[Federal Register Volume 73, Number 140 (Monday, July 21, 2008)]
[Notices]
[Pages 42411-42414]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-16525]


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DEPARTMENT OF VETERANS AFFAIRS


Determination of Presumption of Service Connection Concerning 
Illnesses Discussed in National Academy of Sciences Report on Gulf War 
and Health: Updated Literature Review of Sarin

AGENCY: Department of Veterans Affairs.

ACTION: Notice.

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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, Public 
Law 105-277, title XVI, 112 Stat. 2681-742 through 2681-749 (codified 
in part at 38 U.S.C. 1118), has determined that there is no basis to 
establish a presumption of service connection for any of the diseases, 
illnesses, or health effects discussed in the August 2004 report of the 
National Academy of Sciences, titled ``Gulf War and Health: Updated 
Literature Review of Sarin,'' based on exposure to sarin during service 
in the Persian Gulf during the Persian Gulf War.

FOR FURTHER INFORMATION CONTACT: Maya Ferrandino, Regulations Staff 
(211D), Compensation and Pension Service, Veterans Benefits 
Administration, Department of Veterans Affairs, 810 Vermont Avenue, 
NW., Washington, DC 20420, (727) 319-5847.

SUPPLEMENTARY INFORMATION:

I. Statutory Requirements

    The Persian Gulf War Veterans Act of 1998, Public Law 105-277, 
title XVI, 112 Stat. 2681-742 through 2681-749 (codified in part at 38 
U.S.C. 1118), and the Veterans Programs Enhancement Act of 1998, Public 
Law 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 to which service 
members may have been exposed during service in the Persian Gulf during 
the Persian Gulf War. Congress directed NAS to identify agents, 
hazards,

[[Page 42412]]

medicines, and vaccines to which service members may have been exposed 
during service in the Persian Gulf during the Persian Gulf War.
    Congress mandated that NAS determine, to the extent possible: (1) 
Whether there is a statistical association between exposure to the 
agent, hazard, 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, medicine, or vaccine; and (3) whether a plausible biological 
mechanism or other evidence of a causal relationship exists between 
exposure to the agent, hazard, medicine, or vaccine, and the illness.
    Section 1602 of Public Law 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 Public Law 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 or 
replication, and withstand peer review.'' Simply comparing the number 
of studies that report a significantly increased relative risk to the 
number of studies that 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. NAS Reports on Sarin

    NAS issued its initial report titled, Gulf War and Health, Volume 
1: Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines, on 
January 1, 2000. In that report, NAS limited its analysis to the health 
effects of depleted uranium, the chemical warfare agent sarin, 
vaccinations against botulism toxin and anthrax, and pyridostigmine 
bromide, which was used in the Gulf War as a pretreatment for possible 
exposure to nerve agents. On July 6, 2001, VA published a notice in the 
Federal Register announcing the Secretary's determination that the 
available evidence did not warrant a presumption of service connection 
for any disease discussed in that report, including sarin. See 66 FR 
35702.
    NAS issued a supplemental report, titled ``Gulf War and Health: 
Updated Literature Review on Sarin'' in August 2004. In that report, 
the Committee focused on the health effects associated with exposure to 
sarin and related compounds, including relevant epidemiologic studies. 
This Notice addresses the August 2004 Update on sarin.

III. The Committee's Review

    In the August 2004 Update on sarin, the Committee reviewed the 
peer-reviewed literature published since its earlier 2000 report on 
health effects associated with exposure to sarin and related compounds. 
These included both animal and human studies. In reviewing published 
studies, the Committee based its determinations on the strength of the 
evidence of associations between compound exposure and human health 
effects as reported in those studies. The Committee also considered 
other relevant issues, including exposure to multiple chemicals and 
genetic susceptibilities.
    The literature search on sarin and cyclosarin located about 250 
articles published after the 2000 report. The Committee relied only on 
published peer-reviewed articles for their review, although each 
article was carefully reviewed for its relevance and quality. The 
Committee relied primarily upon epidemiological studies that involved 
humans. Animal studies had a lesser role in its assessment of the 
potential relationship between sarin exposure and health effects, and 
were used, as in previous NAS studies, primarily for making assessments 
of biological plausibility in support of epidemiological findings.
    The Committee reviewed 19 epidemiological studies of sarin health 
effects published since its original 2000 report. These included three 
studies on non-Gulf War veterans, four studies of Gulf War veterans 
potentially exposed at Khamisiyah, six population-based studies of U.S. 
and U.K. Gulf War veterans using self-reported exposures, and six 
studies of specific military units of Gulf War veterans also using 
self-reported exposures. They also looked again at all of the studies 
used in the 2000 report. The non-Gulf War veteran studies reviewed in 
both the 2004 update and the earlier 2000 report were based on U.S. 
military volunteers who had been exposed several decades ago to non-
lethal doses of sarin and other chemical warfare agents; on industrial 
workers with documented acute exposure to sarin; and on victims of the 
sarin terrorist attacks in Matsumoto City in 1994 and Tokyo in 1995. 
The Committee pointed out that a major limitation of virtually all 
human studies is a lack of good exposure information.
    The Committee report pointed to the uncertainties surrounding the 
Department of Defense (DoD) sarin exposure assessment for Khamisiyah, 
and how those uncertainties limit the ability of studies that rely upon 
that modeling data to provide strong evidence for the presence or the 
absence of any association between sarin exposure and health outcomes. 
They stated, ``none of the studies using exposure information showed 
persistent neurological effects in Khamisiyah-exposed troops compared 
to non-Khamisiyah exposed troops. Because of the uncertainty in the 
exposure assessment models those studies do not provide strong evidence 
for or against the presence of neurologic effects.'' Therefore, the 
studies based upon the DoD Khamisiyah modeling had little impact on the 
Committee's findings.
    The Committee also reported on new published data regarding 
experimental animals that were designed to mimic the potential 
exposures in the Gulf War. These data had precipitated the interest in 
an updated study of sarin health effects. The Committee reported that 
the data were an important step in ``determining whether a biologically 
plausible mechanism could underlie any long-term effects of low 
exposure to chemical verge agents, but more work

