[Federal Register Volume 75, Number 109 (Tuesday, June 8, 2010)]
[Notices]
[Pages 32540-32553]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-13653]
-----------------------------------------------------------------------
DEPARTMENT OF VETERANS AFFAIRS
Health Effects Not Associated With Exposure to Certain Herbicide
Agents
AGENCY: Department of Veterans Affairs.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: As required by law, the Department of Veterans Affairs (VA)
[[Page 32541]]
hereby gives notice of a May 2008 determination by the Secretary of
Veterans Affairs that evidence available at that time did not warrant a
presumption of service connection based on exposure to herbicides used
in the Republic of Vietnam during the Vietnam era for the following
health outcomes: Cancers of the oral cavity (including lips and
tongue), pharynx (including tonsils), or 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;
cancers of brain and nervous system (including eye); endocrine cancers
(thyroid, thymus, and other endocrine); leukemia (other than chronic
lymphocytic leukemia (CLL)); cancers at other and unspecified sites;
neurobehavioral disorders (cognitive and neuropsychiatric); movement
disorders (including Parkinson's disease and amyotrophic lateral
sclerosis (ALS)); chronic peripheral nervous system disorders;
respiratory disorders; gastrointestinal, metabolic, and digestive
disorders (changes in liver enzymes, lipid abnormalities, and ulcers);
immune system disorders (immune suppression, allergy, and
autoimmunity); ischemic heart disease; circulatory disorders (including
hypertension); endometriosis; effects on thyroid homeostasis; certain
reproductive effects, 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, childhood cancer
(including acute myelogenous leukemia) in offspring of exposed people;
and any other condition for which the Secretary has not specifically
determined a presumption of service connection is warranted.
The Secretary's determinations regarding individual diseases are
based on all available evidence in a 2006 report of the National
Academy of Sciences (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 2006 report. Information
regarding additional relevant studies is stated in VA's prior notices
following earlier NAS reports, and generally will not be repeated here.
This notice relates only to the Secretary's May 2008 determination
based on a 2006 report of the National Academy of Sciences (NAS) and
prior NAS reports. Subsequent to the Secretary's May 2008
determination, NAS in 2009 issued a further report discussing
additional evidence concerning Veterans and Agent Orange. Based on that
2009 report, VA in March 2010 proposed to establish presumptions of
service connection based on herbicide exposure for three conditions
(Parkinson's disease, ischemic heart disease, and b-cell leukemias).
See 75 FR 14391 (Mar. 25, 2010). The discussion in this notice does not
in any way affect those proposed presumptions, but merely explains the
basis for the Secretary's prior May 2008 decision, as required by law.
FOR FURTHER INFORMATION CONTACT: Thomas Kniffen, Chief, Regulations
Staff, Compensation and Pension Service, Veterans Benefits
Administration, Department of Veterans Affairs, 810 Vermont Avenue,
NW., Washington, DC 20420, (202) 461-9725.
SUPPLEMENTARY INFORMATION: 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 NAS to review and summarize the scientific
evidence concerning the association 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 suspect
diseases and herbicide exposure, taking into account the strength of
the scientific evidence and the appropriateness of the methods used to
detect the association; (2) the increased risk of disease among
individuals exposed to herbicides during service in the Republic of
Vietnam during the Vietnam era; and (3) whether there is a plausible
biological mechanism or other evidence of a causal relationship between
herbicide exposure and the health outcome. Section 3 of Public Law 102-
4 also required that NAS submit reports on its activities every 2 years
(as measured from the date of the first report) for a 10-year period.
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 findings and analyses of the NAS and aspects of the
relevant studies, including the magnitude and the statistical
significance of the findings, their capability of replication, and
whether that study will withstand peer review.
[[Page 32542]]
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 effects.
Scope of This Notice
NAS issued its seventh report, entitled ``Veterans and Agent
Orange: Update 2006'' (Update 2006), on July 27, 2007. As required by
law, this notice explains a determination made by the Secretary in May
2008 that then-existing evidence, as summarized in Update 2006, did not
warrant a presumption of service connection for several specific
diseases. Among other things, this notice conveys the Secretary's
determination that the evidence and analysis in Update 2006 and prior
reports did not provide a basis for establishing presumptions of
service connection, based on herbicide exposure, for movement disorders
(including Parkinson's disease), ischemic heart disease, and leukemia
(other than chronic lymphocytic leukemia).
Subsequent to the May 2008 determination that is the subject of
this notice, VA in 2009 received another NAS report, entitled
``Veterans and Agent Orange: Update 2008.'' Based on the 2009 report,
the Secretary of Veterans Affairs has determined that presumptions of
service connection based on herbicide exposure are now warranted for
Parkinson's disease, ischemic heart disease, and b-cell leukemias, and
VA published a proposed rule in the Federal Register of March 25, 2010
(75 FR 14391) to establish such presumptions. We emphasize that nothing
in this notice affects the Secretary's more recent determination, based
on additional evidence and analysis by NAS, to establish presumptions
of service connection for those three diseases. The Secretary's May
2008 determinations are set forth here merely for the purpose of
providing public notice of those determinations as required by statute.
