Findings & Conclusions
D. DOD USED INVESTIGATIONAL DRUGS IN THE PERSIAN GULF WAR IN WAYS THAT WERE NOT EFFECTIVE.
The DOD persuaded FDA that informed consent should be waived for pyridostigmine bromide and botulism vaccine because these investigational products had been used safely in the past. However, based on documents provided to the Committee staff, it is doubtful that either of these products would have been effective as used in the Persian Gulf War.
Pyridostigmine bromide, according to DOD, improves the survival of animals exposed to soman and treated with atropine and 2-PAM. However, pyridostigmine pretreatment makes individuals more vulnerable to other nerve agents, such as VX and sarin. (Note 98) The DOD scientists who studied pyridostigmine and sarin therefore concluded that pyridostigmine should only be used when the chemical warfare threat is soman. (Note 99)
The Pentagon, however, had no reason to believe that the Iraqis were more likely to use soman rather than sarin. According to a report by the Persian Gulf Veterans Coordinating Board, Iraq had several chemical weapons, including sarin. (Note 100) Moreover, at a briefing for Senators and staff on November 10, 1993, Under Secretary of Defense John Deutch stated that the Czechoslovakian military detected low levels of sarin in the Saudi theater during the opening days of the air war against Iraq. This statement was also made by Joseph Corrivean, U.S. Army Foreign Science and Technology Center, on April 27, 1994, at a National Institutes of Health workshop on “The Persian Gulf Experience and Health.”
Even if U.S. troops had been exposed to soman, it is unclear that the pyridostigmine would have provided adequate protection against nerve damage. When DOD began the second phase of research on pyridostigmine, it was noted that the atropine and 2-PAM did not seem to save the lives of animals that were exposed to soman. As a result, the dose of atropine was increased to 0.40 mg/kg, which according to FDA, increased the survival of Rhesus monkeys exposed to soman. (Note 101) However, when the Department of Defense developed a treatment regimen for U.S. troops during the Persian Gulf War, it was based on the inadequate dose of atropine in the animal studies (0.096 mg/kg) rather than the higher, effective dose. (Note 102) Therefore, even if Persian Gulf soldiers had been exposed to soman, it is questionable if the pyridostigmine pretreatment would have provided any protection, since the dose of atropine was apparently inadequate.
In response to posthearing questions about this dosage discrepancy from Sen. Rockefeller, the DOD stated “the dose of atropine in the Mark I kit was established based exclusively on safety, rather than on efficacy, considerations.” (Note 103) This statement suggests that hundreds of thousands of servicemembers were put at risk by requiring them to take a drug with known risks (pyridostigmine bromide) in a situation where it might have done little good since the atropine dose in the Mark I kits, 6 mg, was inadequate. Based on the monkey data, a dose of 27 mg would have been required for a 150-pound man. (Note 104) However, the side effects of only 2 mg of atropine in a normal young person (without nerve-agent exposure) include increased heart rate, decreased sweating, visual blurring, and others. (Note 105) Apparently, DOD officials decided that the high dosage required for protection would impair performance, so they selected the much lower dosage, even though its effectiveness was questionable. Although results for monkeys may not be exactly comparable to those for humans, it seems unlikely that humans would respond dramatically differently. It is therefore likely that the dose of atropine in the Mark I kits was inadequate for efficacy, and even with this very low dose could have compromised the ability of servicemembers during war. (Note 106)
Botulism vaccine was given too late to U.S. troops to be of any use had the Iraqis actually used biological warfare during Desert Storm. At a briefing on April 20, 1994, DOD officials informed Committee staff that botulism vaccine was not administered to most military personnel in the Persian Gulf until January 23, 1991, which was 7 days after the onset of the air war. Approximately 8,000 individuals received the vaccine, but most received only one or two inoculations. Because the war ended on February 27, 1991, before the third injection was scheduled to be given, it is unlikely that these soldiers were adequately immunized. Moreover, because of the severe shortage of the product, the remainder of those deployed received no inoculations, and hence no protection against botulism.
According to the Department of Veterans Affairs, 696,562 individuals participated in Operation Desert Shield/Desert Storm. Therefore, 99 percent of the military personnel deployed would have received no protection due to the shortage of botulinum toxoid, and the remaining 1 percent were probably not protected because the vaccine distribution started too late.
Additionally, in December 1990, the FDA advised the Department of Defense that it would be unable to test the botulism vaccine for efficacy, presumably because of limited time before the onset of the war. (Note 107) Therefore, in addition to the limited supply of vaccine and late onset of inoculations, efficacy of the existing supply was not determined prior to the onset of the war.
