24-hour period without effects that cause a significant decrease in operational effectiveness? What is the highest vapor concentration to which an unmasked soldier can be continuously exposed over a 24-hour period without causing chronic or delayed heath effects? Should the commander risk the loss of combat efficiency and the likelihood of heat stress by placing troops in full mission-oriented protective posture (MOPP)? Should the commander consider the risk of potential long-term health effects from exposure to a low level of CWAs that may be in the environment but cannot be detected with currently fielded technology? The commander must have evidence that there is a hazard and that the hazard poses a threat. In other words, the commander or decision maker must have the ability to know if a CWA is present and at what concentration and if that concentration can induce adverse operational impairments or adverse delayed health effects in exposed personnel. However, there are limitations in the detection and measurement of CWAs as well as in the validity of human exposure criteria in a deployed military setting. With regard to detection, a listing of the CWA-detection technologies and the manufacturers of fielded instruments have been compiled in various documents (CBIAC 1995, 1998a, b; O’Hern et al. 1997; NRC 1999).

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents To maximize the utility of data from accidental or malicious releases, the committee recommends developing more-sensitive chemical sensors to improve exposure data. The sensitivity of the sensors should be sufficient to measure concentrations of these agents at the lowest levels that are considered to result in operational impairment or produce delayed health effects, as discussed in Chapter 4. Enhanced sensors also might be useful on the battlefield, although greater sensitivity of real-time sensors may lead to more frequent false positives, which in turn would risk distracting soldiers from combat-related tasks and overburdening them by requiring them to don physically restrictive personal protective gear. RISK COMPARISONS In a deployed military setting, being too protective can be as lethal as underestimating the potency of a CWA. In the above scenario, the CWA is not the only significant health or military threat. Protective equipment not only interferes with the individual’s ability to fight, it can cause significant heat stress and produce serious casualties. It is critical that operational doctrine does not require implementing maximum physical protective measures at exposure levels that are significantly below those likely to produce casualties or long-term disabilities. Therefore, human toxicity must be estimated as accurately as possible, and appropriate toxicologic data are required to minimize the uncertainty around those values. There is a risk of health effects associated with exposure to CWAs. At the most extreme level, death may follow exposure to CWAs. Lesser degrees of impact may inhibit the ability of military personnel to function in combat. Competing with the potential health risks is the risk associated with donning full MOPP. Restrictions in movement and vision coupled with the risk of dehydration when operating in hot climates lower the attractiveness of this option. Strategies are needed for balancing the risk of health effects associated with exposure and with reduced effectiveness when wearing gear. If possible, it might be informative to plot the probability of miosis given CWA exposure versus the probability of severe dehydration or other operational end points for a number of concentration-time combinations. Because these effects differ in severity, an even more important comparison is the probability of an operationally relevant decrement in performance due to CWA exposure versus

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents the probability of a performance decrement resulting from donning MOPP. Data are available on the performance decrement resulting from donning MOPP, but data are needed on the performance decrement (if any) resulting from various degrees of miosis (or whatever the critical effect is, recognizing that this comparison may vary as a function of environmental condition—e.g., ambient temperature). One of the main objectives of the Research Plan is to support operational risk management decisions with focused research. Army risk management doctrine (Department of the U.S. Army 1998) provides commanders with methods to evaluate and manage the risks posed by operational hazards to the force. Risks are managed by evaluating hazards and implementing operational risk management options during the course of action development. Risk-risk comparisons (balancing exposure to contamination and other risks) are carried out within this existing framework. This critical premise of the Research Plan is supported by recent recommendations of the NRC report stating the following: [T]he establishment of “conservative” estimates of dose-response relations, that is, those designed to err on the side of safety when faced with uncertainty about how to project expected human responses from available data, might not be appropriate for certain military uses. When risks cannot be avoided and decisions are made to accept some risks rather than others, or to bear some risk in furtherance of a more fundamental military objective, it is important to make these trade-off decisions with unbiased estimates of the impacts of various courses of action. In other applications, such as the setting of health-protective exposure standards for application in less severe circumstances, protective estimates might be much more acceptable…. [Analyses should be] conducted and…results presented, so that different uses appropriate for different risk-management settings can be made [NRC 2000, pp. 66-67]. Characterization of uncertainty and the limitations of available data are important to all risk analysis, but they might play an especially important role in the analysis of deployment threats, where high-consequence decisions might require taking one risk to avoid others. Risk management ap-

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents proaches exist to help make such decisions, but when the risks to be compared are quite uncertain, or uncertain to different degrees, good [characterization] of uncertainty is necessary in order to arrive at sound solutions [NRC 2000, pp. 60-61]. The need for sound science-based risk assessment data was reinforced by the findings summarized in a recent report (NRC 2004). Best exposure guidance estimates are required for making appropriate course-of-action decisions. In summary, DOD requires accurate and reliable estimates of the effects of low-level CWA exposures on human performance. DOD states that accurate estimations cannot be derived from the universe of existing data on studies with animals and human research subjects and proposes in this Research Plan a multiyear, multimillion dollar research effort to acquire such information.