Relationship of Mustard Agent and Lewisite Exposure to Psychological Dysfunction
During the course of this study the committee decided to consider the psychological, as well as the physiological, health effects of exposure to mustard agents and Lewisite. This decision was based on three areas of inquiry. The first was examination of the experimental protocols used in the World War II (WWII) chemical warfare testing programs. It became clear through this examination that numerous aspects of the experiments could be expected to cause moderate to extreme stress to the human subjects involved. The second area of inquiry was the public hearing process (also see Chapter 4). Nearly two months before the April 15, 1992, hearing, more than 50 veterans had already contacted the committee. Among their reported health problems, long-standing psychological problems were common, especially problems with depression and anxiety, and some individuals had been diagnosed with post-traumatic stress disorder (PTSD; see Chapter 4 and Appendix G). Finally, the committee investigated whether or not any scientific literature existed that might apply specifically to a possible causal relation between exposure to these warfare agents, under circumstances that existed in WWII, and the development of psychological dysfunction. On April 15, 1992, Robert Ursano, who heads the Department of Psychiatry at the Uniformed Services University of the Health Sciences and has studied the psychological effects of chemical and biological warfare environments, presented information about what characteristics of such environments are important in the etiology of stress reactions (see Appendix A).
Following this presentation and consideration of evidence from the other areas of inquiry, the committee appointed an additional committee member to review the information already gathered, along with appro-
priate scientific literature relating to the development of psychological dysfunction as a result of exposure to environmental toxins or experiences in chemical and biological warfare environments. Although the amount of scientific literature in this narrow area of focus was found to be quite small, it can be assessed against the background provided by intensive research into PTSD and other stress-related syndromes.
This chapter begins with a description of the historical development of the concept of PTSD. It also relates the findings from the literature and places those findings in context with what is known about the chemical warfare testing programs in WWII. Finally, this chapter outlines the committee's conclusions on the likelihood of adverse psychological health effects from exposure to mustard agents and Lewisite, particularly exposures such as those experienced in WWII testing programs.
The emphasis is on PTSD because the majority of work on the psychological sequelae of "war" experiences, such as those experienced by veterans contacting this committee, emphasizes PTSD. In this context, depression and anxiety are most often considered to be part of a constellation of psychological and psychiatric symptoms that comprise PTSD. In addition, mood disorders (e.g., major depressive disorder, bipolar disorder, and dysthymia) and anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and phobia) can also occur independently or as diagnostic entities coincident with PTSD (defined as comorbidity).
The precise definition of PTSD comes from the Diagnostic and Statistical Manual of the American Psychiatric Association (APA), 3rd Revised Edition (DSM-III-R, 1987; Box 11-1). The DSM is constantly undergoing revision by panels of experts who reexamine each diagnostic category and refine definitions and criteria based on the latest research data. It is also important to note that the diagnostic categories must be broad enough to cover PTSD caused by combat stress, sexual abuse and violence, environmental disasters, and many other types of stress. In addition, the exact combination of symptoms may also be dependent on age, gender, and other variables. At present there are four diagnostic criteria for PTSD:
the existence of a recognizable stressor that would evoke significant symptoms of distress in almost anyone and is outside the range of usual human experience;
reexperiencing of the trauma and intensification of symptoms with exposure to events that symbolize or resemble the traumatic event;
numbing of responsiveness to, or reduced involvement with, the world, beginning after the trauma and including avoidance of activities that arouse recollection of the traumatic event; and
BOX 11-1 DIAGNOSTIC CRITERIA FOR 309.89 POST-TRAUMATIC STRESS DISORDERS
Specify delayed onset if the onset of symptoms was at least six months after the trauma.
SOURCE: American Psychiatric Association, 1987.
a miscellaneous group of symptoms including symptoms of increased arousal, hypervigilance, irritability, and exaggerated startle responses.
A total of 17 symptoms are encompassed by the final three of these four categories, and specific numbers of each symptom type are required for a diagnosis of PTSD. These criteria are a matter of ongoing revision and controversy, however, and failure to meet the full criteria for PTSD does not preclude the presence of other psychiatric disorders or other forms of traumatic stress disorder. Further modification of these characteristics is likely in the future publication of DSM-IV (American Psychiatric Association, 1991; Davidson and Foa, 1991). Possible changes include the incorporation of subjective experiences of a stressor, greater distinctions between the anxiety symptoms in PTSD and those associated with panic disorder, and more precise definition of subtypes of PTSD.
