[Federal Register Volume 75, Number 247 (Monday, December 27, 2010)]
[Notices]
[Pages 81332-81335]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-32332]


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DEPARTMENT OF VETERANS AFFAIRS


Health Outcomes Not Associated With Exposure to Certain Herbicide 
Agents; Veterans and Agent Orange: Update 2008

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 of the Agent Orange Act of 1991, Public Law 102-4 (codified 
in relevant part at 38 U.S.C. 1116), has determined that a presumption 
of service connection is not warranted based on exposure to herbicides 
used in the Republic of Vietnam during the Vietnam Era for any of the 
diseases, illnesses, or health effects identified in the July 24, 2009, 
National Academy of Sciences (NAS) report entitled ``Veterans and Agent 
Orange: Update 2008'' (Update 2008), except for hairy cell leukemia 
(HCL) and other chronic b-cell leukemias, Parkinson's disease, and 
ischemic heart disease. In this regard, the Secretary of Veterans 
Affairs determined, based upon the NAS report, that there is a positive 
association between exposure to herbicides and the subsequent 
development of HCL and other chronic b-cell leukemias, Parkinson's 
disease, and ischemic heart disease. The Secretary recently published a 
notice of proposed rulemaking to implement this decision. See 75 FR 
14391 (Mar. 25, 2010).
    The determination to not establish a presumption of service 
connection, based on exposure to herbicides used in the Republic of 
Vietnam during the Vietnam era for any other of the diseases, 
illnesses, or health effects identified in the July 24, 2009, NAS 
report, does not in any way preclude VA from granting service 
connection for these diseases, including those specifically discussed 
in this notice, nor does it change any existing rights or procedures.
    The Secretary's determinations regarding individual diseases are 
based on all available evidence in the 2008 report of the NAS and prior 
NAS reports. This notice generally states specific information only 
with respect to significant additional studies that were first reviewed 
by NAS in its 2008 report. Information regarding additional relevant 
studies is stated in VA's prior notices following earlier NAS reports, 
and generally will not be repeated here.

FOR FURTHER INFORMATION CONTACT: Gerald Johnson, Regulations Staff 
(211D), Compensation and Pension Service, Veterans Benefits 
Administration, Department of Veterans Affairs, 810 Vermont Avenue, 
NW., Washington, DC 20420, telephone (202) 461-9727. (This is not a 
toll-free number.)

SUPPLEMENTARY INFORMATION:

I. Statutory Requirements

    Section 3 of the Agent Orange Act of 1991, Public Law 102-4, 105 
Stat. 11, directed the Secretary to seek to enter into an agreement 
with the NAS to review and evaluate the available scientific evidence 
regarding associations between exposure to herbicides used in support 
of military operations in the Republic of Vietnam during the Vietnam 
era and each disease suspected to be associated with such exposure.
    Congress mandated that NAS determine, to the extent possible: (1) 
Whether there is a statistical association between the suspected 
diseases and herbicide exposure, 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 
disease among individuals exposed to herbicide agents during service in 
the Republic of Vietnam during the Vietnam era; and (3) whether a 
plausible biological mechanism or other evidence of a causal 
relationship exists between herbicide exposure and the health outcome. 
Section 3 of Public Law 102-4 also requires that NAS submit reports on 
its activities every 2 years (as measured from the date of the first 
report) for a 10-year period. The Veterans Education and Benefits 
Expansion Act of 2001, Public Law 107-103, extended this period until 
October 1, 2014.
    Section 2 of Public Law 102-4, codified in pertinent part at 38 
U.S.C. 1116(b) and (c), 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 to an herbicide agent (i.e., a 
chemical in an herbicide used in support of the United States and 
allied military operations in the Republic of Vietnam during the 
Vietnam era) and a disease, the Secretary will publish regulations 
establishing presumptive service connection for that disease. 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.
    Section 2 of the Agent Orange Act of 1991 provided that the 
Secretary's authority and duties under that section would expire 10 
years after the first day of the fiscal year in which NAS transmitted 
its first report to VA. The first NAS report was transmitted to VA in 
July 1993, during the fiscal year that began on October 1, 1992. 
Accordingly, VA's authority under section 2 of the Agent Orange Act of 
1991 expired on September 30, 2002. In December 2001, however, Congress 
enacted the Veterans Education and Benefits Expansion Act of 2001, 
Public Law 107-103. Section 201(d) of that Act extended VA's authority 
under 38 U.S.C. 1116(b)-(d) through September 30, 2015.
    Although 38 U.S.C. 1116 does not define ``credible,'' 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.'' The Secretary reviews studies 
that report a positive relative risk and studies that report a negative 
relative risk of a particular health outcome. He then determines 
whether the weight of evidence supports a finding that there is or is 
not a positive association between herbicide exposure and the 
subsequent health outcome. The Secretary does this by taking into 
account the statistical significance, capability of replication, and 
whether that study will withstand peer review. Because of differences 
in statistical significance, confidence levels, control for confounding 
factors, bias, and other pertinent characteristics, some studies are 
more credible than others. The Secretary gives weight to more credible 
studies in evaluating the overall evidence concerning specific health 
outcomes.