[[Page 42413]]

needs to be conducted to elucidate potential mechanisms and clarify how 
the cellular effects are related to any clinical effects that might be 
seen.''
    The Committee reported that, in the absence of carefully designed 
human studies expressly of sarin's or cyclosarin's long-term health 
effects at doses that do not produce acute signs and symptoms, the 
Committee concludes that the data remain inadequate or insufficient to 
determine whether persistent long-term effects are associated with low-
level sarin exposure.
    At a briefing to VA in August 2004, when questioned about whether 
NAS emphasis on human studies might overlook health concerns revealed 
only in laboratory animal studies, the head of the Committee stated 
that the Committee did thoroughly review available animal studies and 
taken together, they failed to show consistent biological effects that 
could be plausibly tied to potential clinical effects in humans. He 
added that future animal studies might change that result.

IV. The Committee's Conclusions

    In its report, the Committee weighed the strengths and limitations 
of all the epidemiological evidence reviewed for the August 2004 Update 
and in Gulf War and Health Volume 1, and reached its conclusions by 
interpreting the new evidence in the context of the entire body of 
literature. The Committee classified the evidence of an association 
between exposure to sarin and cyclosarin and a specific health outcome 
with reference to five categories: sufficient evidence of a causal 
relationship, sufficient evidence of an association, limited/suggestive 
evidence of an association, inadequate/insufficient evidence of an 
association, and limited/suggestive evidence of no association.
     Sufficient Evidence of a Causal Relationship: This 
category means the evidence is sufficient to conclude that there is a 
causal association between exposure to a specific agent and a specific 
health outcome in humans. The evidence is supported by experimental 
data and fulfills the guidelines for sufficient evidence of an 
association. The evidence must be biologically plausible and satisfy 
several of the guidelines used to assess causality, such as: strength 
of association, dose-response relationship, consistency of association, 
and a temporal relationship.
    The Committee found there is sufficient evidence of a causal 
relationship between acute high-dose exposure to sarin and acute 
cholinergic syndrome that is evident seconds to hours subsequent to 
sarin exposure and resolves in days to months. The Committee noted that 
acute cholinergic syndrome has been recognized for decades, and that 
the syndrome, as well as cholinergic signs and symptoms, is evident 
seconds to hours after exposure and usually resolves in days to months.
     Sufficient Evidence of an Association: This category means 
the evidence is sufficient to conclude that there is a positive 
association. That is, a consistent positive association has been 
observed between exposure to a specific agent and a specific health 
outcome in human studies in which chance and bias, including 
confounding, could be ruled out with reasonable confidence. For 
example, several high-quality studies report consistent positive 
associations, and the studies are sufficiently free of bias, including 
adequate control for confounding.
    The Committee made no conclusions in this category.
     Limited/Suggestive Evidence of an Association: This 
category means the evidence is suggestive of an association between 
exposure to a specific agent and a specific health outcome, but the 
body of evidence is limited by the inability to rule out chance and 
bias, including confounding, with confidence. For example, at least one 
high-quality study reports a positive association that is sufficiently 
free of bias, including adequate control for confounding. Other 
corroborating studies provide support for the association, but they are 
not sufficiently free of bias, including confounding. Alternatively, 
several studies of lower quality show consistent positive associations, 
and the results are probably not due to bias, including confounding.
    The Committee found there is limited/suggestive evidence of an 
association between exposure to sarin at doses sufficient to cause 
acute cholinergic signs and symptoms and a variety of subsequent long-
term neurological effects. The Committee noted that many health effects 
are reported in the literature to persist after such high-dose sarin 
exposure: fatigue, headache, visual disturbances (asthenopia, blurred 
vision, and narrowing of the visual field), asthenia, shoulder 
stiffness, and symptoms of posttraumatic stress disorder. The Committee 
further stated that such sarin exposure has also been followed by 
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.
    The Committee based its conclusion on the persistent effects seen 
in retrospective studies of three exposed populations in which acute 
cholinergic signs and symptoms were documented as acute effects of 
exposure. However, the Committee explained that while a review of the 
literature published since the Committee's initial report confirmed the 
effects seen in those populations, the data, taken together, were not 
adequate to increase confidence in the evidence to that of sufficient 
evidence of an association.
     Inadequate/Insufficient Evidence: This category means the 
evidence is of insufficient quantity, quality, or consistency to permit 
a conclusion regarding the existence of an association between exposure 
to a specific agent and a specific health outcome in humans.
    The Committee found there is 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 neurological health 
effects. In the absence of carefully designed human studies expressly 
of sarin or cyclosarin's long-term health effects at doses that do not 
produce acute signs and symptoms, the Committee concluded that the data 
remain inadequate or insufficient to determine whether such long-term 
effects are associated with low-level sarin exposure.
    The Committee also found there is inadequate/insufficient evidence 
to determine whether an association does or does not exist between 
exposure to sarin and subsequent long-term cardiovascular effects. 
Studies of persistent cardiovascular effects after sarin exposure have 
been inconsistent. Therefore, the Committee concluded that the data are 
inadequate or insufficient to determine whether an association exists.
     Limited/Suggestive Evidence of No Association: This 
category means the evidence is consistent in not showing a positive 
association between exposure to a specific agent and a specific health 
outcome after exposure of any magnitude. A conclusion of no association 
is inevitably limited to the conditions, magnitudes of exposure, and 
length of observation in the available studies. The possibility of a 
very small increase in risk after exposure studied cannot be excluded.
    The Committee made no conclusions in this category.

