[Federal Register Volume 66, Number 130 (Friday, July 6, 2001)]
[Notices]
[Pages 35702-35710]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-16899]


-----------------------------------------------------------------------

DEPARTMENT OF VETERANS AFFAIRS


Illnesses Not Associated With Service in the Gulf During the Gulf 
War

AGENCY: Department of Veterans Affairs.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: As required by law, the Department of Veterans Affairs (VA) 
hereby gives notice that the Secretary of Veterans Affairs, under the 
authority granted by the Persian Gulf War Veterans Act of 1998, Pub. L. 
105-277, 112 Stat. 2681-742 through 2681-749 (codified at 38 U.S.C. 
1118), and the Veterans Programs Enhancement Act of 1998, Pub. L. 105-
368, 112 Stat. 3315, has determined that there is no basis to establish 
a presumption of service connection for any disease based on service in 
the Persian Gulf during the Persian Gulf War.

FOR FURTHER INFORMATION CONTACT: John Bisset, Jr., Consultant or Bill 
Russo, Attorney-Advisor, Compensation and

[[Page 35703]]

Pension Service, Regulations Staff, Veterans Benefits Administration, 
810 Vermont Avenue, NW., Washington, DC 20420, telephone (202) 273-7213 
and (202) 273-7211, respectively.

SUPPLEMENTARY INFORMATION:

I. Statutory Requirements

    Title 16 of the Omnibus Consolidated and Emergency Supplemental 
Appropriations Act of 1999, entitled the Persian Gulf War Veterans Act 
of 1998, Pub. L. 105-277, 112 Stat. 2681-742 through 2681-749 (codified 
at 38 U.S.C. 1118), and the Veterans Programs Enhancement Act of 1998, 
Pub. L. 105-368, 112 Stat. 3315, directed the Secretary to seek to 
enter into an agreement with the National Academy of Sciences (NAS) to 
review and evaluate the available scientific evidence regarding 
associations between illnesses and exposure to toxic agents, 
environmental or wartime hazards, or preventive medicines or vaccines 
associated with Gulf War service. Congress mandated that NAS determine, 
to the extent possible: (1) Whether there is a statistical association 
between exposure to the agent, hazard, or medicine or vaccine and the 
illness, taking into account the strength of the scientific evidence 
and the appropriateness of the scientific methodology used to detect 
the association; (2) the increased risk of illness among individuals 
exposed to the agent, hazard, or medicine or vaccine; and (3) whether a 
plausible biological mechanism or other evidence of a causal 
relationship exists between exposure to the agent, hazard, or medicine 
or vaccine and the illness. These laws also required that NAS submit 
reports on its activities every two years (as measured from the date of 
the first report) for a ten-year period.
    Section 1602 of Pub. L. 105-277 provides that whenever the 
Secretary determines, based on sound medical and scientific evidence, 
that a positive association (i.e., the credible evidence for the 
association is equal to or outweighs the credible evidence against the 
association) exists between exposure of humans or animals to a 
biological, chemical, or other toxic agent, environmental or wartime 
hazard, or preventive medicine or vaccine known or presumed to be 
associated with service in the Southwest Asia theater of operations 
during the Persian Gulf War and the occurrence of a diagnosed or 
undiagnosed illness in humans or animals, the Secretary will publish 
regulations establishing presumptive service connection for that 
illness. If the Secretary determines that a presumption of service 
connection is not warranted, he is to publish a notice of that 
determination, including an explanation of the scientific basis for 
that determination. The Secretary's determination must be based on 
consideration of the NAS reports and all other sound medical and 
scientific information and analysis available to the Secretary.
    Although Pub. L. 105-277 does not define ``credible evidence,'' it 
does instruct the Secretary to ``take into consideration whether the 
results (of any study) are statistically significant, are capable of 
replication, and withstand peer review.'' Simply comparing the number 
of studies which report a significantly increased relative risk to the 
number of studies which report a relative risk that is not 
significantly increased is not a valid method for determining whether 
the weight of evidence overall supports a finding that there is or is 
not a positive association between exposure to an agent, hazard, or 
medicine or vaccine and the subsequent development of the particular 
illness. Because of differences in statistical significance, confidence 
levels, control for confounding factors, and other pertinent 
characteristics, some studies are clearly more credible than others, 
and the Secretary has given the more credible studies more weight in 
evaluating the overall weight of the evidence concerning specific 
illnesses.

II. The National Academy of Sciences Report

    Public Law 105-277 and 105-368 directed the Secretary of Veterans 
Affairs to obtain from the NAS an independent scientific review of the 
evidence regarding associations between diseases and exposure in 
military service to selected risk factors encountered or experienced 
during the Gulf War. Following acceptance of a contract with the 
Department for this purpose, the Institute of Medicine of the NAS made 
a determination to limit its initial review to an analysis of the 
health effects of depleted uranium (DU), the chemical warfare agent 
sarin, vaccinations against botulinum toxin and anthrax, and 
pyridostigmine bromide (PB), which was used in the Gulf War as a 
pretreatment for possible exposure to nerve agents. NAS issued its 
initial report, entitled ``Gulf War and Health, Volume 1. Depleted 
Uranium, Sarin, Pyridostigmine Bromide, Vaccines,'' on September 7, 
2000.
    In reporting its findings, NAS included one exposure in the 
category ``Sufficient Evidence of a Causal Relationship': Exposure to 
sarin and dose-dependent acute cholinergic syndrome that is evident 
promptly (seconds to hours) after sarin exposure and resolves in days 
to months. This category means:

    Evidence is sufficient to conclude that a causal relationship 
exists between the exposure to a specific agent and a health outcome 
in humans. The evidence fulfills the criteria for sufficient 
evidence of an association (below) and satisfies several of the 
criteria used to assess causality: strength of association, dose-
dependent relationship, consistency of association, temporal 
relationship, specificity of association, and biological 
plausibility.