Update 2006
Consistent with its prior reports, NAS in Update 2006 found that
there was ``sufficient evidence of an association'' between herbicide
exposure and five categories of diseases in Veterans. VA has previously
established presumptions of service connection for each of these
diseases. See 38 CFR 3.309(e). NAS, in Update 2006, 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,
prophyria cutanea tarda; type 2 diabetes (mellitus); and spina bifida
in offspring of exposed people. VA has previously established
presumptions of service connection for each of these diseases, see 38
CFR 3.309(e), with the exception of spina bifida, for which VA pays a
monetary allowance under 38 CFR 3.814. NAS, in Update 2006,
additionally categorized AL amyloidosis and hypertension as having
limited or suggestive evidence of an association. VA recently
established a presumption of service connection for AL amyloidosis. See
74 FR 21258 (May 7, 2009).
NAS, in Update 2006, categorized certain health outcomes as having
inadequate or insufficient evidence to determine whether an association
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 tongue), pharynx (including lips
and tonsils), or 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; cancers of brain and nervous
system (including eye); endocrine cancers (thyroid, thymus, and other
endocrine); leukemia (other than CLL); cancers at other and unspecified
sites; neurobehavioral disorders (cognitive and neuropsychiatric);
movement disorders (including Parkinson's disease and ALS); chronic
peripheral nervous system disorders; respiratory disorders;
gastrointestinal, metabolic, and digestive disorders (changes in liver
enzymes, lipid abnormalities, and ulcers); immune system disorders
(immune suppression, allergy, and autoimmunity); ischemic heart
disease; circulatory disorders (excluding hypertension); endometriosis;
effects on thyroid homeostasis; certain reproductive effects, 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.
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 2006 review and 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 (May 20,
2007).
I. Cancer
Cancer of the Oral Cavity, Pharynx, or Nasal Cavity
NAS found that the new occupational studies of cancers of the oral
and nasal cavities or pharynx were generally small and so yielded
unstable estimates of risk. Integration of the evidence on this set of
cancers is challenging because different studies group cases
differently. Two studies of agricultural pesticide applicators found
significant decreases in certain oral cancers rather than excess risk
associated with exposure. Studies on Australian Vietnam Veterans showed
some increases in risk, but the results were not adjusted for
cigarette-smoking or alcohol use, both of which are known risk factors.
On the basis of its evaluation of the evidence reviewed in Update
2006 and in previous reports, NAS concluded that there was inadequate
or insufficient information to determine whether there is an
association between herbicide exposure and oral, nasal, and pharyngeal
cancers.
Lip Cancer
NAS evaluated lip cancer as a separate entity for the first time in
[[Page 32543]]
Update 2006 and found that the available studies suffered from certain
limitations. Some studies had very low specificity with respect to
exposure to the compounds of interest. NAS noted that these studies
defined exposure status almost exclusively in terms of occupation, and
even the determination of occupation usually could not be regarded as
rigorous.
Other studies used computer techniques to link records in
comprehensive databases, such as those matching entries in tumor
registries with compendiums of national censuses. NAS noted that these
studies amass large samples that may have the effect of inflating
power. Such investigations are useful for generating hypotheses, but
NAS noted that suggestive findings must be replicated by studies with
more refined designs that are capable of gathering more extensive
information about the subjects to use in adjusting for confounders.
NAS further noted that the certainty of the diagnostic categories
culled directly from death certificates or other databases may be
questionable and that diagnoses of lip cancer might overlap with non-
melanoma skin cancers in the sources from which the information was
gathered for the studies discussed.
NAS also noted the studies in question did not adjust for smoking
and sunlight exposure, as would be necessary before inferring that
agricultural chemicals played a role in any observed association in an
occupational group.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and lip cancer.
Tongue Cancer
NAS also evaluated tongue cancer as a separate category for the
first time in Update 2006, and concluded that interpretation of the
evidence on tongue cancer is constrained by the grouping of data on
them with data on other oral cancers. Most of the studies with
information on this specific tumor site observed only a small number of
cases and therefore had unstable estimates of risk.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and tongue cancer.
Tonsil Cancer
NAS noted that there is a paucity of findings specifically related
to tonsil cancer, because of the extreme rarity of this type of cancer
and its occurrence in an anatomic region whose cancers are generally
grouped fairly idiosyncratically. That the tissue type developing into
a neoplasm at this location might generate a carcinoma, a lymphoma, or
a sarcoma has further constrained NAS's ability to assemble a
meaningful body of evidence addressing risk factors for this unusual
type of cancer. NAS noted that further research, such as a case-control
protocol, would be needed to evaluate whether tonsil cancer is
associated with exposure to the herbicides used in Vietnam.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and tonsil cancer.