[[Page 42414]]

V. Response to the NAS Report

    After careful review of the findings of the August 2004 NAS report, 
the Secretary has determined that the conclusions contained in the 
report do not provide adequate basis to support a presumption of 
service connection for any health condition resulting from sarin 
exposure. Specifically, the Secretary has determined that the 2004 NAS 
Committee conclusions concerning both acute high-dose exposure to sarin 
and low-level exposure to sarin are consistent with the findings in the 
2000 NAS report, and therefore do not warrant any change in current VA 
policy.
    Following the 2000 NAS report, VA determined that a presumption 
based on acute high-dose exposure was not warranted for a number of 
reasons. First, VA and Department of Defense have determined, with a 
high degree of confidence, that no service members were exposed to 
levels of sarin sufficient to induce acute cholinergic syndrome. 
Further, if such exposures had occurred, the symptoms would have been 
present within seconds to hours following exposure and would be 
compensable by VA on a direct service-connection basis. Additionally, 
any long-term neurological effects would be compensable under VA 
presumptions for undiagnosed illness. See 38 CFR 3.317. Finally, 
because it is very unlikely that a presumption would benefit anyone, 
such a presumption would likely be confusing and have a negative impact 
on the claims adjudication process.
    Nothing in the 2004 NAS report changes the bases for VA's prior 
determination. The 2004 report notes that current available information 
is ``consistent with the absence of reports of acute cholinergic 
symptoms by medical personnel or veterans'' and that the level of 
exposure experienced by service members during the Gulf War ``would 
have been insufficient to produce the cholinergic syndrome.''
    Similarly, the Secretary has determined that the conclusions 
contained in the 2004 NAS report regarding long-term health effects 
from exposure to low levels of sarin are essentially identical and lend 
further support to the conclusions contained in the 2000 report. Based 
upon the findings contained in the 2000 NAS report, the Secretary 
determined that there was not an adequate basis to support establishing 
a presumption of service connection for any health problem resulting 
from sarin exposure. NAS's findings in the 2004 Update provide further 
support for existing VA policy on these issues.
    In conclusion, the Secretary has determined that the findings in 
the 2004 NAS report did not provide any new basis to establish a 
presumption of service connection for any diseases, illnesses, or 
health effects resulting from exposure to sarin during service in the 
Persian Gulf during the Persian Gulf War. Therefore, the Secretary has 
determined that there is no scientific basis to revise earlier policy 
determinations published in the Federal Register at 66 FR 35702 on July 
6, 2001, on health effects from exposure to sarin based upon the NAS's 
2000 Report.

    Approved: July 11, 2008.
Gordon H. Mansfield,
Deputy Secretary of Veterans Affairs.
[FR Doc. E8-16525 Filed 7-18-08; 8:45 am]
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