The following document was produced by the Pentagon's Persian Gulf Investigation Team.

REPORT ON POSSIBLE EFFECTS OF ORGANOPHOSPHATE "LOW-LEVEL" NERVE AGENT EXPOSURE

INTRODUCTION

The Persian Gulf Illnesses' Investigation Team has been asked to prepare a report on the possible adverse effects on human health of organophosphate chemical warfare agents at "low" concentrations. The agents are generally defined to include Sarin (GB), Soman (GD), Tabun (GA), GF, and VX, and because of their similarities, can, for many purposes, usually be discussed as a group without specifying a specific agent.

Low agent exposure is defined in this report as the contact of molecules of agent with a living organism at concentration and duration insufficient to produce initial clinical symptoms. The pharmacologic literature defines the concept of the "Ct", an instantaneous concentration of agent integrated over time at the location of a subject (victim), a minimum value of which is necessary to produce threshold symptoms [1] The agents are highly lipophilic and readily absorbed through the lungs and skin, such that target sites in the nervous system are quickly affected. The threshold symptoms are commonly stated to be miosis, rhinorrhea, and airway constriction, generally appearing at a Ct of 2-3 mg min/m3 [2].

The concept of the Ct appears to have been employed for a single exposure lasting over minutes and not for periods of hours or days. One author suggests that the value he arrives at, 0.5 (versus 2-3 reported in another text, Somani, ref 2) [2]is applicable only up to 20 minutes [3]. Since there is a reciprocal relationship between concentration and time expressed in the definition of the Ct, on pharmacologic grounds alone, any value derived for long times would increase as the homeostatic mechanisms of the body deal with the lower concentrations prescribed by the Ct for longer times. The concept of the Ct then loses meaning for long times, and a search of the literature yields no papers addressing the issue of "low" concentrations for long times (hours to days or weeks). This is consistent with the generally held view that the injury mechanism of nerve agents is understood, that is, the irreversible binding of the agent to cholinesterase. The injury is a mass effect, requiring a minimal concentration of agent; recovery occurs by degradation of the bound molecule, elimination of the product and synthesis of new acetylcholinesterase. The pharmacology of this process has been well studied.

Most probably, another reason why "low agent" studies do not appear in the literature is one articulated by leading investigators in this field [4] The concept of low-agent exposure is not realistic. These are highly volatile substances and disappear quickly. If employed in warfare, they must be introduced into a local environment at very high concentration in order to maintain injury levels for the short time they are present. It is hard to imagine an open-air situation in which low concentrations would not disappear to zero levels within moments. Even leakage from damaged munitions would probably have to occur in a tightly confined chamber with no ventilation to produce symptomatic levels, a situation hard to imagine in any real setting and not likely to affect large numbers of people without detection.

The agents also break down by hydrolysis to nontoxic products in the environment at varying rates depending on specific environmental conditions, but, in the cases of Soman and Tabun, not exceeding two to three days [5].

What evidence does the literature provide that low nerve agent exposure produces chronic disease states or chronic symptoms of any kind? We are unable to identify any controlled human study in which measured doses, contrived to avoid symptoms, employing any route of administration, were utilized, and subjects monitored over extended periods of time. However, reasonable extrapolations can be made from the few controlled human studies, a few accident investigations, and a number of animal studies, all of which involved symptomatic levels of exposure. The human studies have been tabulated by Ballantyne [6]. Some of these studies were described to the Presidential Advisory Committee by COL David Moore of the US Army Medical Research Institute for Chemical Defense in his testimony of 2 May 1996. We comment on these studies in the ensuing paragraphs.

CONTROLLED HUMAN STUDIES

The largest controlled human studies known were performed at Edgewood, starting in the 1950s and ending in the 1970s. These studies were brought together, analyzed, and the results published in a three volume study, prepared by a National Academy of Sciences panel [7].

Referring to OP nerve agents tested on over 1400 subjects, the panel concluded, in its 1982 report that no evidence had been developed that any of the anticholinesterase compounds had produced any long range effects in the doses used. According to Dr. Fred Sidell, who conducted many of the studies, dose rates varied from low-asymptomatic dosages to frank-illness producing doses. The panel deferred a final conclusion pending a longer temporal study. This study was published in 1985, consisting of an analysis of a questionaire sent to subjects of the earlier studies.