    The NAS included three entries in the category ``Sufficient 
Evidence of an Association'': (1) PB and transient acute (that is, 
short-lasting, and immediately after exposure) cholinergic effects in 
doses normally used in treatment and for diagnostic purposes; (2) 
Anthrax vaccination and transient acute local and systemic effects; and 
(3) Botulinum toxoid vaccination and transient acute local and systemic 
effects. This category means:

    Evidence is sufficient to conclude that there is a positive 
association. That is, a positive association has been observed 
between an exposure to a specific agent and a health outcome in 
human studies in which chance, bias, and confounding could be ruled 
out with reasonable confidence.

    The NAS placed one item in the category ``Limited/Suggestive 
Evidence of an Association'': exposure to sarin at doses sufficient to 
cause acute cholinergic signs and symptoms and subsequent long-term 
effects. This category means:

    Evidence is suggestive of an association between an exposure to 
a specific agent and a health outcome in humans, but is limited 
because chance, bias, and confounding could not be ruled out with 
confidence.

    Roughly half of the NAS conclusions were in the category 
``Inadequate/ Insufficient Evidence to Determine Whether an Association 
Does or Does Not Exist.'' This category means:

    The available studies are of insufficient quality, consistency, 
or statistical power to permit a conclusion regarding the presence 
or absence of an association between an exposure to a specific agent 
and a health outcome in humans.

    The health effects in this category included: (1) Exposure to 
uranium and lung cancer at higher levels of cumulative exposure 
(greater than 200 mSv or 25 cGy); (2) Exposure to uranium and lymphatic 
cancer; bone cancer; nervous system disease; nonmalignant respiratory 
disease; or other health outcomes (gastrointestinal disease, immune-
mediated disease, effects on hematological parameters,

[[Page 35704]]

reproductive or development dysfunction, genotoxic effects, 
cardiovascular effects, hepatic disease, dermal effects, ocular 
effects, or musculoskeletal effects); (3) PB and long-term adverse 
health effects; (4) Exposure to sarin at low doses insufficient to 
cause acute cholinergic signs and symptoms and subsequent long-term 
adverse health effects; (5) Anthrax vaccination and long-term adverse 
health effects; (6) Botulinum toxoid vaccination and long-term adverse 
health effects; and (7) Multiple vaccinations and long-term adverse 
health effects.
    The NAS included two items in the final category ``Limited/
Suggestive Evidence of No Association'': (1) Exposure to uranium and 
lung cancer at cumulative internal dose levels lower than 200 mSv or 25 
cGy; and (2) Exposure to uranium and clinically significant renal 
dysfunction. This category means:

    There are several adequate studies, covering the full range of 
levels of exposure that humans are known to encounter, that are 
mutually consistent in not showing a positive association between 
exposure to a specific agent and a health outcome at any level of 
exposure. A conclusion of no association is inevitably limited to 
the conditions, levels of exposure, and length of observation 
covered by the available studies. In addition, the possibility of a 
very small elevation in risk at the levels of exposure studied can 
never be excluded.

    NAS noted that detecting adverse health effects as the result of a 
specific vaccination is a complex task due to a number of factors, 
including lack of long-term follow-up, small sample sizes, multiple 
vaccinations, multiple end points, lack of symptoms specific to that 
vaccination, passive reporting systems, high vaccination rates, 
restricted population, and progress in vaccine technology.

III. VA Response to the National Academy of Sciences Report

    Following receipt of the NAS report, the VA formed a task force to 
review the report and pertinent studies and make recommendations to the 
Secretary to assist him in determining whether a positive association 
exists between exposure to an agent, hazard, or medicine or vaccine and 
any illness. This review involved a collaborative effort between 
representatives from the Veterans Health Administration, the Veterans 
Benefits Administration, the Office of General Counsel, and the Office 
of Policy and Planning. Reviewers included VA scientists, attorneys, 
medical care providers, and policy planners. That review was completed, 
and the task force's recommendations were submitted to the Secretary. 
The review provided the scientific and medical basis for the 
Secretary's determination regarding medical consequences of service in 
the Gulf War.
    This notice, pursuant to Pub. L. 105-277, conveys the Secretary's 
determination that there is no positive association between: Lung 
cancer and exposure to uranium at higher levels of cumulative exposure 
(greater than 200 mSv or 25 cGy); lymphatic cancer, bone cancer, 
nervous system disease, nonmalignant respiratory disease, 
gastrointestinal disease, immune-mediated disease, effects on 
hematological parameters, reproductive or development dysfunction, 
genotoxic effects, cardiovascular effects, hepatic disease, dermal 
effects, ocular effects, or musculoskeletal effects and uranium 
exposure; long-term adverse health effects and pyridostigmine bromide 
(PB) treatment; long-term adverse health effects and exposure to sarin 
at doses insufficient to cause cholinergic signs and symptoms; long-
term adverse health effects and anthrax vaccination; long-term adverse 
health effects and botulinum toxoid vaccination; long-term adverse 
health effects and multiple vaccinations; lung cancer and exposure to 
uranium at cumulative internal dose levels lower than 200 mSv or 25 
cGy; and clinically significant renal dysfunction and uranium exposure. 
The Secretary's determination on these health outcomes is based on NAS' 
findings that there is inadequate/insufficient evidence to determine 
whether an association does or does not exist, regarding all but the 
last two of these health outcomes, and limited/suggestive evidence of 
no association as to the last two. Accordingly, regarding all the 
health outcomes listed above, the Secretary found that the credible 
evidence for association is not equal to or greater than the credible 
evidence against the association or that there is insufficient credible 
evidence of a positive association, and he determined that a positive 
association does not exist.