II. Prior NAS Reports

    The Secretary's determination that there is not a positive 
association between herbicide exposure and the diseases addressed in 
this notice is based upon the NAS's 2008 review and

[[Page 81333]]

analysis of the relevant scientific evidence as summarized below, the 
additional analyses provided in this notice, and NAS's and VA's 
previous analyses of the scientific and medical literature set forth in 
earlier Federal Register notices at: 59 FR 341 (Jan. 4, 1994), 61 FR 
41442 (Aug. 8, 1996), 64 FR 59232 (Nov. 2, 1999), 66 FR 2376 (Jan. 11, 
2001), 67 FR 42600 (Jun. 4, 2002), 68 FR 27630 (May 30, 2003), 72 FR 
32395 (June 12, 2007), and 75 FR 32540 (Jun. 8, 2010).

III. Update 2008

    NAS issued Update 2008 on July 24, 2009. The report is available at 
http://www.nap.edu/catalog.php?record_id=12662. For Update 2008, NAS 
conducted a search of literature published through September 30, 2008, 
and identified more than 7,000 potentially relevant citations. About 
850 were retained for closer consideration, and about 300 contributed 
information for the NAS's detailed analysis.

a. Sufficient Evidence of Association

    Consistent with its prior reports, NAS in Update 2008 found that 
there was ``sufficient evidence of an association'' between herbicide 
exposure and five categories of diseases in veterans. VA has previously 
established or proposed presumptions of service connection for each of 
these diseases. See 38 CFR 3.309(e); 75 FR 14391 (Mar. 25, 2010) 
(proposing to add HCL and other chronic b-cell leukemias to the 
category of chronic lymphocytic leukemia (CLL)).