The 1985 study concluded that subjects tested with anticholinesterase chemicals "did not differ significantly from control subjects or from those tested with other classes of drugs in their replies to questions about their current health status. Almost 90% of all these respondents reported no health problems related to the exposures under scrutiny, and 79% reported good to exellent health."

The panel stated that the experimental methods and the available comparison groups were such that only large effects were likely to be uncovered. The large standard errors and the self-reporting nature of the questionnaire study all would tend to obscure small differences.

The panel focused on the issue that long-term health effects might occur in the form of subtle changes in EEG, sleep patterns and behavior--such as increased irritability, inability to concentrate, and depression. There was a concern that such changes might be identified as general health problems or identified by physicians as mental disorders. In fact, the panel concluded that answers from subjects who received nerve agents compared favorably with answers from controls who had received no chemical treatment.

Post-test admissions to Army or VA hospitals were studied and did not appear to be significantly increased, either during the years immediately after testing or later. The panel found that responses to questions about current health status by subjects exposed to anticholinesterases suggested that these subjects were not different from a comparison group with no exposure to chemical agents.

A number of reports of controlled human studies, tabulated in Ballantyne, emerged from the ongoing Edgewood studies. A few studies were performed in Great Britain at Porton Down (see Ballantyne reference). These studies followed subjects for the most part for periods not exceeding a few days until recovery appeared to be complete. Bowers et al [8] reported that subjects had difficulty with memory for 24 hours after admininstration of VS, but did not have major thought disorders. Depression occurred just after exposure, but did not persist. Sleep disturbances occurred but did not persist.

In another controlled human study [9], concentration and vigilance were impaired after nerve agent exposure. These effects persisted for several weeks before disappearing. The same authors, in a review of their work and that of others to date [10] reported that "recovery from moderate intoxication due to 'nerve gas' has always been complete." It was further stated that there are no known effects other than inhibition of cholinesterase enzymes of the blood and tissues. There is no other alteration of the chemical constitutents of the blood, no alteration of the formed elements of the blood and no change in the urine or in renal or hepatic function.

The thrust of the controlled studies reviewed is that, in subjects deliberately rendered ill with symptoms of anticholinesterase poisoning, long-term clinical effects were not found. This is to be borne in mind in considering any hypothetical exposures of Gulf War veterans which would presumptively have involved much lower levels of exposure.

ACCIDENTAL EXPOSURES.

Several reports have described industrial accidents involving nerve agent release. In reviewing all such reports one must distinguish between OP pesticides and OP nerve warfare agents. This appears to be a source of confusion in the public mind. Since the nerve agents and insecticides are both OPs there is a tendency to extrapolate from the effects of one type of OP to the other. Among the critical differences is the fact that the cholinergic crisis from severe intoxication with the insecticides [11]is much longer than that caused by nerve agents [12], days to weeks for insecticides as opposed to hours for nerve agents. Another critical difference is that nerve agents require doses many-fold the LD50 to produce polyneuropathy and inhibition of neurotoxic esterase (NTE) in nerve tissue, as opposed to the far lower doses required for such effects by OP pesticides.

Consistent with other clinical studies of OP pesticides Durham et al [13], reporting on 187 individuals who were routinely involved with pesticide work, concluded that mental effects were not seen in the absence of clinical signs of poisoning. It appears that neither OP nerve agents at symptomatic levels nor OP pesticides at asymptomatic levels produce long-term mental effects.

A report of 297 cases of accidental exposure to nerve agent among manufacturing workers [14] revealed that about 20% of the subjects had disturbed sleep, irritability, mood disturbances, absent mindedness, fatiguability, and lightheadeness. The report does not make clear the duration of these effects, but does indicate that the subjects eventually returned to work fully functional.