HISTORICAL DEVELOPMENT OF THE CONCEPT OF PTSD
Since time immemorial, human beings have faced major to maximal stressors—floods, fires, earthquakes, plagues, and wars. While the vastness of human misery is overwhelming, however, the consequences of stressors are uniquely experienced by individuals. At least since the 1600s, the diaries kept by literary men of the day have recorded these individual responses to trauma. Trimble (1985) reported several. For example, Samuel Pepys described the Great Fire of London in his Diary, relating his experiences on September 2, 1666, as the fire approached his home and he saw the terror in others. Subsequently, Pepys developed dreams of the fire and falling houses. Six months later, he wrote that he was still unable to sleep "without great terrors of fire" and in his diary referred to the sequelae of the disaster for others, including attempted suicide. In 1865, Charles Dickens was involved in a railroad accident in which he was "shaken up" from viewing the dead and dying around him. He wrote, "I am curiously weak—weak as if I were recovering from a long illness." Later, Dickens developed a phobia of railway travel. Since the late 1800s and early 1900s, industrial accidents, major natural and man-made disasters, concentration camps, terrorist activities, and especially wars have been the source of observations about human responses to major traumatic events. (Andreasen, 1980, 1985; Boehnlein et al., 1985; Giller, 1990; Horowitz, 1976, 1986; Hulbert, 1920; Idelson, 1923; Jewett, 1942; Kardiner, 1941; Kinzie, 1989; Kolb, 1990; Krystal, 1968; Macleod, 1991; Nemiah, 1980; Rennie and Small, 1943; Ross, 1966; Solomon, 1989; Tabatabai et al., 1988; Trimble, 1985; Ursano and Holloway, 1985; Ursano et al., 1981).
Anxiety syndromes in war settings were reported by military sur-
geons in the Franco-Prussian War of 1870, in the Civil War (DaCosta, 1871), and in the Boer War of 1899-1902 (Nemiah, 1980). Various labels have been given what is now called PTSD. In the Civil War, PTSD was called ''soldier's heart" (Horowitz, 1976); later in that century Oppenheim introduced the term "traumatic neurosis"; and Mott used the World War I (WWI) term "shell shock" (Trimble, 1985). Idelson (1923), writing about his observations on one of the larger samples of men with "traumatic neuroses" from WWI, attempted to distinguish between "toxic sequelae" and "psychic or psychogenic sequelae." Without achieving the separation, yet in the best tradition of clinical observation, he described clearly and convincingly in men exposed to toxic gases, those behaviors and responses that are now termed PTSD.
There was little understanding of combat stress reactions in WWI, however, and many of the disagreements about labels were really disagreements about whether or not certain individuals were "predisposed" to develop adverse psychological effects following traumatic events (Horowitz, 1976). Further, there was uncertainty regarding the contributions of physical trauma and the precise type of mental disturbances that could be caused by stressful experiences. A paper by Hulbert in 1920 deemed "gas neurosis" to be the reaction of "discontented soldiers with a morbid, ignorant fear of being gassed." Later analysis by Jewett (1942) distinguished between panic and anxiety states in groups of WWI combat casualties. He further defined a subgroup that exhibited "psychoneuroses" typified by anxiety with psychosomatic components, conversion reactions, and dissociation (amnesia). In one field hospital, Jewett reported that 500 troops suffered psychological symptoms, which were accepted as real effects of combat (as opposed to malingering) because these were all seasoned troops. In his conclusion, Jewett called for "intelligent handling" of psychological casualties.
In WWII (Andreasen, 1980; Kinzie, 1989), many labels appeared: "traumatic war neurosis, combat neurosis, combat fatigue, combat exhaustion, battle stress, operational fatigue, and gross stress reaction." Early in WWII, Kardiner (1941) wrote of the traumatic neuroses of war, warning that while some men were responding rapidly to treatment of acute stress symptoms (now recognizable as PTSD), studies were needed of all phases of such responses, including chronic phases. The importance of the chronic phase of PTSD in WWII veterans was recently affirmed by Kolb (1990), who wrote, "We now know that such symptoms may persist up to 40 years." Yet as van Kammen and Ver Ellen (1990) noted, "After every war, disaster, or publicized atrocity of the last 125 years, the renewed public interest in the stress response syndromes quickly wanes, whereas the victims continue to suffer."