IV. Depleted Uranium

    Although depleted uranium is the form of uranium that was present 
in the Gulf War, there are few studies of the health effects of this 
form of uranium. Consequently, NAS studied the health effects of 
natural and processed uranium in workers at plants that processed 
uranium for use in weapons and nuclear reactors. The NAS noted that the 
chemical toxicity of DU is virtually identical to that of natural 
uranium. NAS also noted that natural uranium is a low-level radioactive 
element, and DU emits radioactivity that is 40% lower than natural 
uranium. Lung cancer mortality has been the focus of many studies of 
workers employed in the uranium processing industry. In a large study 
of employees at Oak Ridge, Tennessee uranium processing and research 
facilities NAS found that the employees experienced a small increase in 
lung cancer mortality. NAS stated that analysis showed that uranium 
exposure was not associated with lung cancer mortality, and that other 
factors related to socioeconomic status could account for the lung 
cancer deaths. (Frome EL, Cragle DL, McLain RW. 1990. Poisson 
regression analysis of the mortality among a cohort of World War II 
nuclear industry workers. Radiat Res 123(2):138-152).
    Another study combined data from four separate studies. (Dupree EA, 
Watkins JP, Ingle JN, Wallace PW, West CM, Tankersley WG. 1995. Uranium 
dust exposure and lung cancer risk in four uranium processing 
operations, Epidemiology 6(4):370-375). NAS stated that this study 
found that the dose-response did not suggest any lung cancer risk up to 
25 cGy exposure. Above that level, there were too few cases to draw any 
conclusions. A dose-response relationship refers to the finding of a 
greater health effect (response) with higher exposure to an agent. The 
gray (Gy), formerly the rad, is the unit that describes the amount or 
exposure to absorbed radiation in terms of energy deposited on a 
tissue.
    NAS found that a significant association with lung cancer appeared 
in a recent study in which significant increases in lung cancer 
mortality occurred in the small group of workers with a cumulative 
internal dose of 200 mSv or more. (Ritz B. 1999. Radiation exposure and 
cancer mortality in uranium processing workers. Epidemiology 10(5):531-
538). The sievert (Sv) is the International System unit of radiation 
absorbed equivalent, defined as that producing the same biologic effect 
in a specific tissue as 1Gy of high-energy x-rays. NAS viewed this 
finding with caution, however, because the subgroup with the elevated 
risk had only three cases of lung cancer and because the study did not 
consider the confounding factor of cigarette smoking. NAS also noted 
that after controlling for external dose in this study, internal doses 
up to 200 mSv are not associated with excess risk of lung cancer. 
Accordingly, the Secretary has determined that the credible evidence 
against an association between lung cancer and uranium exposure 
outweighs

[[Page 35705]]

the credible evidence for such an association, and he determined that a 
positive association does not exist.
    NAS found that the number of cases was too small and the confidence 
intervals for standardized mortality ratios (SMRs) too wide to draw any 
conclusions about an association between uranium and lymphatic cancer. 
NAS noted that the largest study included the period early in the 
nuclear industry in which workers were exposed to relatively high 
amounts of inhaled uranium. (Polednak AP, Frome EL. 1981. Mortality 
among men employed between 1943 and 1947 at a uranium processing plant. 
J Occup Med 23(3):169-178). In that study, NAS stated that there were 
fewer deaths (37) from lymphatic cancer than the expected (SMR=61). 
Accordingly, the Secretary has determined that the credible evidence 
against an association between lymphatic cancer and uranium exposure 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.
    NAS noted that bone cancer is rare; thus, the number of cases in 
all studies is small. NAS concluded that studies to date have not found 
an increase in bone cancers due to uranium exposure. As one example, 
NAS noted that the large size of the Oak Ridge cohort provides some 
evidence that exposure to uranium is not associated with a large excess 
risk of bone cancer (i.e., a relative risk of 3.0 or greater) (Polednak 
and Frome, 1981). Accordingly, the Secretary has determined that the 
credible evidence against an association between bone cancer and 
uranium exposure outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.
    NAS noted that the preponderance of evidence indicates little or no 
clinically important renal effects from exposure to uranium. The 
strongest evidence is the absence of kidney damage in workers exposed 
to high levels of soluble uranium compounds (Kathren RL, Moore RH. 
1986. Acute accidental inhalation of U: A 28 year follow-up. Health 
Phys 51(5):609-619) and in veterans exposed to depleted uranium from 
embedded shrapnel. Kidney function was normal in Gulf War veterans with 
embedded depleted uranium fragments years after exposure, despite high 
urinary uranium concentrations in some of the subjects (McDiarmid MA, 
Keogh JP, Hooper FJ, McPhaul K, Squibb K, Kane R, DiPino R, Kabat M, 
Kaup B, Anderson L, Hoover D, Brown L, Hamilton M, Jacobson-Kram D, 
Burrows B, Walsh M. 2000. Health effects of depleted uranium on exposed 
Gulf War veterans. Environ Res 82(2):168-180). Accordingly, the 
Secretary has determined that the credible evidence against an 
association between clinically significant renal dysfunction and 
uranium exposure outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.
    NAS found that the evidence regarding exposure to uranium and 
diseases of the nervous system is not strong enough to form a firm 
conclusion. In a study of Gulf War veterans, results from a battery of 
computer-based neurocognitive tests suggest a statistical relationship 
between elevated urinary uranium levels and ``problematic performance 
on automated tests assessing performance efficiency and accuracy'' 
(McDiarmid et al., 2000). NAS found that the authors of this study did 
not adequately define their testing methods or the method for deciding 
the expected level of performance. Traditional tests of neurocognitive 
function did not show any statistical differences in performance 
between the veteran cohort and a control group. Accordingly, the 
Secretary has determined that the credible evidence against an 
association between diseases of the nervous system and uranium exposure 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.
    Several studies found a significant excess risk of nonmalignant 
respiratory disease. (Dupre EA, Cragle DL, McLain RW, Crawford-Brown 
DJ, Teta MJ. 1987. Mortality among workers at a uranium processing 
facility, the Linde Air Products Company Ceramics Plant, 1943-1949. 
Scand J Work Environ Health 13(2):100-107; Frome et al., 1990). NAS 
noted, however, other, larger studies which showed SMRs insufficient 
credible evidence to conclude that there is a positive association of 
less than or close to 100 (unity), do not confirm those findings. 
(Checkoway H, Pearce N, Crawford-Brown DJ, Cragle DL. 1988. Radiation 
doses and cause-specific mortality among workers at a nuclear materials 
fabrication plant. Am J Epidemiol 127(2):255-266; Polednak and Frome, 
1981; Ritz, 1999). NAS noted that none of the above studies was able to 
control for smoking. Accordingly, the Secretary has determined that the 
credible evidence against an association between nonmalignant 
respiratory disease and uranium exposure outweighs the credible 
evidence for an association, and he has determined that a positive 
association does not exist.
    In one study, after the accidental inhalation exposure to high 
levels of uranium, one individual experienced transient 
gastrointestinal distress. (Lu S, Zhao F-Y. 1990. Nephrotoxic limit and 
annual limit of intake for natural uranium. Health Phys 58(5):619-623). 
In that same study, however, NAS found that a case of accidental dermal 
exposure to uranium produced no reported gastrointestinal effects. 
Accordingly, the Secretary has determined that the credible evidence 
against an association between gastrointestinal disease and uranium 
exposure outweighs the credible evidence for such an association, and 
he has determined that a positive association does not exist.
    NAS noted that the available scientific literature lacks 
documentation on adverse immunological effects of uranium. Two studies 
found that quartz dust-exposed uranium miners had a higher risk for the 
development of systemic autoimmune disease (Conrad K, Mehlhorn J, 
Luthke K, Dorner T, Frank K-H. 1996. Systemic lupus erythematosus after 
heavy exposure to quartz dust in uranium mines: Clinical and 
serological characteristics. Lupus 5(1):62-69; Conrad K, Levy Y, Blank 
M, Mehlhorn J, Frank K-H, Roch B, Shoenfeld Y. 1998. The pathogenic 16/
6 idiotype in patients with silica associated systemic lupus 
erythematosus (SLE) and uranium miners with increased risk for 
development of SLE. JRheumatol 25(4):660-666). Another study reported 
that uranium miners were more likely to develop scleroderma. NAS stated 
that it is important to note that exposure to silica in quartz dust may 
be associated with both SLE and scleroderma. (Baur X, Rihs HP, Altmeyer 
P, Degens P, Conrad K, Mehlhorn J, Weber K, Wiebe V. 1996. Systemic 
sclerosis in German uranium miners under special consideration of 
autoantibody subsets and HLA class II alleles. Respiration 63:368-375). 
Accordingly, the Secretary has determined that there is insufficient 
credible evidence to conclude that there is a positive association 
between adverse immunological effects and uranium exposure.
    NAS found that only a few studies have examined the effects of 
uranium on human reproduction and development. In a subgroup of Gulf 
War veterans with embedded depleted uranium fragments in soft tissues 
and muscles, semen contained uranium (McDiarmid et al., 2000). However, 
the semen characteristics were the same in Gulf War veterans with high 
urinary uranium excretion as in veterans with low excretion. 
Accordingly, the