Cancer of the Pleura, Mediastinum, and Other Unspecified Sites Within
the Respiratory System and Intrathoracic Organs
NAS's default category for any health outcome for which no
epidemiologic research findings have been recovered has always been
``inadequate evidence'' of association, which in principle is
applicable to specific cancers. Cancers of the pleura, mediastinum, and
other unspecified respiratory cancers are rarely reported individually
and are not as yet seen for the chemicals of interest, reflecting the
paucity of information. NAS concluded there is inadequate or
insufficient information to categorize such a disease outcome.
Esophageal Cancer
NAS noted that previous updates did not review the risk of
esophageal cancer separately. In Update 2006, NAS concluded that the
epidemiologic studies of esophageal cancer to date yielded no evidence
of an increased risk associated with the compounds of interest,
although updates of the health status of the Australian Vietnam
Veterans presented an interesting but non-significant pattern of
increased risk of esophageal cancer. No toxicologic studies provide
evidence of biologic plausibility of an association between the
compounds of interest and tumors of the esophagus.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and esophageal cancer.
Stomach Cancer
NAS found that the risk of stomach cancers had not been reviewed
separately in previous updates. Among the newly reviewed studies, only
one reported a significant relationship, which was between stomach
cancer and the rather non-specific exposure of being a forestry worker.
The NAS noted some evidence of biologic plausibility in animal models,
but concluded that the epidemiologic studies to date do not support an
association between exposure to the compounds of interest and stomach
cancer.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and stomach cancer.
Colorectal Cancer
NAS found that previous updates had not reviewed the risk of
colorectal cancers separately. In Update 2006, NAS found no evidence to
suggest an association between the compounds of interest and colorectal
cancer in the epidemiologic studies reviewed to date. The only
significant increase in intestinal cancers noted in Update 2006 was a
reported result concerning cancer of the small intestine based on cases
in two exposed people. NAS explained that this is a very uncommon tumor
and was reported in Update 2006 with the more common cancers of the
large intestine and rectum for completeness of coverage. NAS found no
evidence of biologic plausibility of an association between exposure to
any of the compounds of interest and the development of tumors of the
colon or rectum. NAS concluded that the available evidence does not
support an association between the compounds of interest and colorectal
cancer.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and colorectal cancer.
Hepatobiliary Cancers
For Update 2006, NAS found that no new reports of a definitive link
between exposure to the compounds of interest and hepatobiliary tumors
were found. One study suggested a reduced risk of hepatic cancers in
Veteran populations, and one suggested an increased risk of cancer of
the gallbladder among forestry
[[Page 32544]]
workers. However, given the relatively low incidence of hepatobiliary
cancers in Western populations, NAS concluded that the evidence from
epidemiologic studies remains inadequate to link the compounds of
interest with hepatobiliary cancer.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and hepatobiliary cancer.
Pancreatic Cancer
NAS noted that one study reported increased rates of pancreatic
cancer among Australian Vietnam National Service Veterans, but that the
findings could be associated with increased rates of smoking and cannot
be attributed to exposure to the compounds of interest. NAS noted that
other reports have been largely negative.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and pancreatic cancer.
Bone and Joint Cancer
NAS reviewed results of several pertinent studies published since
the previous update. The studies either reported a non-significant
increase in risk of bone and joint cancer, observed too few events to
estimate relative risk (RR) adequately, or did not present data that
sufficiently linked observed results to specific compounds of interest
to this report. NAS concluded that the new results add little to the
previous body of results that, taken together, do not indicate an
association between exposure to the compounds of interest and bone
cancer.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and bone and joint cancer.
Skin Cancer-Melanoma
NAS found that new occupational studies were small and could not
provide stable estimates of RR associated with herbicide exposure. NAS
stated that the evidence from a number of studies of occupational and
environmental populations is inconsistent, but that significant
associations have been demonstrated in some studies of populations with
well-characterized exposures to the compounds of interest. NAS noted,
however, that the evidence of an association with melanoma in these
studies may be limited by the possibility of bias or chance. Further,
NAS noted that positive findings of a study of Australian Vietnam
Veterans are limited by internal inconsistency, and that an increase in
mortality reported by the Centers for Disease Control and Prevention
Vietnam Experience Study is consistent but too small to be considered
significant.
NAS stated that the results of the Air Force Health Study (AFHS)
have long been anticipated as the most directly pertinent to the
experience of US Vietnam Veterans, so NAS was impressed by recent
reports of a strong dose-response relationship between serum TCDD
concentrations and melanoma in this population. Some members of the
committee were concerned, however, that the findings of the AFHS have
not been presented in a complete and systematic fashion. Further, NAS
noted that the two recent Ranch Hand studies are based on diagnoses
rendered up to 1999 and 2003, respectively, but that there is some
indication that more recent melanoma diagnoses among the control
subjects greatly exceeds that of the Ranch Hands, which might produce
quite different results. NAS therefore endorses further evaluation and
longitudinal analysis of the entire data set on cancer outcomes
generated in the important AFHS population. NAS noted that, despite the
findings in the AFHS study, there was a persisting concern that there
was little suggestion of an association in other relevant populations.