Labels continued to change through the 1950s and 1960s. In 1952, the first edition of APA's Diagnostic and Statistical Manual (DSM-I) used the
term "gross stress reaction." Interestingly, this term was omitted in the revised DSM-II released in 1968, a year synonymous with the peak of the Vietnam War. That war was destined to produce great numbers of veterans suffering from PTSD, so many that there are now Centers for Post Traumatic Stress Disorder in a number of locations, established and funded by the Department of Veterans Affairs. It was not until 1980, with the release of DSM-III, that stress response syndromes, called PTSD for the first time, became a diagnostic category once again. This category and its accompanying criteria represented a landmark in the development of the concept of PTSD in that the first criterion, "existence of a recognizable stressor that would evoke significant symptoms of distress in almost anyone and is outside the range of usual human experience," clearly indicates that all individuals are at risk, not just those with pre-existing emotional problems.
CURRENT RESEARCH IN PTSD
There are intensive programs of research into the etiology, course, and treatment of PTSD. In considering all the possible causes of PTSD and the variables that affect the course and treatment of PTSD in specific individuals, it is not surprising that the body of PTSD research varies tremendously in focus. In addition, many theoretical approaches are brought to bear on this issue. For example, much of the research is based on classical stress research and animal studies. Other research is focused on various treatment types, from cognitive and behavioral approaches to drug therapies. One of the most active areas of PTSD research is the biological assessment of PTSD and the design of therapies that deal with the psychological, as well as physiological, manifestations of the disorder. These studies employ multivariate techniques that integrate neurochemistry, hormonal status, and other physiological conditions with sophisticated psychological assessment strategies (see Giller, 1990; Kulka et al., 1990). Perusal of the proceedings of the Seventh Annual Convention of the International Society for Traumatic Stress Studies (1991) also underscores the diversity of this research: over 260 presentations were made at this meeting, in 12 different categories.
EVIDENCE FROM STUDIES OF MILITARY PERSONNEL AND VETERANS
Chemical and Biological Warfare Environments
In the mid-1980s, a project was undertaken at the Uniformed Services University of the Health Sciences (USUHS) to examine the psychological
and behavioral responses to chemical and biological warfare (CBW) environments (Ursano, 1987a,b; 1988a,b,c). The project, inspired by the continuing threat of CBW in world conflicts and specifically aimed toward development of effective strategies for use by the U.S. Air Force, had three components. The first component was the development of a database containing available knowledge about the psychological and behavioral responses to stressful environments, CBW environments, and the effects of such responses on performance and health. A second project component was direct observation of CBW training exercises and facilities. Finally, two major conferences were held, supplemented by a variety of small group discussions. Although largely applicable to all CBW agents, the project's major focus was on nerve agents. The final recommendations of this project were published in 1988, covering command, medical care, performance, and training issues (Ursano, 1988d). Similar findings, based on the above project and a review of additional literature, were published in 1990 (Fullerton and Ursano, 1990).
A number of recommendations from the USUHS project are interesting when viewed in reference to the handling of subjects in earlier CBW testing programs. Under the category of command issues, recommendations were made about the value of effective communications between command levels and troops to reduce the likelihood of adverse psychological and behavioral responses to stress. This included ensuring that troops had adequate knowledge of what was happening. The communication issues were so important to the troops' perception of risk and overall fear response that they were reiterated in the medical care, performance, and training categories. A further recommendation from this project was that officers, medical personnel, and others in command roles be sensitive to the problems and concerns of their troops, especially to those problems that were "unique" to CBW environments. These include heat stress,1 concern about exposure levels, stress of confinement in protective structures holding many people, and many others. Another recommendation warned commanders that individuals may appear healthy initially in a psychological sense, but can develop delayed symptoms that warrant attention. It was also determined that an adverse response in one individual, or small group, can be "contagious" to the rest of a group under CBW conditions, and that "over-dedication" to the mission can cause commanders and individual troops to surpass their physiological capabilities and lead to exhaustion, as well as faulty reasoning and decision making.