Other cases of accidental exposure have been reported [15]. In general, the accidental exposures were followed through short-term recovery periods, days to weeks, at the end of which EEGs of some subjects were noted to be abnormal. In the study by Duffy it was noted that the relationship between the EEG changes and a possible alteration in brain function was not known. This study carefully documented the symptoms and inhibition of RBC acetylcholinesterase, but it is not clear if cases of severe poisoning occurred. The EEG changes in the Duffy study were present for up to 1 year after the last exposure and included increased beta activity, increased delta and theta slowing, decreased alpha activity, and increased amounts of rapid eye movement sleep. There is a controversy over the value of computerized analysis of brainwave topography [16] and caveats have been published concerning its use [17].

In a review of the issue of neuropsychiatric effects, Ballantyne and Marrs (ref 6, p79) [6]conclude that "neuropsychiatric disorders are unlikely to occur from repeated exposure to organophosphates at doses not causing overt cholinergic toxicity."

Several descriptions of accidental exposures of individuals can be found in the literature. In one [18] a biochemist was acutely exposed and developed psychiatric symptoms, followed by full recovery. In another case [19] a physician was severely exposed to GB requiring assisted ventilation, but made a full recovery and returned to work with no apparent problems.

Sidell and Hurst (ref 1, p 17 [1]) offered the following comments: "While there are few data on the duration of these neuropsychiatric effects in people, there is suggestive evidence that they are relatively short-lived (days, weeks). Because of the nature of the work, people employed in manufacturing, at depots, or in research and development facilities were relatively few in number, tended to remain in the same job for a long period of time, and were a closely knit group. Most were thoroughly familiar with the effects of nerve agents, and most knew their co-workers very well. If a worker did not seem 'right', his co-worker or supervisor recognized it. A medical facility dedicated to the treatment of nerve agent casualties and with a staff experienced in this type of injury was always available; workers were encouraged to use it, and supervisors were instructed to send employees who were not 'normal.' One of the authors worked in such a medical facility for over a decade, and while there was no routine formal follow-up procedure, e.g., psychological testing, of exposed casualties, informal follow-up visits were common for several weeks after the incident for eye examinations (miosis takes 3 to 6 weeks to recede) and to discuss general health problems. It seems very unlikely that significant lingering effects were not mentioned or not detected."

THE CONTRIBUTION OF ANIMAL STUDIES.

Animal studies are necessary in the evaluation of hazardous agents. These studies permit an exhibition of the full dose-response range and make experimental therapeutics possible. A few of the studies, as they pertain to neurotoxicity, will be described here.

Monkeys were dosed with GB in one of two dose schedules: a single large dose that produced convulsions, or a series of 10 weekly doses that caused no clinical effects [20]. The animals from both dose schedules had increases in high frequency beta activity a year after exposure, but were otherwise healthy.

GB and GD have been found not to be mutagenic [21]. GA was found to be weakly mutagenic in three different assays [22].

In histologic studies rats were given daily illness-producing doses of GA or GD for 90 days by gavage. At the end of the study no abnormalities were found on gross or histological examination of tissue [23]. Dogs were dosed with GB over a six-month period. No tissue abnormalities that could be attributed to the agent were noted on gross or microscopic examination at the end of this period. Several of the male animals were bred after the exposure and the pups were normal [24].

Evidence for neurotoxicity and neuropathology has been searched in a number of studies. A strong motivation to look for such effects derives from the experience of CNS and peripheral nerve damage produced by some organophosphate pesticides. OP-induced delayed neurotoxicity (OPIDN) appears to be unrelated to the the anticholinesterase actions of this class of compounds [25]. The classic findings of peripheral neuropathy include flaccid paralysis after a latent period of about 2 weeks following exposure. They are produced by axonal degeneration and demyelination. A chronic neuropsychiatric syndrome follows with some OP pesticides. A generally held theory is that the proximate cause of the lesions is the inactivation of neurotoxic esterase (NTE). Ballantyne and Marrs (ref 6, p 37 [6]) discuss the evidence for and against the role of this enzyme as a mediator of the peripheral neuropathy of OP poisoning.