b. Limited/Suggestive Evidence of Association

    NAS, in 2008, categorized certain health outcomes to have ``limited 
or suggestive evidence of an association.'' This category is defined to 
mean that evidence suggests an association between exposure to 
herbicides and the outcome, but a firm conclusion is limited because 
chance, bias, and confounding could not be ruled out with confidence. 
Health outcomes placed in the ``limited or suggestive evidence of an 
association'' category are laryngeal cancer; cancer of the lung, 
bronchus, or trachea; prostate cancer; multiple myeloma; early-onset 
transient peripheral neuropathy; porphyria cutanea tarda; type 2 
diabetes (mellitus); spina bifida in offspring of exposed persons; AL 
amyloidosis; hypertension; Parkinson's disease; and ischemic heart 
disease. VA has previously established presumptions of service 
connection for laryngeal cancer; cancer of the lung, bronchus, or 
trachea; prostate cancer; multiple myeloma; early-onset transient 
peripheral neuropathy, porphyria cutanea tarda; type 2 diabetes 
(mellitus); and AL amyloidosis. See 38 CFR 3.309(e). In instances of 
spina bifida in offspring of exposed persons, VA pays a monetary 
allowance under 38 CFR 3.814. VA recently proposed presumptions of 
service connection for Parkinson's disease and ischemic heart disease. 
See 75 FR 14391 (Mar. 25, 2010). Hypertension is discussed below.
    NAS identified and reviewed information from comprehensive 
databases covering biologic, medical, toxicologic, chemical, historical 
and regulatory information to determine whether a statistical 
association with herbicide exposure exists, whether there is an 
increased risk of disease among those exposed to herbicides during 
service in the Republic of Vietnam during the Vietnam era; and whether 
there exists a plausible biological mechanism or other evidence of a 
causal relationship between herbicide exposure and hypertension. In 
Update 2006, the NAS changed the category for hypertension from 
``insufficient evidence'' to ``limited or suggestive evidence,'' but 
clearly could not distinguish the possibility of a small increased risk 
for hypertension due to herbicide exposure from more prevalent 
scientifically established risk factors in evaluating the risk to 
individual Veterans. NAS noted the limitations of the studies regarding 
hypertension. In the Federal Register of June 8, 2010, VA explained why 
the studies reviewed in Update 2006 did not, in VA's view, warrant a 
presumption of service connection for hypertension in veterans exposed 
to herbicides in service. 75 FR 32540 (Jun. 8, 2010).
    In Update 2008, NAS identified six new studies concerning 
hypertension that the committee found to be generally consistent with 
its conclusion in Update 2006 that there is ``limited/suggestive 
evidence'' of an association between herbicide exposure and 
hypertension. However NAS also found significant limitations in each of 
the studies. It noted that a mortality study of a population 
accidentally exposed to dioxin in Seveso, Italy, had little ability to 
control for potentially important confounders. Three of the new studies 
analyzed data from the National Health and Nutrition Examination Survey 
(NHANES), which the committee characterized as broadly consistent with 
the Update 2006 conclusion, but also as limited by selection bias that 
may distort the evidence of association and by the inconsistency of the 
findings among various exposure categories. NAS noted that a study of 
47 exposed people in Florida involved a small survey of a problematic 
sample, making the data difficult to interpret. Finally, the committee 
noted that a study of an exposed population in Taiwan found no 
association between hypertension and being in the exposed population. 
When the analysis was restricted to persons having chloracne (a skin 
condition associated with herbicide exposure), the study found an 
increased incidence of hypertension in women, but not in men, making 
the findings difficult to interpret.
    Relatively few of the positive findings were statistically 
significant and the findings overall are limited by the inconsistency 
of the results, the lack of controls, and other methodological 
concerns. The inconsistent findings within and across the studies limit 
the ability to draw any conclusions regarding dose-response 
relationship. Viewing the new studies published since 2006 in relation 
to the previously reviewed evidence, VA has determined that the 
evidence overall does not establish a positive association between 
herbicide exposure and hypertension. Therefore, a presumption of 
service connection is not warranted.

c. Inadequate or Insufficient Evidence To Determine Whether an 
Association Exists

    NAS, in Update 2008, categorized certain other health outcomes as 
having inadequate or insufficient evidence to determine whether an 
association with herbicide exposure exists. This category is defined to 
mean that the available studies are of insufficient quality, 
consistency, or statistical power to permit a conclusion regarding the 
presence or absence of an association with herbicide exposure. The 
health outcomes that met this category are: cancers of the oral cavity 
(including lips and tongue), pharynx (including tonsils), nasal cavity 
(including ears and sinuses); cancers of the pleura, mediastinum, and 
other unspecified sites within the respiratory system and intrathoracic 
organs; esophageal cancer; stomach cancer; colorectal cancer (including 
small intestine and anus); hepatobiliary cancers (liver, gallbladder 
and bile ducts); pancreatic cancer; bone and joint cancer; melanoma; 
non-melanoma skin cancer (basal cell and squamous cell); breast cancer; 
cancers of reproductive organs (cervix, uterus, ovary, testes, and 
penis; excluding prostate); urinary bladder cancer; renal cancer 
(kidney and renal pelvis); cancers of brain and nervous system 
(including eye); endocrine cancer (thyroid, thymus, and other endocrine 
organs); leukemia (other than all chronic B-cell leukemias including 
chronic