After extensive deliberation concerning new evidence and the
results of studies reviewed in previous updates, NAS was unable to
reach consensus as to whether the evidence concerning an association
between herbicide exposure and melanoma met the criteria for being
considered limited or suggestive or whether this health outcome should
remain in the inadequate or insufficient classification primarily
because the suggestive findings are almost exclusively from the AFHS,
whose final data on both the Ranch Hand and comparison subjects have
not yet been analyzed in a satisfactory and uniform manner.
As indicated in prior NAS reports and reiterated in Update 2006,
occupational and environmental studies generally have not found a
significant increase in the risk of melanoma associated with herbicide
exposure, and the few significant findings are limited by
methodological concerns. In its 2004 report, NAS noted that a 2004
study by Swaen et al. of herbicide applicators in the Netherlands
reported a significantly increased incidence of all skin cancers, but
the data were limited because they could not distinguish the effects of
herbicide exposure from the significant confounding factor of sun
exposure, which was likely to be common among herbicide applicators. In
its 1996 update, NAS also noted that one occupational study of Danish
herbicide-production workers reported a significant increased incidence
of melanoma, but because of the small number of cases (4) and the lack
of adequate information in the study, it was not considered to provide
evidence of an association.
Although recent analyses of the Ranch Hand Veterans provides some
evidence of an association, as noted in Update 2006, the evidence
overall continues to weigh against an association. Occupational
exposures, particularly among herbicide-production workers are
ordinarily expected to exceed in duration and magnitude the types of
exposures that would be seen in Vietnam Veteran populations. As NAS
noted in Update 2006, the general lack of significant findings in
occupational studies is a relevant consideration in interpreting the
more recent findings concerning the Ranch Hand Veterans. Additionally,
based on the indications in Update 2006 that more recent data
concerning the Ranch Hand population could affect the findings of the
recent studies suggests that further inquiry is needed before
definitive conclusions can be drawn regarding the significance of those
findings.
Skin Cancer--Basal-Cell and Squamous-Cell Cancer (Non-Melanoma)
NAS found that the new results demonstrate only a small RR that is
not statistically significant, and the dose-response relationship also
is not statistically significant.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and basal-cell or squamous-cell cancer.
Breast Cancer
NAS reviewed several new studies concerning breast cancer in Update
2006 and, with one exception, found that they did not provide evidence
supporting an association between breast cancer and herbicide exposure.
NAS found that recent results from the Agricultural Health Study (AHS)
cohort
[[Page 32545]]
generally do not support the hypothesis that exposure to the compounds
in Agent Orange increases breast-cancer incidence or mortality in
women, although exposure to the specific compounds of interest was not
specified. NAS noted that recent studies of environmental exposure
found null associations, but that the exposures in some cases were of
questionable relevance. NAS further noted that two studies of
organochlorine concentrations in adipose tissue failed to find any
evidence of increased risk in association with higher adipose
concentrations; in fact, the more relevant study found the risk in the
highest tercile of dioxin concentrations in breast fat was lower than
in the lowest tercile of dioxin concentrations, although not
significantly so.
NAS found that one study published since the last update does
provide some evidence of an association between exposure to 2,4-D and
breast-cancer risk in female farm workers in California. The study is
limited by lack of detailed information on potential confounding
factors and lack of evidence of a dose-response relationship, but it is
large and the investigators were able to estimate individual exposures
by linking work histories to an extensive database on pesticide use.
NAS considered the new information in the context of the cumulative
data from studies reviewed in previous updates. NAS found that the
results of four prior studies lend support to the hypothesis that there
is an association between breast cancer and exposure to the compounds
of interest. However, each study has limitations or weaknesses that
keep its conclusions about the association in question from being
definitive.
NAS noted that the recent data from a 2005 study by Mills and Yang,
although not persuasive in themselves, lend additional weight to an
association between the relevant herbicide exposures and breast-cancer
risk. This study has reasonable size and relatively specific exposure
information but is limited chiefly by the data available to control for
confounding. Some members of the committee considered the body of
evidence as a whole to be suggestive of an association; for others, the
few modestly positive results associated with a diversity of exposures
suggested chance findings rather than a coherent picture. Further
laboratory and epidemiologic work on this association should be
pursued.
The main reason for the unresolved division in the NAS opinion
concerning the adequacy of the available evidence to support an
association between breast cancer and exposure to the components of the
herbicides sprayed in Vietnam was differing individual views about the
specificity and relevance of the studied exposures for the population
of primary concern to the committee, Vietnam Veterans. Overall, the
committee was impressed by the positive results from earlier studies
reviewed, but several members considered this a very small sample upon
which to anchor an association. The degree to which the profile of
chemicals contributing to total toxicity equivalency in the more
positive epidemiologic studies differed from that of Vietnam Veterans
diminished the conviction of some members that these results
constituted fully relevant evidence.
After extensive deliberation concerning the new evidence and the
results of studies reviewed in previous updates, NAS was unable to
reach consensus as to whether the evidence of an association between
exposure to the compounds of interest and breast cancer met the
criteria for being considered limited or suggestive or whether concerns
about chance, bias, and confounding remained so substantial that breast
cancer should remain in the inadequate or insufficient classification.