[[Page 35706]]

Secretary has determined that the credible evidence against an 
association between human reproduction abnormalities and uranium 
exposure outweighs the credible evidence for such an association, and 
he has determined that a positive association does not exist.
    NAS found that, in the study of Gulf War veterans with retained 
fragments of depleted uranium, changes in peripheral blood lymphocytes 
were identical to those of nonexposed Gulf War veterans (McDiarmid et 
al., 2000). Accordingly, the Secretary has determined that the credible 
evidence against an association between changes in peripheral blood 
lymphocytes and uranium exposure outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.
    NAS noted that there was no elevated risk for cardiovascular 
disease in a study of uranium workers (Lu and Zhao, 1990). Accordingly, 
the Secretary has determined that the credible evidence against an 
association between cardiovascular disease and uranium exposure 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.
    NAS found that, in a three-year follow up of an individual 
accidentally exposed to uranium tetrafluoride (Lu and Zhao, 1990), 
serum hepatic enzyme levels and liver function tests were within normal 
limits. Accordingly, the Secretary has determined that the credible 
evidence against an association between hepatic disease and uranium 
exposure outweighs the credible evidence for such an association, and 
he has determined that a positive association does not exist.
    NAS found that dermal, ocular, and musculoskeletal effects of 
uranium have not been reported in the literature. Accordingly, the 
Secretary has determined that there is insufficient credible evidence 
to conclude that there is a positive association between adverse 
effects on these body systems and uranium exposure.

V. Sarin

    Sarin is a highly toxic nerve agent produced for chemical warfare. 
In its report, NAS noted that exposure to sarin can be fatal within 
minutes to hours. In vapor or liquid form, sarin can be inhaled or 
absorbed, respectively, through the skin, eyes, or mucous membranes.

Possible Sarin Exposure During the Gulf War

    According to Department of Defense (DoD) investigators, during the 
Gulf War no U.S. service members were exposed to chemical warfare nerve 
agents, including sarin, at levels sufficient to cause acute 
cholinergic poisoning signs and symptoms. In November 1996 DoD 
established the Office of the Special Assistant to the Deputy Secretary 
of Defense for Gulf War Illnesses (OSAGWI) to coordinate DoD's 
investigations into incidents that may have involved exposure to 
chemical warfare agents. OSAGWI's activities have been overseen by 
external independent groups, initially by the Presidential Advisory 
Committee on Gulf War Veterans Illnesses, and since February 1998 by 
the Presidential Special Oversight Board.
    Khamisiyah was the site of a large ammunition storage area located 
in southern Iraq. In March 1991, shortly after the cease-fire, U.S. 
forces used explosives to destroy unmarked chemical warfare munitions 
at this site. The September 4, 1997, OSAGWI report ``Modeling the 
Chemical Warfare Agent Release at the Khamisiyah Pit,'' describes joint 
efforts by DoD and the Central Intelligence Agency to model the release 
of chemical warfare nerve agents, including sarin, from demolition of 
chemical warfare munitions at Khamisiyah. This effort involved 
interviews with U.S. servicemembers present at the demolitions, 
investigations of amounts and purity of chemical munitions and the 
agent they contained, meteorological reconstruction studies to evaluate 
wind directions and atmospheric movement of chemical agents following 
release, and experimental demolitions of similar chemical warfare 
munitions.
    These results were put together to model an exposure plume showing 
a geographical area in which any U.S. servicemember present would be 
exposed to chemical warfare nerve agents, including sarin, at a level 
sufficient to cause first noticeable effects, i.e., minimum acute 
cholinergic signs and symptoms. DoD also mailed nearly 20,000 surveys 
to U.S. servicemembers who had been within 50 km of Khamisiyah at the 
time of the demolition. Of 7,400 responses received, ``* * * over 99 
percent show[ed] no physical effects that could be correlated with 
exposure to the chemical warfare agent sarin.'' The report concluded, 
``No military units were located under the first-effects portion of the 
plume, which is consistent with the lack of reported effects and with 
DoD's survey results, which had over 99 percent of the respondents 
showing no signs of physical effects that could be correlated with 
exposure to sarin. The troops that performed the demolition had 
evacuated the area.''
    On December 5, 2000, OSAGWI announced the results of its revised 
modeling of possible sarin exposure from the Khamisiyah demolition. 
Based on this modeling, OSAGWI revised its estimate of the numbers of 
U.S. troops who may have been exposed to very low levels of chemical 
agent for a brief period of time (less than 3 days) after the 
demolition. As part of that announcement, OSAGWI stated that medical 
personnel and others who were near Khamisiyah in March 1991 have been 
interviewed and reported no evidence of health problems related to 
chemical agent exposure at the time of the demolitions. In addition, 
OSAGWI stated that its analysis continued to show that the exposure 
levels would have been too low to activate chemical alarms or to cause 
any acute or long-term health effects among U.S. troops.
    In summary, OSAGWI's investigations of possible exposure or injury 
of U.S. servicemembers by chemical warfare nerve agents during the Gulf 
War have found only a single incident--demolition activities at 
Khamisiyah, Iraq--where exposure was found to be likely. In all other 
incidents investigated, OSAGWI found that exposure was unlikely, 
indeterminate or had definitely not occurred. OSAGWI includes a notice 
in all reports that additional information could change their 
conclusions. OSAGWI found no other instance where exposure to sarin or 
other chemical warfare agents was likely.