[[Page 81334]]

lymphocytic leukemia (CLL) and HCL); cancers at other and unspecified 
sites; neurobehavioral disorders (cognitive and neuropsychiatric); 
movement disorders (including amyotrophic lateral sclerosis (ALS) but 
excluding Parkinson's disease); chronic peripheral nervous system 
disorders; respiratory disorders (wheeze or asthma, chronic obstructive 
pulmonary disorder, and farmer's lung); gastrointestinal, metabolic, 
and digestive disorders (changes in liver emzymes, lipid abnormalities 
and ulcers); immune system disorders (immune suppression, allergy and 
autoimmunity); circulatory disorders (other than hypertension or 
ischemic heart disease); endometriosis; effects on thyroid homeostasis 
and certain reproductive effect i.e., infertility, spontaneous 
abortion, neonatal or infant death and stillbirth in offspring of 
exposed people, low birth weight in offspring of exposed people, birth 
defects (other than spina bifida) in offspring of exposed people, and 
childhood cancer (including acute myelogenous leukemia) in offspring of 
exposed people.
    After considering the NAS report, the Secretary has determined that 
presumptions of service connection are not warranted for any of the 
diseases listed above. As noted above, VA has previously explained, in 
a series of Federal Register notices, its analysis of prior NAS reports 
concerning these diseases. The additional evidence and analysis 
addressed in Update 2008 with respect to these conditions is summarized 
below.
    In Update 2008, NAS identified no additional studies relevant to 
the possible association between herbicide exposure and cancers of the 
pleura, mediastinum, and other unspecified sites within the respiratory 
system and intrathoracic organs; esophageal cancer; bone and joint 
cancer; cancers of the male reproductive organs (other than prostate 
cancer), endocrine cancer, movement disorders (including ALS but 
excluding Parkinson's disease); endometriosis; effects on thyroid 
homeostasis; and certain reproductive effects. Accordingly, the NAS's 
conclusions regarding those conditions were unchanged from Update 2006.
    In Update 2008, NAS found that the relevant new studies it 
identified did not include any statistically significant findings of 
association between herbicide exposure and the following diseases: 
oral, nasal, and pharyngeal cancers; colorectal cancer; hepatobiliary 
cancer, melanoma, non-melanoma skin cancer; cancers of the female 
reproductive organs; urinary bladder cancer; renal cancer; chronic 
peripheral nervous system disorders; gastrointestinal, metabolic, and 
digestive disorders (including changes in liver enzymes, lipid 
abnormalities, and ulcers); and endometriosis. Accordingly, NAS found 
that the additional evidence generally did not support an association 
between herbicide exposure and those health outcomes.
    With respect to several other health outcomes, NAS in Update 2008 
found that, although the new studies included some statistically 
significant positive findings, those findings did not warrant a change 
in the conclusion that the evidence overall is inadequate or 
insufficient to determine whether the health outcome is associated with 
herbicide exposure, as explained below.
    NAS discussed two new studies regarding stomach cancer. One of the 
studies found no increased mortality from stomach cancer in the exposed 
population. The other study found a statistically significant increased 
risk of stomach cancer among farm workers who used pesticides. NAS 
noted that this study was consistent with findings of a previously-
reviewed occupational study finding evidence of an association between 
exposure to phenoxy herbicides (but not other types of herbicides) and 