Relatively few studies provide evidence of a positive association
between herbicide exposure and breast cancer. As NAS noted, most of the
recent studies do not support an association, although some of the
studies are of questionable relevance and thus would not provide strong
evidence against an association. Of the five positive studies
identified by NAS, two are limited by potential confounding factors. As
noted above, the 2005 study by Mills and Yang lacked data to control
for confounding. A 2001 study by Revich et al. found an increased
mortality from breast cancer among persons exposed to dioxins from
working in or residing near a chemical plant, but the potential for
confounding exists because the subjects were exposed to a number of
other toxic chemicals. One of the positive studies, a 2000 Vietnam
Veteran study by Kang et al., reported an increase in breast cancer
among female Vietnam Veterans, but the result was not statistically
significant. The other two studies showed positive results, although
the NAS noted some limitations related to study size and relevance of
exposures. Although those studies provide some supportive evidence, the
overall weight of the current evidence does not support an association
between herbicide exposure and breast cancer.
Cancers of the Female Reproductive System
NAS found that two analyses of the same cohort found increased
incidence of and mortality from ovarian cancer in women who had been
engaged in pesticide application. The weight of those studies for the
present purposes is limited by the lack of detail on chemical exposures
and the absence of data that would allow for control of confounding.
Future studies of ovarian cancer should be watched carefully,
particularly studies that use biomarkers of exposure or more detailed
chemical-exposure histories.
On the basis of its evaluation of the evidence in Update 2006 and
in previous reports, NAS has concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and uterine, ovarian, or cervical cancer.
Testicular Cancer
NAS found that the evidence from epidemiologic studies is
inadequate to link herbicide exposure and testicular cancer. The
relative rarity of this cancer makes it difficult to develop risk
estimates with any precision. Most cases occur in men 25-35 years old,
and men who have received such a diagnosis could be excluded from
military service; this could explain the slight reduction in risk
observed in some Veteran studies.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and testicular cancer.
Bladder Cancer
NAS found that available analyses of an association between
exposure to the compounds of interest and bladder-cancer risk are
characterized by low precision because of the small numbers, low
exposure specificity, and lack of ability to control for confounding.
No new data have emerged since Update 2004 to alter the conclusion that
the cumulative evidence of such an association is inadequate or
insufficient.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and bladder cancer.
Renal Cancer
NAS found that available analyses of an association between
exposure to the
[[Page 32546]]
compounds of interest and renal-cancer risk are limited by the small
number of cases and lack of exposure specificity. No new data have
emerged since Update 2004 to alter the committee's conclusion that the
evidence is inadequate or insufficient to determine whether there is an
association.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and renal cancer.
Cancer of the Eye and Orbit
NAS found that most of the epidemiologic studies of findings on eye
cancer alone reported few or no cases, were of low power, and had
statistically non-significant results. The studies with the largest
numbers of cases did not indicate significant increases in risk
associated with herbicide exposure. Some analyses of the Australian
Vietnam Veterans showed excess risk, but it was probably due to excess
exposure to UV radiation, which was not adjusted for. It should be
noted that eye cancer is sometimes reported in a combined category with
brain cancers.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and eye cancer. Any future findings for this
cancer site will be tracked with results on brain cancer.
Brain Cancer
NAS found that since Update 2004, several relevant studies have
been identified, including cohort and case-control designs. Many
studies rely on surrogate indicators of exposure, such as occupational
titles, but several studies estimated exposure to one or more of the
compounds of interest on the basis of a job-exposure matrix or self-
reported exposure history. Most used cancer-registry data with a high
degree of diagnostic certainty. However, each study has limitations or
weaknesses that keep its conclusions about the association in question
from being definitive.
Most of the relevant prior cohort studies do not show substantial
risk differences from the null hypothesis, but this may reflect the
limited power of the cohort method to identify risk differences in rare
diseases, such as brain cancer. However, with the accumulation of
findings that deviate from consistency with the null hypothesis, the
present committee can no longer retain the original VAO committee's
conclusion that the available evidence is suggestive of no association.
On the basis of detailed evaluation of the epidemiologic evidence
from new and previously reported studies of populations with potential
herbicide exposure, NAS concluded that the categorization in prior
updates (limited or suggestive evidence of no association) should be
revised to inadequate or insufficient to determine whether there is an
association between herbicide exposure and brain cancer and other
nervous system cancers.
Endocrine Cancers
Update 2006 is the first to consider endocrine cancers as
constituting a separate cancer type. NAS found several relevant studies
that show low thyroid-cancer incidence and cancer mortality in various
populations. The studies assessed exposure to one or more of the
compounds of interest although the metrics often were based on
surrogate indicators or self-reported exposure. Some of the cohort
studies used cancer-registry data with a high degree of diagnostic
certainty. Several of the studies show somewhat increased risks of
thyroid or other endocrine cancers in association with the compounds of
interest. The two studies with any indication of statistical
significance both had mixed results. The authors were conducting
analyses on large samples whose exposure was no better characterized
than ``agricultural worker'' on a death certificate or census response,
whereas in a third study, the risks of endocrine cancers were lower in
phenoxy herbicide workers who also had exposure to TCDD. Most showed no
substantial risk differences in association with the compounds of
interest. Many of the studies had very small numbers of cases, and
their limitations preclude risk estimation. There were no significant
findings in Vietnam-Veteran studies. Thus, the studies reviewed do not
provide sufficient evidence to determine whether there is an
association between exposure to the compounds of interest and thyroid
cancer.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and thyroid or other endocrine cancers.