Numerous issues emerged as relevant to appropriate medical care in CBW environments. For example, it was found that, at least for nerve agents, stress and fear increased with prolonged and low-dose exposures. The need for health workers trained to deal with stress reactions was emphasized, as well as the need for commanders and supervisors to be sensitive to the manifestations of stress among their troops. To reduce the incidence of severe adverse reactions, certain strategies were recommended, including making certain troops had privacy and time during rest periods to interact with others about their concerns and experiences. Attention was also specifically directed at those who may witness grotesque injuries and handle the dead. Such activities were judged to be among the most stressful experiences possible in these environments. In cases of actual CBW exposures, it was also recommended that spouses of the affected troops be briefed about what had occurred so that the spouse could be an active participant in the post-trauma support efforts.
The recommendations outline the possibility of major decreases in performance and concentration arising from the psychological reactions to CBW environments, decrements that could in some cases cause life-threatening mistakes. Such decrements could also result from the physiological effects of nerve agents, or from heat stress alone, so the importance of distinguishing the causes and treating them appropriately was emphasized.
Under issues of training, the recommendations underscored the importance of prior training to reduce stress and to strengthen group cohesiveness, which further reduces stress. These training issues were quite varied, from training to deal with injuries and death to training in handling the protective gear effectively. An interesting recommendation addressed the costs versus benefits of the use of live agents in training and concluded that further investigation was needed to resolve this question. Finally, CBW trainers were warned to expect a certain number of individuals to develop claustrophobia during training exercises and were advised to attempt "talk down" procedures or remove the individual from the area.
In summary, then, numerous aspects of CBW environments can cause stress reactions of varying magnitudes in those involved. Although no direct statements are made regarding the long-term effects of such stress reactions, some of the characteristics of CBW environments fall into the description of experiences "outside the usual human experience ... [and] ... stressful to almost anyone" (DSM-III-R). Thus, it may be assumed that experiences in these environments may result in adverse psychological effects, including depression, anxiety, and PTSD-like symptoms in certain individuals.
Studies of PTSD in Veteran Populations
It is difficult to estimate how many veterans in the United States suffer from PTSD, but estimates range from 500,000 to 1.5 million (Kulka et al., 1990). The large numbers of veterans affected and a greater appreciation for the disabling effects of PTSD have inspired an increased research effort on the causes, psychological and physiological mechanisms, diagnostic criteria, course, and treatment of PTSD. Although it is impossible to review all of this work here, examples of this research bear directly on some of the key aspects of the experiences of veterans who contacted this committee.
A recent study of Vietnam veterans examined the kind of stressors most likely to result in PTSD in combination with other psychological disorders, including depression, panic disorder, phobic disorder, and alcoholism (Green et al., 1989). Over 52 percent of the sample of 196 individuals met the criteria for some type of psychiatric disorder: 29 percent met the criteria for PTSD, 21 percent were found to have phobic disorder, 15 percent suffered from major depression, 11 percent were alcoholic, and 7 percent exhibited panic disorder. Interestingly, a little more than 10 percent met criteria for both PTSD and major depression, and over 14 percent had both PTSD and phobic disorder. When these disorders were correlated with specific types of military experiences, some intriguing associations emerged. For example, the younger the individuals were entering the military, the higher was the percentage of PTSD found. In addition, the most potent predictor of PTSD and anxiety disorder comorbidity (PTSD with phobic or panic disorder) was involvement in dangerous and high-pressure "special assignments." Exposure to grotesque scenes of death and mutilation was associated with higher incidence of multiple disorders (e.g., PTSD and some other disorder, but no one disorder in particular). None of the results could be reliably attributed to psychiatric conditions prior to the war experiences.