Acute Effects of Sarin

    NAS reported that, in humans, exposure to high doses of sarin 
produces a well-characterized acute (i.e., immediate) cholinergic 
syndrome featuring a variety of signs and symptoms affecting the 
peripheral and central nervous systems (Gunderson CH, Lehmann CR, 
Sidell FR, Jabbari B. 1992. Nerve agents: A review. Neurology 
42(5):946-950). This syndrome, as well as cholinergic signs and 
symptoms, is evident seconds to hours after exposure and usually 
resolves in days to months. At high doses, convulsions and death can 
occur. The peripheral effects are categorized as either muscarinic or 
nicotinic, in reference to the type of receptor stimulated by 
acetylcholine. The muscarinic signs and symptoms usually appear first 
(Lotti M. 2000. Organophosphorous compounds. In:

[[Page 35707]]

Spencer P, Schaumburg H, Ludolph A, eds. Experimental and Clinical 
Neurotoxicology. 2nd edition. New York: Oxford University Press. Pp. 
897-925), although the sequence of effects may vary according to the 
route of sarin's absorption (Stewart CE, Sullivan J Jr. 1992. Military 
munitions and antipersonnel agents. In: Sullivan JB Jr, Krieger G, eds. 
Hazardous Materials Toxicology: Clinical Principles of Environmental 
Health. Baltimore: Williams & Wilkins. Pp. 986-1014). If the dose of 
sarin is sufficiently high, death results after convulsions and 
respiratory failure (Lotti, 2000).
    NAS reported that the acute health effects of sarin are highly 
dependent on dose. Because the actual doses to humans under battlefield 
or terrorist circumstances cannot be measured, and may be difficult to 
reconstruct, they can be inferred on the basis of their acute clinical 
effects. A high level of sarin exposure of humans (after single or 
multiple exposures) is presumed to have occurred when the acute 
cholinergic syndrome is manifest. An intermediate-level exposure is 
presumed to have occurred when the acute cholinergic effect is limited 
to miosis (contraction of the pupil), rhinorrhea (an extreme type of 
runny nose), and depressed cholinesterase levels in the blood. Finally, 
low-level exposure may have occurred even though there are no 
immediately detectable cholinergic signs and symptoms (Brown MA, Brix 
KA. 1998. Review of health consequences from high-, intermediate-and 
low-level exposure to organophosphorous nerve agents. J Appl Toxicol 
18(6): 393-408). NAS reported that U.S. troops did not report acute 
cholinergic symptoms at the time, but the possibility of low-level, 
asymptomatic exposures cannot be discounted. In a series of studies on 
members of a naval battalion (n = 249) called to active duty for the 
Gulf War, Haley and Kurt (1997) found that veterans who believed 
themselves to have been exposed to chemical weapons \1\ were more 
likely to be classified as having one of six postulated syndromes 
(Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical 
combinations in the Gulf War. A cross-sectional epidemiologic study. 
JAMA 277(3):231-237). Specifically, this syndrome--labeled by the 
investigators as ``confusion--ataxia'' or ``syndrome 2'' features 
problems with thinking, disorientation, balance disturbances, vertigo, 
and impotence. This was the only syndrome of the six to have been 
associated with self-reported chemical weapons exposure. There is no 
evidence of sarin exposure among the veterans in the two studies 
summarized above.
---------------------------------------------------------------------------

    \1\ Based on self-reports about their perceptions of CW 
exposure, rather than any evidence of symptomatology. Their 
geographical and temporal location in relation to the Khamisiyah 
demolition site was not reported. The questionnaire was sent to 
participants in 1994, before DoD reported that chemical weapons 
exposure could have occurred.
---------------------------------------------------------------------------