Leukemia (Other Than CLL)
NAS found that the new studies did not provide any new evidence of
an association between exposure to the compounds of interest and
leukemia.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that, at the time of Update
2006, there was inadequate or insufficient evidence to determine
whether there is an association between herbicide exposure and
leukemias other than CLL.
Acute Myelogenous Leukemia
NAS found that taken together, the occupational, environmental, and
Veteran studies are limited by the paucity of reports related to the
types of leukemia and to acute myelogenous leukemia (AML) in
particular. In concluding its review of the available findings related
to the occurrence of AML in Veterans exposed to the herbicides sprayed
in Vietnam, NAS notes the finding in Update 2000 of limited or
suggestive evidence of an association between exposure to the compounds
of interest and AML in the children of Vietnam Veterans and the
reversal of the finding in the report on AML. The recognition of an
error in a key publication and new information on the illness resulted
in reclassification of AML in children to inadequate evidence to
determine whether there is an association.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and AML.
Cancers at Other and Unspecified Sites
NAS' default category for any health outcome for which no
epidemiologic research findings have been recovered has always been
``inadequate evidence'' of association, which in principle is
applicable to specific cancers. Cancers at other and unspecified sites
are rarely reported individually and not as yet seen for the chemicals
of interest, reflecting the paucity of information. NAS concluded there
is inadequate or insufficient information to categorize such a disease
outcome.
II. Reproductive and Developmental Effects
Fertility
NAS found that although there is much evidence of the biologic
plausibility of disruption of male and female fertility by exposure to
the chemicals of interest, there continues to be a lack of substantive
epidemiologic data that demonstrate any association in human
populations.
[[Page 32547]]
On the basis of its evaluation of the evidence reviewed in Update
2006, NAS concluded that there is inadequate or insufficient evidence
of an association between herbicide exposure and altered hormone
concentrations, menstrual-cycle abnormalities, decreased sperm counts
or sperm quality, and sub-fertility or infertility.
Spontaneous Abortion
NAS found that no additional information was available to the
committee responsible for Update 2006 to motivate changing the
assessment of the last two committees. Given the age of the Vietnam-
Veteran cohort, it is highly unlikely that additional information on
this outcome among the population will appear.
In Update 2006, NAS concluded that paternal exposure to TCDD is not
associated with risk of spontaneous abortion and that insufficient
information is available to determine whether an association exists
between the risk of spontaneous abortion and maternal exposure to TCDD
or either maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or
cacodylic acid.
Stillbirth, Neonatal Death, and Infant Death
NAS found that the study reviewed for Update 2006 did not find
significant associations between the relevant exposures and rates of
infant or fetal deaths. The study was limited in that exposure was
based on environmental concentrations of dioxin and individual exposure
data were not obtained. Furthermore, several risk factors that could
confound associations between exposure and outcome were not assessed.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and stillbirth, neonatal death, or infant
death in offspring of exposed people.
Low Birth Weight and Preterm Delivery
NAS found that the three studies reviewed in Update 2006 did not
find an association between exposure to the compounds of interest and
the risk of low birth weight or prematurity. The two new weakly
significant findings may simply be spurious results arising among many
comparisons; a modest increase in average birth weight would not be
construed as an adverse effect, and the small decrease in average
gestation is of questionable biologic importance. Although the results
overall suggest a lack of an association, they should be interpreted
with caution because of some methodologic limitations, such as a long
recall period in the cohort study and exposure misclassification in the
environmental studies.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and low birth weight or preterm delivery in
offspring of exposed people.
Birth Defects (Other Than Spina Bifida)
NAS found only one new occupational study of birth defects and
exposures to the chemicals of interest, and the information generated
was too sparse to provide additional insights into the risks of birth
defects. Birth defects were addressed indirectly by a new environmental
study, which found an association between residence in the areas with
the highest soil dioxin concentrations and deaths before the first
birthday due to any congenital abnormality, but this relationship did
not carry over to deaths occurring in the first month or in the first
week of life.
Only one study addressed birth defects among the offspring of
female Vietnam War Veterans, who overall constitute fewer than 10,000
of the roughly 3 million U.S. Vietnam Veterans. NAS noted that, in
general, the relatively small number of offspring among Vietnam
Veterans seriously restricts the ability to detect statistically
significant increases in specific birth defects. In addition, as the
offspring of Veterans become older, the risk of diseases stemming from
congenitally transmitted defects that alter normal physiologic
function, such as endocrine and reproductive function, merits
increasing attention.
