[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