stomach cancer. However, NAS noted that several other significant 
studies it had previously reviewed--including studies of Vietnam 
veteran cohorts, studies of the International Agency for Research on 
Cancer (IARC) cohort, and the U.S. Agricultural Health Study--had 
provided no evidence suggestive of an association between herbicide 
exposure and stomach cancers. Accordingly, NAS in Update 2008 concluded 
that the overall evidence does not support an association between 
exposure to the herbicides of interest and stomach cancer.
    NAS discussed two new studies regarding pancreatic cancer. One of 
the studies found no increased mortality from pancreatic cancer in the 
exposed population. The other study found a statistically significant 
increase in pancreatic cancer among deployed U.S. female Vietnam 
veterans in comparison to their nondeployed counterparts. NAS noted 
that a previously reviewed study also found evidence of an increased 
risk of pancreatic cancer in deployed Australian Vietnam veterans. NAS 
noted that no increase in risk has been detected to date in U.S. male 
Vietnam veterans or in agricultural cohorts or IARC follow-up studies. 
It further noted that the Vietnam veteran studies were limited due to 
lack of control for smoking and lack of supportive evidence from 
occupational or environmental studies. NAS found that the overall 
evidence remained insufficient or inadequate to determine whether an 
association exists.
    NAS discussed four new studies concerning breast cancer. Three of 
the studies, including a Vietnam veteran study, found no increased risk 
of breast cancer in exposed populations. One study found an increased 
risk of breast cancer associated with self-reported use of household 
pesticides. NAS concluded that the new evidence tended to weigh against 
an association and that the one positive study was limited by potential 
recall bias and the lack of information regarding specific exposures.
    NAS discussed four new studies regarding cancers of the brain and 
nervous system (including the eye). It found that the new studies were 
consistent in finding no association between herbicide exposure and the 
development of gliomas (the most common type of brain cancer). NAS 
noted that one of the new studies provided evidence of a possible 
relationship between herbicide exposure and meningiomas (a type of 
nervous system cancer) in women, but that the lack of identification of 
specific chemicals of interest makes interpretation of that result 
uncertain. NAS concluded that the overall evidence remained inadequate 
or insufficient to determine whether and association exists.
    NAS discussed three new studies addressing whether all forms of 
leukemia are associated with herbicide exposure. One of the studies 
found no evidence of an association between herbicide exposure and 
leukemias, while the other two found evidence of such an association. 
However, NAS found that one of the positive studies was limited by 
concern over possible misclassification of causes of death for the few 
people whose deaths were attributed to forms of leukemia other than 
those already considered to be associated with herbicide exposure 
(i.e., b-cell leukemias). Viewing the new evidence in relation to the 
previously reviewed evidence, NAS found that the overall evidence was 
inadequate or insufficient to determine whether an association exists. 
NAS's finding that the evidence does not establish an association 
between herbicide exposure and all forms of leukemia does not affect 
its independent finding that there is sufficient evidence of a causal 
association between herbicide exposure and specific forms of leukemia 
(i.e., CLL and other chronic b-cell leukemias).