Anthrax vaccine was given to approximately 150,000 military personnel in the Persian Gulf. Anthrax vaccine is considered effective for protecting against anthrax exposure of the skin; however it is unclear whether it provides protection against inhaling aerosolized anthrax. (Note 108) According to the Department of Defense, in biological warfare the anthrax would be sprayed, so the efficacy of the vaccine against aerosolized anthrax would have been the relevant test. (Note 109) As stated earlier in this report, the DOD has only one study indicating that the vaccine might be useful against aerosolized anthrax, but there are no data on humans.
Findings & Conclusions
E. DOD DID NOT KNOW WHETHER PYRIDOSTIGMINE BROMIDE WOULD BE SAFE FOR USE BY U.S. TROOPS IN THE PERSIAN GULF WAR.
Committee staff reviewed all the clinical studies and related research regarding pyridostigmine on healthy individuals which DOD provided to FDA to support their IND and their NDA (new drug approval) application. (Note 110) The number of human subjects in most studies was less than 35; several studies included as few as two or four individuals.
According to the materials that FDA provided to the Committee, virtually all the studies excluded women. The lack of studies on women is a problem, because dosage should be based on the weight of the person taking the drug, and because some scientists believe that pyridostigmine may affect men and women differently. (Note 111), (Note 112) For example, women on birth control pills may have different levels of AChE than other women or men. Similarly, women in different stages of their reproductive cycle respond differently to pyridostigmine. (Note 113) Since studies excluded women, there is no information on the potential long-term side effects of pyridostigmine on diseases unique to women (such as menstrual cycle irregularities or breast cancer).
Because of the DOD researchers’ concerns about serious adverse reactions to pyridostigmine bromide, many of the studies screened the men to determine whether they were hypersensitive to pyridostigmine bromide before allowing their participation in the experiment. In some cases they used test doses; in other cases they asked questions regarding similar medications and sensitivity to bromide. In many of the studies, patients were excluded if they were taking any medications, since adverse reactions could occur when pyridostigmine was administered with other drugs (i.e., propranolol, birth control medications, or anti-malarial drugs). In some studies, smokers were excluded; in many studies, participants were told not to drink any alcoholic beverages. Most research study participants were less than 35 years of age. In addition, individuals with abnormal blood pressure, asthma, glaucoma, low serum AChE levels, gastrointestinal disorders, urinary or intestinal blockage, or hyperthyroidism, were excluded from the studies. (Note 114)
Despite these precautions, serious adverse reactions were reported for several of the studies. For example, in one study, pyridostigmine bromide was administered to a group of 28 active duty Air Force pilots. (Note 115) One pilot experienced respiratory arrest 91 minutes after swallowing the third in a series of three 30-mg pyridostigmine tablets. This pilot had shown no sensitivity to the test dose of pyridostigmine prior to the study. In another study of 32 male subjects, one subject lost consciousness following vision problems and headache. (Note 116) In other studies, abnormal liver tests, unusual electrocardiograms, gastrointestinal disturbances, and anemia were reported. (Note 117), (Note 118), (Note 119)
Results also showed that pyridostigmine impaired performance, including tasks which require short-term memory, and prevented a number of test subjects from exercising in hot environments during the second or third day of treatment. A study of the impact of pyridostigmine on swimming in cold water had to be terminated when it was determined that its use caused severe cramps that could cause drowning.
Research published in 1978 on neostigmine, a “close relative” of pyridostigmine, found that the drug caused “profound physiological, electrophysiological, and electron microscopic disruption of nerve endings and muscles.” Some of these changes increased in severity over time with continued treatment. (Note 120) The author of that study believes this study has worrisome implications for pyridostigmine.
In August 1990, just before U.S. troops were sent to the Gulf, DOD scientists requested approval for a study of four men that would evaluate the effects of pyridostigmine on vision. This study was deemed urgent because of the situation in Kuwait, and it was approved quickly. It is important to note that this study, conducted just prior to the Gulf War, included extensive safety precautions, including giving medical exams to the men before giving the pyridostigmine. The researchers indicated that pyridostigmine should not be given to individuals who had bronchial asthma, peptic ulcer, liver, kidney, heart disease, or hypersensitivity to pyridostigmine or related drugs. They informed study volunteers that possible adverse side effects include nausea, vomiting, slow heart rate, sweating, diarrhea, abdominal cramps, increased salivation, increased bronchial secretions, and pupil constriction. They also warned of other side effects, including “weakness, muscle cramps, and muscle twitches” and explained that, “Because of these side effects, all subjects will be admitted to Lyster Army Hospital as in-patients so that they will be medically monitored during evening periods of nontesting. A drug will be available at the test site to counteract the possible adverse side effects.” (Emphasis added) (Note 121) In addition, the Human Subjects Committee that reviewed this study considered whether the possibility of pyridostigmine causing death should be mentioned in the informed consent form; after some discussion, it was decided that such a warning was unnecessary since death was unlikely.