Another study reported a substantially greater strength of
association between exposure to Agent Orange and birth defects in the
studies of Vietnamese populations than in those of non-Vietnamese
populations. The non-Vietnamese study populations consisted of Vietnam
Veterans, who were almost exclusively men, whereas the Vietnamese
populations had a much greater likelihood of maternal exposure. This
study also conducted subgroup meta-analyses based on presumed exposure
intensity. Meta-analytic methods are the best approach to assessing the
overall import of the studies of exposures to the chemicals of interest
and the risk of specific birth defects. However, the numbers of cases
reported were too small to allow meta-analysis of specific types of
birth defects.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and birth defects (other than spina bifida)
in offspring of exposed people.
Childhood Cancer
NAS found that the studies reviewed for this update did not find
significant associations between the relevant exposures and childhood
cancers. As with other outcomes in the offspring of Vietnam Veterans,
the small number of these rare childhood cancers expected among the
circumscribed number of Vietnam Veterans would seriously hinder
detection of any actual increases. NAS reviewed newly available
occupational and environmental studies but found the value of these
studies to be limited by the questionable reliability of self-reported
exposures or other factors.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and childhood cancers in offspring of
exposed people.
III. Neurologic Disorders
Neurobehavioral (Cognitive and Neuropsychiatric) Disorders
NAS found that there is not consistent epidemiologic evidence of an
association between neurobehavioral disorders (cognitive or
neuropsychiatric) and Agent Orange exposure. Difficulties in case
identification and diagnosis, misclassification of exposures because of
a lack of contemporaneous measures, subject ascertainment and selection
bias, and uncontrolled confounding from many comorbid conditions are
common weaknesses in the studies reviewed. The variability of the test
results over time, the weak and inconsistent associations, and a lack
of consistent dose-response relationships also detract from evidence of
an association between the compounds of interest and neurobehavioral
disorders.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide
[[Page 32548]]
exposure and neurobehavioral disorders (cognitive or neuropsychiatric).
Movement Disorders, Including Parkinson's Disease
NAS found that epidemiologic studies have pursued various
occupational exposures as potential risk factors for Parkinson's
disease; pesticide use is among those receiving the most attention, but
it has rarely been possible to isolate the effects of selected chemical
herbicides, because exposures often are mixed and assessments usually
are retrospective, relying on such broad categories as ``ever exposed
to any pesticide,'' which is not considered informative for this
report. In addition, reported associations have been inconsistent, and
only rarely has evidence supported dose-response relationships. Thus,
the data are weakened for the committee's purposes by persistent
methodologic limitations and by the lack of specificity for the
compounds of interest.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that, at the time of Update
2006, there was inadequate or insufficient evidence to determine
whether there is an association between herbicide exposure and
Parkinson's disease.
Peripheral Neuropathy
NAS found that epidemiologic studies that used appropriate
comparison groups and standard techniques for diagnosis and assessment
of exposure have not demonstrated consistent associations between
exposure to the compounds of interest and the development of peripheral
neuropathy. Several reports have shown no significant association, and
in the reports that did indicate an association, chance, bias, or
confounding could not be ruled out with confidence. In particular,
diabetes might confound the results, inasmuch as many of the subjects
with neuropathy also had diabetes, which is a known cause of
neuropathy. Controlling for the effects of diabetes is a technical
challenge because there is evidence of an association between diabetes
and exposure to at least one of the compounds of interest; in many
cases, diabetes could be in the causal pathway that links exposure and
peripheral neuropathy.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and delayed or persistent peripheral
neuropathy.
IV. Other Health Effects
Respiratory Disorders
NAS found that results of the new studies of mortality from
nonmalignant respiratory diseases do not support the hypothesis that
herbicides increase mortality from them. The results of one study
showed a positive association, although it is based on only nine deaths
in the high-exposure area, and this finding could have been due to
chance or misclassification of causes of death. More important,
although it recognizes that mortality studies are limited by small
numbers of events and misclassification of causes of death, especially
respiratory conditions, NAS does not believe that scientific
conclusions can be based on health outcomes that are defined vaguely,
for example, by combining a wide array of disparate respiratory health
outcomes into one large category.
Two new cross-sectional studies have reported positive associations
between exposure and the prevalence of various chest conditions. The
nonspecificity of the types of respiratory conditions reported in one
of the two studies makes it exceedingly difficult to draw any
conclusions regarding specific respiratory conditions, and the lack of
observed association with serum TCDD concentrations also argues against
the existence of an association. The issue of nonspecificity is key to
interpreting this study. The results of a second study were weakened by
a definition of ``wheeze'' that was very broad and included any episode
in the year before administration of the questionnaire. Further, only
28 percent of subjects reporting this symptom also reported having
asthma or atopic conditions.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and the respiratory disorders specified.
Immune-System Disorders (Immune Suppression, Allergy, and Autoimmunity)
NAS found that TCDD is a well-known immunosuppressive agent in
laboratory animals. Therefore, one would expect that exposure of humans
to sufficiently high doses would result in immune suppression. However,
several studies of various measures of human immune function have
failed to reveal consistent correlations with TCDD exposure, and no
detectable pattern of increased infectious disease has been documented
in Veterans exposed to TCDD or other herbicides used in Vietnam.