In contrast to certain OP pesticides, nerve agents have caused polyneuropathy in animals only at doses many-fold the LD50, doses that require massive pretreatment and therapy to insure survival of the animals. Davies et al [26] produced polyneuropathy in chickens with GB only at 60-fold the LD50. In another study [27] polyneuropathy was found in hens after 30-60 times the LD50 for GB but not at 38 times the LD50 for GD or 82 times the LD50 for GA.. According to Sidell and Hurst (ref 1, p 8 [1]) the syndrome "has not been noted in the handful of humans severely exposed to nerve agents or in the hundreds of humans with mild to moderate effects from nerve agents."

An acute neurologic syndrome called the 'intermediate syndrome,' seen in insecticide poisoning, "has not been described after administration of nerve agents to animals, nor has it been noted in a handful of individuals severely exposed to nerve agents." (ref 1, p 11 [1])

REPORTS IN THE LITERATURE SUPPORTING THE CONCEPT OF "LOW-LEVEL" TOXICITY.

Reference has been made to allegations of chronic effects of organophosphate nerve agents following exposures which may or may not produce acute symptoms. These allegations are contained in a monograph titled Delayed Toxic Effects of Chemical Warfare Agents, A "Stockholm International Peace Research Institute" publication authored by Professor Karlheinz Lohs, dated June 1975.

In this monograph, in which all "poison gas" agents are treated together, often indistinguishably, the organophosphate agents are repeatedly asserted to produce a number of chronic disorders including neurologic illnesses. These illnesses are summarized on page 40 of the monograph in which the organophosphate nerve agents are not distinguished from organophosphate pesticides.

This part of the monograph relies entirely on two papers by Spiegelberg:

Spiegelberg, U., "Psychopathologisch-neurologische Schäden Nach Einwirkung synthetischer Gifte", Wehrdienst und Gesundheit, Vol.III. Darmstadt: Wehr und Wissen Verlagsgesellschaft mbH, 1961.

Spiegelberg, U., "Psychologish-neurologische Spät- und Dauerschäden nach gewerblicher Intoxikation durch Phosphorsäureester (Alkylphosphate)", Proc.Int.Cong.Occup.Health 14th, 1963. Excerpta Med.Found.Int.Cong.Ser.n62, 1778-80.

Careful review of the two Spiegelberg papers does not support the contention of Professor Lohs. Spiegelberg, in the 1950s identified workers in the chemical industry during the 3rd Reich in the 1930s and 1940s. These plants were making a large number of different agents and workers were constantly shuttled back and forth between different agent production areas, including areas making organophosphate pesticides and many other non-war related agents. Spiegelberg concedes that actual exposures, including the identity of individual agents and amounts could not be documented. In his 1963 paper he identifies only 3 workers out of 129 who may only have been exposed to Tabun or Sarin. They are described as ill, with vague neurologic problems. The studies are undocumented and uncontrolled.

Dr. Fred Sidell, one of this country's leading authorities on the toxicology of OP nerve agents, commenting on the Spiegelberg papers, asserts that many of the workers were in poor health in the 1930s and 1940s, having been rejected for service in the Wehrmacht, and then were forcibly impressed into the chemical plants. Discovered by Spiegelberg in the 1950s as they entered old age, many were found to be ill.

In his 1961 paper, Spiegelberg explicitly states, in an English translation supplied to the author, that "acute intoxication by nerve gases can come to full recovery. We have no reason to doubt this on the basis of our own results as well as data in the literature." "As far as chronic intoxications due to nerve poisons are concerned, we have found nothing in the literature, neither could we find any information there concerning delayed or chronic injuries."

It is hard to escape the conclusion that Lohs has either misrepresented the findings of his primary source, or has confused the issue by lumping a large number of different agents, warfare and non-warfare related, together.

The relevance of any of the work reported by Lohs to possible Gulf war exposure to OP nerve agents is completely unclear. Although there is no evidence that personnel in the Gulf had any exposure, if there had been such an occurrence, it probably would have been episodic over a few days, (undetected and without symptoms, as we know from the record) and therefore far less than that of industrial workers, who, if they were exposed, might have had an exposure over a period of years.

We are therefore in the position of finding that the assertions of Lohs are without foundation in fact and also irrelevant to any hypothetical Gulf War exposure.