Reasonable arguments may be made that Vietnam veterans, as a group, are quite different from WWII veterans due to a difference in the public perception of the respective conflicts, generational value differences, and other variables. Davidson and colleagues (1990) have compared Vietnam veterans with WWII and Korean War veterans on measures of depression, anxiety, severity and types of symptoms, and intensity and nature of combat experiences. The two groups of veterans were generally the same in terms of the sequential emergence of diagnoses and the age of onset of diagnoses: PTSD was followed by a general anxiety, which was then followed by panic disorder, major depression, and intermittent depressions. Alcoholism tended to emerge later in World War II and Korean War veterans than in Vietnam veterans. In addition, Vietnam veterans had, among other
differences, more severe symptoms, higher depression scores, greater survivor guilt feelings, and more work disruption than World War II and Korean War veterans. In addition, despite similar rates of comorbidity overall, the Vietnam veterans were more likely to have panic disorder and PTSD. The differences in the veterans' reports of intensity of their experiences were interesting: WWII and Korean War veterans were most upset by general fear, fear of physical injury, and fear of incapacitation; Vietnam veterans, on the other hand, were traumatized most by witnessing brutality, sight of mutilated bodies, and loss of a friend in combat.
That stress reactions can set the stage for lifetime psychological difficulties is important in view of the nearly 50 years that have passed since the WWII testing programs with mustard agents and Lewisite. Indeed, a constellation of psychological problems may result from traumatic experiences, including depression, anxiety, panic disorders, and PTSD. Almost no data exist regarding the natural course of these adverse psychological effects over decades in the absence of treatment. A collection of case studies published by Macleod (1991) is pertinent to this issue.
Eighteen WWII veterans from New Zealand, identified as suffering from chronic PTSD, were interviewed extensively following routine psychiatric review for the War Pensions Claims Panel. Most of these men had not been treated for PTSD, but some had been treated for other psychiatric illnesses. The majority of the men recalled traumatic experiences during the war with great vividness and detail. Key among their emotional responses to these events was fear, physiological arousal, and helplessness. Two thirds of the men reported lifelong troubles with, or distance from, their spouses and families. Most interesting was the commonality of the reported long-term course of their emotional problems. This course generally began with a controlled response at the time of the trauma, followed by superficial attempts at coping with the incident. After the war ended, the men experienced significantly greater emotional difficulty for a period of time, but the schedule and routine of their working years was associated with a moderation of symptoms. A second escalation of symptoms arose in these men after retirement. The author concluded from this sequence that work became a distraction for the men and the cessation of working caused a reemergence of underlying problems. Although the conclusions drawn from this case study must be tentative, the paper supports the concept that PTSD symptoms, untreated and unrecognized over long periods of time, may nevertheless be traceable and diagnosable. Further, the suggestion is unavoidable that there may be many WWII veterans who have struggled unknowingly with PTSD or PTSD-like symptoms for decades.
EVIDENCE FROM STUDIES OF THE PSYCHOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINATIONS
Scientists interested in stress reactions have also begun to look at groups of people who have been exposed to environmental contaminations of various kinds, or who have lived in close proximity to contaminated areas. It is useful to consider the findings of such studies, because some of the characteristic stressors of these experiences are relevant to the WWII testing programs.
Longitudinal studies of people living near the ill-fated Three Mile Island (TMI) nuclear power plant have been reported by Baum and colleagues (1981, 1987). A number of measures have been employed in these studies, including performance tests, depression and anxiety measurements, interviews, and physiological assessments. In addition, the TMI group was compared to other communities located nearby, or distant from, toxic waste dumps. One of the main problems for members of the TMI group has been the high level of uncertainty they have lived with since the accident. There has been uncertainty about the level of exposure they experienced, whether radioactivity is still present, and what the short-and long-term health effects will be. The uncertainty has been exacerbated by conflicting reports from government officials, the press, and members of the community themselves. The authors further argue that the very presence of the "smokestacks," so identified with the accident in the minds of all, serves as a constant reminder to those who continue to live in the area.
Among the TMI group, there is a widespread concern about cancer and somatic complaints are common, especially headaches, backaches, and gastric distress. Measures of anxiety have increased with time, as have specific physiological measures of stress. Blood pressure measurements in the TMI group, assessed by examination of personal physician records from before the accident, show increases by one year after the accident and have remained high; 10 to 15 percent have developed hypertension since the accident, a percentage not explained by smoking or other controlled variables. Compared to other groups studied, the TMI population also exhibits higher concentrations of urinary catecholamines, which are indicative of physiological stress responses.