In contrast to the extensive precautions taken before giving pyridostigmine every 8 hours for 3 days to four volunteers, a few months later approximately 400,000 U.S. soldiers were ordered to take the same dosage of the drug for days, weeks, or months, none of whom had been screened for any of the diseases mentioned in the informed consent form given to the four men, none of whom were warned about the risks associated with the drug, and none of whom were given a choice of whether or not to take it. Additionally, approximately 28,000 of the 400,000 receiving the pyridostigmine were women, who were required to take an investigational drug that DOD had never tested on healthy women. (Note 122)
The repeated claims by DOD and FDA at the Committee’s May 6, 1994, hearing and at other times since the war that they were sure pyridostigmine was perfectly safe as used is not consistent with the concerns of DOD scientists regarding the potential serious adverse reactions and drug interactions while conducting research. It does not make sense that the researchers would establish such elaborate safeguards when giving the drug to four men, and then have none of those safeguards when giving the drug to more than 400,000 U.S. troops, none of whom had been tested for sensitivity to pyridostigmine, and most of whom were not screened for medical problems or medication use that could preclude the safe use of pyridostigmine. DOD researchers were aware of the shortcomings of their research. For example, in 1989 William K. Prusaczyk suggested, “Because of the existing incidence of asthma in soldiers in the U.S. Army,” the medical monitor believes that pyridostigmine should be studies on individuals who have asthma. (Note 123)
Findings & Conclusions
F. WHEN U.S. TROOPS WERE SENT TO THE PERSIAN GULF IN 1994, DOD STILL DID NOT HAVE PROOF THAT PYRIDOSTIGMINE BROMIDE WAS SAFE FOR USE AS AN ANTIDOTE ENHANCER.
When U.S. troops were sent to the Persian Gulf in the fall of 1994 because of concern about Kuwait, the DOD considered the use of pyridostigmine to protect against chemical weapons. However, in the 3 years since the Persian Gulf War of 1991, the DOD had not conducted studies that proved the safety of pyridostigmine bromide for that use.
The safety of pyridostigmine was evaluated during and after the Persian Gulf War. In one study, approximately 37 percent of 213 soldiers reported at least one severe symptom 24 hours after beginning to take the 30-mg pyridostigmine tablets. (Note 124) Additionally, the DOD conducted three surveys concerning the use of pyridostigmine in Operation Desert Shield/Storm which were reported in 1992. (Note 125) These surveys indicated that side effects were frequently experienced by military personnel taking pyridostigmine bromide. One published article, based on reports from medical personnel providing care to 41,650 soldiers (6.5 percent women) who took pyridostigmine bromide in the Persian Gulf, found that over half experienced gastrointestinal disturbances. (Note 126) Urinary urgency and frequency, headaches, nasal discharge, profuse sweating, and tingling of hands and feet were reported to occur in a range of 5 to 30 percent. (Note 127) Several doctors who were interviewed for the study expressed concerns that the dose for women may have been too high.
In the 3 years that have elapsed since the Gulf War, the DOD has apparently not conducted research on the safety of pyridostigmine for healthy women. In early 1994, DOD submitted an NDA (new drug approval) application to FDA, urging that FDA determine that pyridostigmine bromide is safe and effective as an antidote enhancer. The studies provided in that application did not include women.
In the last few year, several studies have been published on the effects of pyridostigmine on growth hormones of women and men. In one study, three of the eight women who received one 120 mg dose of pyridostigmine bromide became so ill they had to be excluded from the study. (Note 128) The entire study consisted of eight women and eight men who received pyridostigmine in single doses of 30, 60, or 120 mg. The women in the study experienced more severe and prolonged symptoms than men, especially at the 120 mg dose, such as severe abdominal cramps, nausea, vomiting, asthenia, and muscle cramps. Three subjects who received 120 mg had vision impairment that lasted several hours. (Note 129)
In addition, none of the studies of pyridostigmine evaluated the safety of pyridostigmine if taken over a period of weeks or months, as was done in the Gulf War. Moreover, none of the studies evaluated the long-term safety of pyridostigmine by providing followup information about men who had taken the drug years earlier.