SUMMARY AND RECOMMENDATIONS

Concerns have been expressed that Gulf War veterans may have been exposed to low levels of organophosphate nerve agents which later manifested as chronic neurologic illness. This report assembles the relevant medical data base bearing on such a phenomenon. The concern then focuses on the possibility of inadvertent or accidental release of nerve agents, especially in or around supply depots possibly containing such agents, as UN forces took possession of or destroyed such facilities.

In discussion with experts on storage and release of such agents, those individuals have challenged the concept of lingering low concentrations of these volatile agents. Only in the rigid and artificial environment of a laboratory could agents be held at some finite, low concentration more than momentarily. Because of rapid dispersal the efficacy of such agents depends on efficient delivery of high concentration of agent causing rapid incapacitation. If one can get beyond the lack of reality of the concept, then one must depend on a data base mostly concerned with defining the relationship of dose to toxicity. Taken in the aggregate, controlled studies of human exposure, reports of accidental exposures, and animal studies point consistently to the fact that exposures to symptomatic levels of OP nerve agents do not produce chronic illnesses. The finding of abnormal EEGs is discordant but this abnormality is not accompanied by functional illness and is of uncertain significance in any event. Older studies from Germany in the 1950s, arguing for chronic illnesses, were methodologically weak and not confirmed by much more careful and systematic studies in the ensuing decades.

If one ignores the evidence, and posits some Gulf War exposure of unknown origin, such a contact with agent would probably have been episodic, sporadic, and, in any event, far less than that of industrial workers, who, if they were exposed, might have had an exposure over a period of years. We are left to ponder the possibility of illnesses from very low exposures in the presence of overwhelming evidence that those illnesses do not occur with higher and longer levels of exposure. This would be incompatible with empirical science and the principles of biology and pharmacology.

We therefore conclude that there is no credible evidence for chronic illnesses caused by exposure to organophosphate nerve agents at concentrations too low to produce signs or symptoms of acute anticholinesterase poisoning and that such a process cannot be reasonably advanced as having a role in Gulf War illnesses.

While further research on animals might contribute some information to the general data base on toxicity, it is unlikely in the extreme that such research would enhance our understanding of Gulf War illnesses. ------------------------------------------------------------------------

[1] Sidell, FR, and Hurst, CG, The Long-Term Health Effects of Nerve Agents and Mustard, U.S. Army Medical Research Institute of Chemical Defense, (in preparation).

[2] Somani, SM. ed. Chemical Warfare Agents. San Diego, CA: Academic Press; 1992: 156-194.

[3] McNamara BP, and Leitnaker F., Toxicological Basis for Controlling Emission of GB into the Environment, Edgewood Arsenal Special Publication, EASP 100-98, March 1971, p 5.

[4] personal communication from Dr. Fred Sidell.

[5] Sanches ML, Russell CR, Randolph CL, Chemical Weapons Convention (CWC) Signatures Analysis, Technical Report, Defense Nuclear Agency, DNA-TR-92-73, March 1993, Appendix B-14.

[6] Ballantyne, B., and Marrs, TC, Clinical and Experimental Toxicology of Organophosphates and Carbamates, Butterworth Heinemann, p380.

[7] Panel on Anticholinesterase Chemicals, Panel on Anticholinergic Chemicals, Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol. I, Anticholinesterases and Anticholinergics, Committee on Toxicology, Board on Toxicology and Environmental Health Hazards, Assembly of Life Sciences: National Academy Press, Washington, DC, June 1982.

Coodinating Subcommittee, Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol. III, Final Report, Current Health Status of Test Subjects, Committee on Toxicology, Board on Toxicology and Environmental Health Hazards, Commission on Life Sciences, National Research Council, National Academy Press, Washington, DC, 1985.

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Ward JR. Exposure to a nerve gas In: Whittenberger JL. ed. Artificial Respiration. Theory and Applications. New York City: Harper and Row; 1962:258-265.

[13] Durham WF, Wolfe HR, Quinby GE. Organophosphorus insecticides and mental alertness. Arch Environ Health. 10:55-66, 1965.

[14] Gaon MD, Werne J. Report of a study of mild exposures to GB at Rocky Mountain Arsenal. Rocky Mountain Arsenal, Colorado: US Army Medical Department.