Some of the individuals in the TMI group scored high on all three types of measures: performance tasks, depression scales, and physiological measures. Such individuals were categorized as a "high-stress" group and studied further in comparison to "low-stress" and control groups. It was found that, although the entire population showed decreased lymphocyte counts (monocytes, B cells, T cells, T helper, and T suppressor cells), the high-stress group exhibited clear indications of immune system depression by these measures. Interestingly, it was found that individuals who
had strong social supports reported fewer symptoms of any kind, but these individuals nevertheless exhibited differences in biochemical and physiological measurements. Finally, there were no differences reported in any of the groups between those individuals who were actually exposed and those who believed they were exposed.
Indeed, the entire issue of exposure to toxic chemicals or radiation is complex in terms of psychological, physiological, and social responses. Uncertainty is probably the most important characteristic in increased perception of risk and level of stress, yet uncertainty on the part of the involved health professionals can also decrease the effectiveness of health care for those exposed. The interplay of such variables has been the subject of Henry Vyner's 1988 analysis of the psychosocial correlates of exposure to toxic chemicals and radiation, so-called invisible environmental contaminants. In his book, Vyner analyzed numerous studies done with various "exposed" populations, including people living at Love Canal, veterans exposed to radiation during the A-bomb tests, people in Michigan who were affected when a toxic chemical known as PBB was mistakenly put into cattle feed, and the TMI community.
According to Vyner, the psychological effects of such exposures proceed in sequential fashion, from uncertainty arising from the individual's attempt to adapt to the possible health threats of the exposure, to hypervigilance about one's health and the development of nonempirical belief systems, to "traumatic neuroses."
Vyner argues that this sequence can become a vicious circle in which these individuals get caught. The more hypervigilant they are, the more they believe their health is threatened, the less seriously their complaints are taken by the medical establishment or other groups charged with the medical care or compensation of these individuals. Institutional responses to persons exposed to toxic chemicals or radiation often show a tendency to blame the victims and view them as hypochondriacs or malingerers. When this happens, the individual becomes more threatened and more vigilant. Vyner writes that the challenge to physicians and health care providers is to recognize such an individual's uncertainty and vigilance, and to provide the patient with as much information and control as possible, in order to increase the effectiveness of health care for that person and, likely, the eventual outcome.
The experiences of the human subjects represent a combination of variables seen in combat stress and environmental contaminations. Such a combination fits quite well into several of the broad categories of reactions to stressful life events outlined above and would be expected to increase the likelihood of adverse psychological effects for a certain
percentage of individuals. It is the judgment of this committee that the best available evidence indicates a causal relation between the experiences of the subjects in chamber and field tests of mustard agents and Lewisite and the development of adverse psychological effects. These effects may be highly individual, but diagnosable, and may include long-term mood and anxiety disorders, PTSD, or other traumatic stress disorder responses. In addition, some of the experiences of those who worked with chemical warfare agents or who were exposed to sulfur mustard at Bari harbor, such as explosions, injuries, and witnessing of injury and death, may also have resulted in development of such adverse psychological effects.
There are many aspects of the chamber and field test situations that individually may have been sufficient to produce adverse psychological effects in certain human subjects. These include (1) the number and duration of chamber trials in the presence of live agent and under hot, humid conditions; (2) the inability to escape the chamber without fear of severe reprisals; (3) the sight and/or experience of severe blistering, especially to genital areas; (4) the young age and lack of adequate preparation of the subjects; (5) the commands of secrecy and its resultant isolation of subjects; and (6) certainty that an exposure occurred (in the chamber tests, evidence of exposure was the end point of the experiments). Such conditions certainly qualify as "outside the range of normal experience" and they would be upsetting to almost anyone. For those involved with handling warfare gases, who witnessed or were injured by explosions and other types of accidents, these would also qualify as stressful experiences outside the normal range of human experiences.
The aspects above are, however, only part of the total experience of many of the human subjects. The passage of time, the imposed silence, the lack of medical follow-up, and the institutional denials have almost certainly complicated the original trauma and worsened its effects. Such effects would include hypervigilance and the establishment of long-held beliefs regarding health problems and their causes.
Despite intensive research, it is not possible to know the degree to which PTSD and other psychological disorders are accompanied or caused by physiological perturbations such as changes in hormone levels, tone of the autonomic nervous system, levels of circulating lymphocytes, and other measures of physiological function. It is not possible, therefore, to draw any conclusions about specific physiological conditions and their possible psychological concomitants or causes.
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