    A follow-up study of vestibular function (sense of balance) was 
performed on a subset of those veterans (n = 23) who had the highest 
factor scores on three of the syndromes postulated in 1997 by Haley and 
Kurt (Roland et al., 2000). The study was designed to probe the nature 
of veterans' vestibular symptoms, rather than to examine the 
relationship between vestibular performance and exposure in the Gulf 
War. Of the 23 veterans in this study, 13 exhibited syndrome 2, whereas 
the others exhibited syndromes 1 (impaired cognition) and 3 
(arthromyoneuropathy). Based on a new questionnaire, veterans with 
syndrome 2 reported dizzy spells with greater frequency and longer 
duration than veterans with the other two syndromes. Veterans with 
syndrome 3, but not syndrome 2, performed significantly differently 
from controls on dynamic platform posturography (a test similar to that 
used by Japanese researchers to identify impairment in sarin-exposed 
females). (Yokoyama K, Araki S, Murata K, Nishikitani M, Okumura T, 
Ishimatsu S, Takasu N. 1998a. A preliminary study on vestibulo-
cerebellar effects of Tokyo subway sarin poisoning in relation to 
gender difference: Frequency analysis of postural sway. J Occup Med 
40(1):17-21). Veterans with other syndromes also had performance 
decrements on some of the measures of vestibular function. The study 
concluded that there was both subjective and objective evidence of 
injury to the vestibular system in this group of Gulf War veterans with 
newly postulated syndromes. Haley and Kurt (1997) hypothesized that 
these newfound chronic syndromes represent variants of 
organophosphorous induced delayed neuropathy (OPIDN) caused by exposure 
to various combinations of organophosphates (pesticides and nerve 
agents) and carbamate pesticides that inhibit certain enzymes.
    According to NAS, four human populations have been studied 
following exposure to sarin: military volunteers who were exposed 
several decades ago to nonlethal doses of sarin and other chemical 
warfare agents (National Research Council. 1982. Possible Long-Term 
Health Effects of Short-Term Exposure to Chemical Agents, Vol. 1: 
Anticholinesterases and Anticholinergics. Washington, DC: National 
Academy Press. National Research Council. 1985; Possible Long-Term 
Health Effects of Short-Term Exposure to Chemical Agents, Vol. 3. Final 
Report. Current Health Status of Test Subjects. Washington, DC: 
National Academy Press); industrial workers with documented accidental 
acute exposure to sarin (Duffy FH, Burchfiel JL, Bartels PH, Gaon M, 
Sim VM. 1979. Long-term effects of an organophosphate upon the human 
electroencephalogram. Toxicol Appl Pharmacol 47(1):161-176); and 
victims of the sarin terrorist attacks in Matsumoto City in 1994 and 
Tokyo in 1995 (Morita H, Yanagisawa N, Nakajima T, Shimizu M, 
Hirabayashi H, Okudera H, Nohara M, Midorikawa Y, Mimura S. 1995. Sarin 
poisoning in Matsumoto, Japan. Lancet 346(8970):290-293).
    NAS noted that major limitation of most human studies of either 
long- or short-term health effects is the inability to document actual 
exposure levels. Most studies of sarin were undertaken in the aftermath 
of occupational accidents or terrorist attacks. In such cases, the 
exposure levels were inferred from clinical effects. NAS further noted 
that high-level exposure is inferred from the acute cholinergic 
syndrome with outcomes including miosis, rhinorrhea, apnea, 
convulsions, and possibly death. NAS noted that high-level exposure 
requires hospitalization or emergency treatment. Intermediate-level 
exposure is inferred from minimal or threshold cholinergic effects such 
as miosis or rhinorrhea and limited decline in cholinesterase activity 
measured in the blood (20 percent). Low-level exposure can be inferred 
from proximity to a documented exposure with no clinically detectable 
cholinergic signs or symptoms or detectable change in blood 
cholinesterase activity (Brown and Brix, 1998).

Long-Term Health Effects of Sarin

    According to NAS, there have been relatively few human studies of 
sarin's long-term health effects. NAS noted that, in the literature on 
the survivors of the Japanese terrorist attacks, many health effects 
were reported to persist after sarin exposure: Fatigue, headache, 
visual disturbances (asthenopia, blurred vision, and narrowing of the 
visual field), asthenia, shoulder stiffness, and symptoms of post-
traumatic stress disorder; fear of subways; and abnormal test results 
of unknown clinical significance on the digit symbol test of 
psychomotor performance, EEG records of sleep, event-related potential, 
visual evoked potential, and computerized posturography. However, given 
the mixed exposure not only to sarin, but

[[Page 35708]]

also to the trauma of the terrorist attack, it is unclear which of 
these effects are specifically associated with sarin exposure.
    NAS' conclusions were based on retrospective studies of three 
different exposed populations in which the acute cholinergic signs and 
symptoms were documented as an acute effect of exposure. The findings 
from those studies are based on comparisons with control populations. 
One population consisted of industrial workers accidentally exposed to 
sarin in the United States; the other two populations were civilians 
exposed during terrorism episodes in Japan. The health effects listed 
above were documented at least 6 months after sarin exposure, and some 
persisted up to a maximum of 3 years, depending on the study. Whether 
the health effects noted above persist beyond the 3 years has not been 
studied. There are no well-controlled human studies expressly of 
sarin's long-term health effects at doses that do not produce acute 
signs and symptoms.

VA Determination on Sarin

    The NAS report concluded that there is ``sufficient evidence of a 
causal relationship between exposure to sarin and a dose-dependent 
acute cholinergic syndrome that is evident seconds to hours subsequent 
to sarin exposure and resolves in days to months.'' The NAS report also 
found ``limited/suggestive evidence of an association'' between 
``exposure to sarin at doses sufficient to cause acute cholinergic 
signs and symptoms and subsequent long-term health effects.'' Finally, 
the NAS found ``inadequate/insufficient evidence to determine whether 
an association does or does not exist'' between ``exposure to sarin at 
low doses insufficient to cause acute cholinergic signs and symptoms 
and subsequent long-term adverse health effects.''
    The Secretary determined that the decision whether to establish 
presumptions of service-connection based on sarin exposure properly 
should be based on certain factual determinations and policy 
considerations. The Secretary determined, as a factual matter, that (1) 
no U.S. Armed Forces personnel were exposed to sarin in the Gulf War 
theatre in amounts sufficient to cause severe, acute effects; and, (2) 
even if personnel were so exposed, their symptoms would have been such 
that VA would undoubtedly compensate them anyway for chronic effects 
under existing law. Given the high level of confidence of the DoD, as 
evinced by its reports and studies, that no service-members were 
exposed to sarin at a level producing any acute symptoms or signs of 
exposure, the Secretary has concluded that it is extremely unlikely 
that any United States military personnel were exposed to sarin to a 
degree that would trigger such a presumption during the Gulf War. Based 
on these factual findings, the Secretary has concluded that such 
presumptions would be very unlikely to benefit any veterans. Under 
these circumstances, creation of presumptions of service connection 
could lead to confusion among potential claimants and have a negative 
impact on the claims adjudication process. In addition, the Secretary 
has concluded that the law does not require creation of a presumption 
in this situation.
    Furthermore, the Secretary has concluded that if any veteran had 
experienced severe, acute sarin-exposure symptoms (such as the 
cholinergic reactions discussed in the NAS report), those symptoms 
would have been observed and reported and any disability resulting 
therefrom could be compensated on a direct-service-connection basis, 
without the need of a presumption. Also, it is very likely that the 
existing presumption of service-connection codified at 38 CFR 3.317 
regarding undiagnosed illnesses suffered by Gulf War veterans would 
provide a basis for service connection in the case of veterans 
suffering from long-term effects suspected of being residuals of sarin 
exposure. Under section 3.317, if a veteran suffers from a chronic 
disability resulting from an undiagnosed illness (or combination of 
undiagnosed illnesses) that became manifest during service or that 
becomes manifest to a degree of 10 percent or more before December 31, 
2001, the disability shall be presumed to be service connected.
    For the foregoing reasons, the Secretary has concluded that neither 
the acute and transient symptoms resulting from possible sarin 
exposure, nor any long-term health consequences associated with 
possible sarin exposure, warrant a presumption of service-connection.