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Sidell FR. Soman and Sarin: Clinical manifestations and treatment of accidental poisoning by organophosphates. Clin Toxicol. 7:1-17, 1974.

Ward JR. Exposure to a Nerve Gas, in Whittenberger JL ed. Artificial Respiration; Theory and Applications.. New York City: Harper and Row; 1962:158-265.

[16] Duffy FH, Bartels PH, and Neff R. A response to Oken and Chiappa. Ann Neurol, 19:494-496, 1986.

Oken, BS, and Chiappa KH, Statistical issues concerning computerized analysis of brain wave topography. Ann Neurol, 19,494-494, 1986.

[17] American Electroencephalographic Society. Statement on the clinical use of quantitative EEG. Clin Neurophysiol, 4,75, 1987.

[18] Sidell FR, Soman and sarin: Clinical manifestations and treatment of accidental poisoning by organophosphates. Clin Toxicol. 1-17, 1974.

[19] Ward JR. Exposure to a nerve gas In Whittenberger JL. ed. Artificial Respiration. Theory and Applications. New York City: Harper and Row; 1962: 258-265.

[20] Duffy FH, Burchfiel JL. Long-term effects of the organophosphate Sarin on EEGs in monkeys and humans. Neurotoxicol, 1:667-689, 1980.

Burchfiel, JL, Duffy FH. Organophosphate neurotoxicity: Chronic effects of Ssarin on the electroencephalogram of monkey and man. Neurobehav Toxicol Teratol. 4:767-778, 1982.

Burchfield JL, Duffy FH, Sim V. Persistent effect of Sarin and Dieldrin upon the primate electroencephalogram. Toxicol Appl Pharmacol. 35:365-379, 1976.

[21] Goldman M, Klein Ak, Kawakami TG, Rosenblatt LS. Toxicity studies on agents GB and GD. Davis, CA: Univ. California Davis Lab for Energy: 1987.

[22] Kawakami TG, Goldman M, Rosenblatt L, Wilson BW. Toxicity studies in agent GA: Mutagenicity of agent GA (Tabun) in the mouse lymphoma assay. Davis, CA: Univ. California Davis Lab for Energy: 1989.

Nasr M, Cone N, Kawakami TG, Goldman M, Rosenblatt L, Mutagenicity of Tabun (GA) in the in vitro cytogenetic sister chromatid exchange test phase I. Davis, CA: Univ. California Davis Lab for Energy: 1988.

Goldman M, Nasr M, Cone N, Rosenblatt LS, Wilson, BW. Toxicity studies on agent GA. Mutagenicity of Tabun (GA) in the Ames mutagenicity assay. Davis, CA: Univ. of California Davis Lab for Energy: 1989.

Bucci TJ, Parker RM, Crowell JA, Thurman JD, Gosnell PA. Toxicity studies on agents GA (phase II); 90 day subchronic study of GA (Tabun) in CD rats. Jefferson, AK: National Center for Toxicological Research; 1992.

[23]Bucci TJ, Parker RM, Gosnell PA. Toxicity studies on agents GB and GD (Phase II): 90-day subchronic study of GD (Soman) in CD-rats. Jefferson, Ak: National Center for Toxicological Research; 1992.

[24] Jacobson KH, Christensen MK, DeArmon IA, Oberst FW. Studies of chronic exposures of dogs to GB (isoprpyl methyphosphonofluoriddate) vapor. Arch Indust Health. 19:5-10, 1959.

[25] Abou-Donia Md. Organophosphorus ester-induced delayed neurotoxicity. Ann Rev Pharmacol Toxicol, 21,511-548, 1981.

[26] Davies DR, Holland P, Rumens MJ. The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds. Brit J Pharmacol. 15:271-278, 1960.

[27] Gordon JJ, Inns RH, Johnson MK, Leadbeater L, Maidment MP, Upshall DG, Cooper GH, Rickard RL. The delayed neuropathic effects of nerve agents and some other organophosphorus compounds. Arch Toxicol. 52:71-81, 1983.

[28] personal communication to the author.

8 August

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