[[Page 81335]]

    NAS discussed three new studies regarding neurobehavioral effects. 
Two of the studies found an increased reporting of neurobehavioral 
symptoms with self-reported pesticide exposure, but no associations 
specific to herbicide exposure. The third study found an increased 
incidence of abnormalities on neurobehavioral testing among persons 
chronically exposed to herbicides, but NAS found this study limited by 
the small sample size, the lack of information on methodology, and the 
possibility that many other environmental and age-related factors may 
have affected the results. Further, the data do not clearly relate the 
increased symptoms or abnormal test results to specific neurobehavioral 
diseases or diagnoses. NAS concluded that the overall evidence remained 
inadequate or insufficient to detect an association.
    NAS noted that several previously reviewed studies failed to 
support the hypothesis that herbicide exposure is associated with 
respiratory mortality from non-cancer diseases. In Update 2008, NAS 
identified one new study showing increased respiratory mortality, but 
determined that no conclusions could be drawn from the study due to 
lack of specificity regarding the health outcomes and due to other 
methodological concerns. In Update 2008, NAS also discussed new and 
previously reviewed studies relating to three specific categories of 
respiratory effects: chronic obstructive pulmonary disease (COPD), 
``wheeze'' and asthma, and farmer's lung. NAS concluded that most 
prevalence studies found no association between herbicide exposure and 
COPD, and the two that did find evidence of such association were 
limited by methodological concerns. NAS found that the relevant studies 
did not detect an association between herbicide exposure and ``wheeze'' 
or asthma after adjusting for known confounders, and that the sole 
relevant study on farmer's lung was inconclusive.
    NAS discussed two new studies regarding immune system disorders. 
One study found no evidence of immune system disorders in persons 
highly exposed to dioxin. The other study found an increase in self-
reported arthritis (thought to be an autoimmune disorder) among exposed 
women, but not men. NAS concluded that the positive finding was 
unsupported by experimental evidence and that the overall evidence 
remained inadequate or insufficient to determine whether an association 
exists.
    NAS identified one study finding evidence of an increased risk of 
mortality from rheumatic heart disease in an exposed population, but 
concluded that the basis for the observed association was unclear and 
that the data were limited by the lack of control for significant 
confounders and other methodological concerns. NAS found that the 
overall evidence was inadequate or insufficient to determine whether 
herbicide exposure is associated with any circulatory disorders other 
than ischemic heart disease or hypertension.
    NAS discussed four new studies regarding thyroid homeostasis. It 
found that the new studies were generally consistent with previously 
reviewed studies suggesting that herbicides may exert some effect on 
thyroid function. However, NAS concluded that the significance of the 
observed effects is unclear because the body's adaptive capacity should 
be sufficient to accommodate them. NAS concluded that there was 
inadequate or insufficient evidence to determine whether herbicide 
exposure is associated with clinical or overt adverse effects on 
thyroid homeostasis.
    NAS noted that previous Veterans and Agent Orange (VAO) committee 
findings did not find any significant association between the relevant 
exposure and several reproductive outcomes. In Update 2008, NAS 
determined that there is inadequate or insufficient evidence of an 
association between herbicide exposure and endometriosis; semen 
quality; infertility; spontaneous abortion; late fetal, neonatal, or 
infant death; low birth weight or preterm delivery; birth defects other 
than spina bifida; and childhood cancers (including acute myelogenous 
leukemia) in offspring of exposed people.
    Among three new studies on endometriosis, two found no significant 
evidence of association and the third found a decreased risk among the 
most highly exposed persons. NAS found that several new studies 
regarding the effects of herbicide exposure on semen quality and female 
infertility provided little evidence of any adverse impact. NAS found 
that two new studies regarding spontaneous abortion provided 
conflicting results and that the overall evidence indicates that 
paternal exposure is not associated with spontaneous abortion and that 
there is inadequate or insufficient evidence to determine whether 
maternal exposure is associated with such outcomes. NAS concluded that 
one new study regarding the effect of dioxin-like substances on 
stillbirth, neonatal, death, or spontaneous abortion, did not provide 
primary evidence for an association between dioxin and such outcomes. 
NAS discussed four new studies concerning low birth weight or preterm 
delivery and found that the evidence overall suggests no association 
between herbicide exposure and those outcomes. NAS concluded that two 
new studies provided no evidence of an association between herbicide 
exposure and birth defects other than spina bifida. NAS concluded that 
the four new studies of childhood cancer in the offspring of exposed 
individuals contained conflicting findings, but that the positive 
findings in two studies were limited by broad exposure classifications.
    Conclusion:
    After careful review of the findings of the NAS Report, Veterans 
and Agent Orange Update 2008, the Secretary has determined that the 
scientific evidence presented in the 2008 NAS report and other 
information available to the Secretary indicates that no new 
presumption of service connection is warranted at this time for any 
disease other than HCL and other chronic b-cell leukemias, Parkinson's 
disease, and ischemic heart disease.

Signing Authority

    The Secretary of Veterans Affairs, or designee, approved this 
document and authorized the undersigned to sign and submit the document 
to the Office of the Federal Register for publication electronically as 
an official document of the Department of Veterans Affairs. John R. 
Gingrich, Chief of Staff, Department of Veterans Affairs, approved this 
document on December 20, 2010, for publication.

    Dated: December 20, 2010.
Robert C. McFetridge,
Director, Regulations Policy and Management, Department of Veterans 
Affairs.
[FR Doc. 2010-32332 Filed 12-23-10; 8:45 am]
BILLING CODE 8320-01-P