Despite the Committee’s hearing in May and numerous television news magazine reports and newspaper articles reporting our concerns about the safety of pyridostigmine, the DOD has apparently not yet conducted any studies that provide any more information than was previously available. (Note 130) Several studies of pyridostigmine conducted by DOD under conditions of heat and/or exercise have been published, but they studied only four to seven young men. In one study of four men, one man became so fatigued on the third day that he was told to stop exercising; this problem was barely mentioned in the published study, and the implication for soldiers during wartime was not discussed. (Note 131)
Findings & Conclusions
G. PYRIDOSTIGMINE MAY BE MORE DANGEROUS IN COMBINATION WITH PESTICIDES OR OTHER EXPOSURES.
In 1993, Dr. James Moss, a scientist at the U.S. Department of Agriculture, conducted research on cockroaches that could have important implications for Persian Gulf War veterans. (Note 132) He found that when pyridostigmine was used in combination with a common insect repellent called DEET (diethyl-m-tolamide), the DEET became almost seven times as toxic as when it was used alone. Similarly, pyridostigmine became four times as toxic when used in combination with DEET. (Note 133) DEET and many other insect repellents and pesticides were widely used in the Gulf War as protection against sand flies, scorpions, and other pests. If individuals who took pyridostigmine bromide became more vulnerable to pesticides, or those exposed to pesticides became more vulnerable to pyridostigmine bromide, this could explain the serious neurological symptoms experienced by so many Gulf War veterans.
The results were similar but not as alarming for permethrin, another insecticide that was used in the Gulf War. Permethrin was used in the military uniforms, impregnating the fabric before it was cut and sewn. In his cockroach studies, Dr. Moss found that DEET became twice as toxic when used with permethrin.
Dr. Moss also studied the combination of DEET and pyridostigmine with other toxic substances that were present in the Gulf War, such as lindane (a treatment for lice) and a wide range of insecticides. These substances also became more toxic when used at the same time than when used individually. Even caffeine was found to have a potential impact on the toxicity of other substances.
Dr. Moss believes his findings regarding cockroaches are likely to be relevant to humans; however, more research is needed to determine if humans would be similarly affected. Nevertheless, his findings are consistent with concerns that have been raised by military researchers, who have stated publicly that carbamates such as pyridostigmine must never be used after nerve agent exposure, presumably because the pyridostigmine could further decrease AChE from nerve agent poisoning. If military personnel were exposed to low levels of nerve agents due to bombing of nerve agent stockpiles as proposed by some, (Note 134) as well as numerous pesticides procured by the Army, (Note 135) and pyridostigmine bromide, it is likely that the combination could have been much more toxic than any of those substances would have been individually.
Dr. Moss’ findings regarding pesticides are also consistent with a note in the Air Force records of Craig Crane, an Air Force crewman who participated in a pyridostigmine experiment in 1986. According to a description of the pyridostigmine study that was signed by medical personnel and included in Mr. Crane’s records, “There is no sensitivity to pesticides or recent significant exposure.” This medical notation suggests that Air Force medical personnel were concerned about a possible interaction between pyridostigmine and pesticides, and therefore avoided including men who had been exposed to pesticides. (Note 136)
Dr. Moss testified about his findings at the Committee’s May 6, 1994, hearing, despite efforts by USDA to prevent him from doing so. On June 31, 1994, his 3-year contract with USDA expired, and it was not renewed. Dr. Moss’ repeated efforts to continue working at USDA were unsuccessful. Sen. Rockefeller wrote to Secretary Espy in May, June, and July to ask how USDA planned to continue Dr. Moss’ research, but received no reply until after a CBS Evening News story on the subject on October 14, 1994. Secretary Espy then wrote to Sen. Rockefeller saying that the USDA had no plans to follow up on Dr. Moss’ research, but would ensure that the data were provided to DOD. (Note 137)
Although Dr. Moss made no accusations against USDA at the Committee hearing, he has subsequently expressed his views that he lost his job at USDA because of his research findings. He also now reports that his supervisor warned him that he should not discuss his research findings with anyone. Moreover, in an internal USDA memo dated December 30, 1993, Dr. Moss stated that he was advised to “keep quiet.” (Note 138) USDA and the Johnson Wax Company are the co-inventors of DEET, an ingredient in most commercially available insecticides, such as Raid.
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