VI. Pyridostigmine Bromide

    Pyridostigmine bromide (PB) is a drug used during the Gulf War as a 
pretreatment to protect troops from the harmful effects of chemical 
warfare nerve agents. NAS noted that a large number of clinical studies 
have reported that PB causes acute transient cholinergic effects in 
normal volunteers, patients given PB as a diagnostic test of 
hypothalamic pituitary function, and myasthenia gravis patients treated 
with the drug for extended periods.
    NAS found that the epidemiologic data do not provide evidence of a 
link between PB and chronic illness in Gulf War veterans, noting that 
there is a paucity of epidemiologic studies on PB and long-term adverse 
health effects in the peer-reviewed literature. Only two epidemiologic 
studies investigated the possible association of PB and chronic 
symptoms among Gulf War veterans. (Haley RW, Kurt TL. 1997. Self-
reported exposure to neurotoxic chemical combinations in the Gulf War. 
A cross-sectional epidemiologic study. JAMA 277(3):231-237; Unwin C, 
Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, 
David A, Wessely S. 1999. Health of UK servicemen who served in Persian 
Gulf War. Lancet 353(9148):169-178). NAS noted that the study by Haley 
and Kurt, 1997, is limited by the small, selected population studied. 
NAS also found that this study suffers from reporting bias for adverse 
health syndromes, and provides an inadequate basis for concluding that 
an association exists. NAS noted that the other epidemiologic study 
(Unwin et al., 1999) showed a similar association with adverse 
symptoms; however, NAS felt that recall and reporting bias may also 
explain this finding. NAS concluded that neither of these studies 
provides a basis for holding that a specific association between PB and 
chronic adverse health effects exists.

VA Determination on PB

    Although the NAS report provided evidence of an association between 
PB and transient, acute cholinergic effects, the report indicated that 
such effects resolved in a matter of hours following exposure. For this 
reason, the Secretary has concluded that these acute effects were not 
in the nature of an illness within the contemplation of the governing 
statute. Accordingly, the Secretary has concluded that such effects 
failed to meet the standards for establishment of presumptive service 
connection based on exposure to PB.
    NAS indicated that there are no reliable reports of chronic 
toxicity related to human PB exposure in clinical or military 
populations. NAS concluded that there was inadequate/insufficient 
evidence to determine whether an association does or does not exist 
between PB and long-term adverse health effects. We are not aware of 
any other reports of chronic toxicity related to human pyridostigmine 
bromide exposure in clinical or military populations. For these 
reasons, the Secretary has determined that the credible evidence 
against an association between long-term adverse health effects and PB 
outweighs the credible evidence for such an association, and he

[[Page 35709]]

has determined that a positive association does not exist.

VII. Vaccinations

Anthrax Vaccination

    Concerns prior to the Gulf War regarding Iraq's offensive 
biological warfare capabilities led to decisions that available 
vaccines should be utilized as preventive measures against biological 
warfare agents. NAS used only the peer-reviewed literature to form its 
conclusions on the weight of the evidence for associations of the 
anthrax vaccine with adverse health effects. Only a few published peer-
reviewed studies have examined potential adverse effects of the anthrax 
vaccine when administered to humans.
    NAS located only one peer-reviewed study of the type of anthrax 
vaccine used in the United States (Brachman PS, Gold H, Plotkin S, 
Fekety FR, Werrin M, Ingraham NR. 1962. Field evaluation of a human 
anthrax vaccine. Am J Public Health 52:632-645). The Brachman study 
(and other early experimental studies) found transient local and 
systemic effects (primarily erythema, edema, induration) from the 
anthrax vaccine. However, this study did not assess adverse effects 
beyond 48 hours after vaccination. (NAS found that other published 
studies (limited to a few short-term studies) reported no significant 
long-term adverse effects of the vaccine.)
    During the development of the anthrax vaccine, several early 
studies examined adverse reactions in humans but did not provide 
detailed information on the nature of the monitoring for adverse 
effects. These studies used early versions of the culture filtrate 
(protective antigen) vaccine. Wright and colleagues (Wright GG, Green 
TW, Kanode RG Jr. 1954. Studies on Immunity in Anthrax. V. Immunizing 
activity of alum-precipitated protective antigen. J. Immunol 73:387-
391) described the reactions of 660 persons at Camp Detrick who 
received a total of 1,936 injections. They found that 0.7 percent of 
vaccinated subjects reported systemic reactions--typically consisting 
of mild muscle aches, headaches, and mild-to-moderate malaise lasting 1 
to 2 days. Significant local reactions--typically swelling (5-10 cm in 
diameter) and local pruritus (itching)--occurred in 2.4 percent of the 
subjects. The incidence of local reactions increased with the number of 
injections.
    In another study at Fort Detrick (Puziss M, Wright GC, 1963. 
Studies on immunity in anthrax. X. Gel absorbed protective antigen for 
immunization of man. J Bacteriology 85:230-236), 0.5-ml injections of 
protective antigen led to similar results. The study reported low rates 
of erythema, edema, or pruritus at the site of injection (no details 
were provided) and no systemic reactions. Darlow and colleagues 
(Darlow, HM, Belton FC, Camb BA. 1956. The use of anthrax antigen to 
immunize man and monkey. Lancet. 2:476-479) reported on the 
administration of 1,057 injections of the anthrax vaccine to 373 
individuals (369 persons received two or more injections) over a period 
of 4 years. Most of the reactions were mild and brief (local tenderness 
and swelling). There was an increase in the number of persons 
experiencing pain after the second dose, and local reactions increased 
with successive booster injections. The study reported that three 
people had brief and mild fever.

Botulinum Toxoid Vaccination

    NAS found only a few published peer-reviewed studies that examined 
the potential adverse health effects of the botulinum toxoid vaccine 
when administered to humans. One study (Fiock MA, Devine LF, Gearinger 
NF, Duff JT, Wright GG, Kadull PJ. 1962. Studies on immunity to toxins 
of Clostridium botulinum. VIII. Immunological response of man to 
purified bivalent AB botulinum toxoid. J Immunol 88:277-283) reported 
on tests of bivalent toxoid preparations by Parke, Davis, and Company. 
NAS noted that the study reported that after 800 injections, no 
systemic or severe local reactions occurred. NAS also noted that the 
report did not discuss the surveillance methods for monitoring adverse 
health effects. A subsequent study (Fiock MA, Cardella MA, Gearinger 
NF. 1963. Studies on immunity to toxins of Clostridium botulinum. X. 
Immunologic response of man to purified pentavalent ABCDE botulinum 
toxoid. J Immunol 90:697-702) examined four different pentavalent 
toxoid lots prepared by Parke, Davis, and Company. NAS noted that the 
only statement about adverse reactions made by the investigators in 
their report was that 400 individuals received the pentavalent toxoid 
with ``no marked local or marked systemic reactions.'' NAS stated that 
the studies have noted transient local and systemic effects of the 
botulinum toxoid vaccine; however, these studies have not used active 
surveillance to systematically evaluate long-term health outcomes.

Multiple Vaccinations

    Military personnel often receive several vaccinations as they 
prepare for service in an environment with many endemic diseases. 
Several studies of Gulf War veterans have tried to discover an 
association between health outcomes and exposure to vaccinations. Unwin 
et al., 1999, reported the results of a large cross-sectional postal 
survey on a random sample of U.K. Gulf War, Gulf War era, and Bosnia 
conflict veterans. The Gulf War and Bosnia troops were vaccinated 
against hepatitis A and B, yellow fever, typhoid, poliomyelitis, 
cholera, and tetanus, as well as against biological warfare agents. NAS 
found that this study provided some limited evidence of an association 
between multiple vaccinations and long-term multisymptom outcomes. NAS 
also noted that this study was conducted through questionnaire and 
relied primarily on self-reports.
    A recently released study (Hotopf M, David A, Hull L, Ismail K, 
Unwin C, Wessely S. 2000. Role of vaccinations as risk factors for ill 
health in veterans of the Gulf War: Cross sectional study. BMJ 
320:1363-1367) reported on a further analysis of the United Kingdom 
data. This study focused on U.K. Gulf War veterans who reported that 
they had copies of their vaccine records. The study examined the 
vaccines received, the timing of vaccinations, and six health outcomes 
(multisymptom outcome, psychological distress, post-traumatic stress 
reaction, fatigue, health perception, and physical functioning). NAS 
found that this study is consistent with the hypothesis that receiving 
multiple vaccinations within a narrow window of time, during a period 
of presumed stress, could be associated with the development of 
multiple symptoms and impaired functional status. NAS noted, however, 
that this study was limited by its cross-sectional nature and the fact 
that it relied on vaccine records that had been retained by only 28 
percent of the study respondents. NAS noted that there were limiting 
and confounding factors in both studies (Unwin et al., 1999; Hotopf et 
al., 2000) and NAS pointed out the need for further research. NAS found 
that certain multiple vaccination programs can lead to antibody 
responses, but there is little evidence of other adverse consequences 
beyond transient local and systemic effects seen frequently with any 
vaccination.

VA Determinations on Anthrax Vaccination, Botulinum Toxoid Vaccination 
and Multiple Vaccination

    Although the NAS report provided evidence of an association between 
anthrax vaccination, botulinum toxoid vaccination and multiple 
vaccinations and transient acute local and systemic effects as are 
typically associated with vaccinations, these effects represent the

[[Page 35710]]

body's normal, short-term reaction to introduction of the beneficial 
vaccines. For this reason, the Secretary has concluded that these acute 
effects were not in the nature of an illness within the contemplation 
of the governing statute. Accordingly, the Secretary has concluded that 
such effects failed to meet the standards for establishment of 
presumptive service-connection based on anthrax vaccination, botulinum 
toxoid vaccination or multiple vaccinations.
    NAS indicated that there are no reliable reports of chronic 
toxicity related to anthrax vaccination, botulinum toxoid vaccination 
or multiple vaccinations in clinical or military populations. NAS 
concluded that there was inadequate/insufficient evidence to determine 
whether an association does or does not exist between these 
vaccinations and long-term adverse health effects. We are not aware of 
any other reports of chronic toxicity related to these vaccinations in 
clinical or military populations. For these reasons, the Secretary has 
determined that the credible evidence against an association between 
long-term adverse health effects and these vaccinations outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.

VIII. Conclusion

    NAS reviewed published scientific and medical articles published, 
and issued the report entitled ``Gulf War and Health, Volume 1. 
Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines.'' In the 
judgment of the Secretary, the comprehensive review and evaluation of 
the available literature which NAS conducted in conjunction with its 
report permitted VA to determine whether a presumption of service 
connection should be established for any illness suffered by Gulf War 
veterans based on exposure to depleted uranium, sarin, PB, and certain 
vaccines. For the foregoing reasons, the Secretary has concluded that 
the establishment of a presumption of service connection is not 
warranted.

    Approved: June 12, 2001.
Anthony J. Principi,
Secretary of Veterans Affairs.
[FR Doc. 01-16899 Filed 7-5-01; 8:45 am]
BILLING CODE 8320-01-P