Although suppression of the immune response by TCDD could increase the
risk of some cancers in Vietnam Veterans, there is no evidence to
support that connection.
Epidemiologic studies have been inconsistent with regard to TCDD's
influence on IgE production in humans (Update 2004). No animal or human
studies have specifically addressed the influence of TCDD on autoimmune
disease. One study of post-service mortality associated with various
causes showed no increase in deaths of Vietnam Veterans that could be
attributed to immune-system disorders.
Few effects of phenoxy herbicide exposure on the immune system have
been reported in animals or humans, and clear association between
phenoxy herbicide exposure and autoimmune or allergic disease has not
been found.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and immune suppression, allergy, or
autoimmune disease.
Lipid and Lipoprotein Disorders
NAS found that previously reviewed literature showed inconsistent
changes in serum lipids or lipoproteins after exposure to the compounds
of interest, and in most cases the sample sizes were insufficient to
support any conclusions. The recent report on Ranch Hand Veterans shows
that serum TCDD concentrations are positively associated with serum
triglycerides; however, even in Ranch Hand Veterans with the highest
TCDD exposure, the mean serum triglyceride concentration (130 mg/dL) is
well below that considered to be abnormal (250 mg/dL). It is notable
that the Ranch Hand Veterans with abnormally high serum triglycerides
tend to be those with the highest TCDD exposure.
Hypertriglyceridemia is considered to be a major risk factor for
acute pancreatitis when serum triglyceride concentrations exceed 1,000
mg/dL, and there is some evidence that it is an independent but weak
risk factor for ischemic heart disease at concentrations over 150 mg/
dL. More commonly, however, high serum triglyceride concentrations
(150-500 mg/dL) are considered to be a consequence of other underlying
diseases, particularly diabetes mellitus and metabolic syndrome, and
hypertriglyceridemia is a
[[Page 32549]]
well recognized marker of these diseases, especially when associated
with low high-density lipid (HDL) concentrations.
The VAO committee responsible for type 2 diabetes concluded that
there was limited or suggestive evidence of an association between type
2 diabetes mellitus and exposure to herbicides in Vietnam. Although the
latest Ranch Hand study adjusted the RR of hypertriglyceridemia for
smoking and body-mass index (BMI), it failed to account for the
presence of diabetes mellitus. Diabetes mellitus is strongly associated
with hypertriglyceridemia, as discussed above, so it is plausible that
the increased percentage of Ranch Hand Veterans with abnormally high
serum triglycerides may be a consequence of diabetes mellitus. In that
regard, the percentage of all Ranch Hand Veterans with a diagnosis of
diabetes mellitus (about 23 percent) could include the percentage with
hypertriglyceridemia (about 13 percent).
Hypertriglyceridemia itself was not considered a health outcome for
Update 2006, but it was recognized that its presence may indicate the
emergence of a more significant health concern, metabolic syndrome.
Metabolic syndrome is characterized by obesity, high triglycerides
(over 150 mg/dL), low HDL (under 40 mg/dL), hypertension (over 130/85
mm Hg), and high fasting plasma glucose or diagnosed diabetes mellitus.
As noted above, NAS previously concluded that there is suggestive
evidence of a link between exposure to herbicides in Vietnam and type 2
diabetes mellitus, whereas the Update 2006 has concluded that there is
suggestive evidence of a link between exposure to herbicides in Vietnam
and hypertension. Thus, an increasing number of Vietnam Veterans may be
exhibiting at least three of the diagnostic criteria for metabolic
syndrome: Hypertriglyceridemia, diabetes mellitus, and hypertension. It
will be important to analyze the incidence of those individual outcomes
as potential components of a larger disease syndrome.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and lipid or lipoprotein disorders.
Gastrointestinal, Metabolic, and Digestive Disorders (Changes in Liver
Enzymes, Lipid Abnormalities, and Ulcers)
In Update 2006, NAS noted there is no evidence that Vietnam
Veterans are at greatly increased risk for serious liver disease, and
reports of increased risk of abnormal liver-function tests have been
mixed. Although increased rates of gastrointestinal disease have not
been reported, the possibility of a relationship between dioxin
exposure and subtle alterations in the liver and in lipid metabolism
cannot be ruled out.
On the basis of its evaluation of the evidence reviewed in Update
2006 and in previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and gastrointestinal and digestive diseases.
Hypertension
In Update 2006, NAS concluded that there was ``limited or
suggestive evidence of an association between exposure to the compounds
of interest and hypertension.'' Prior NAS reports concluded that there
was inadequate or insufficient evidence to determine whether there was
an association between exposure to herbicides and any cardiovascular
diseases, including hypertension. Because Update 2006 suggests that the
evidence for an association between herbicide exposure and hypertension
is stronger than at the time of prior reports, hypertension warrants
close consideration.
As an initial matter, it must be noted that the NAS finding of
``limited or suggestive evidence of an association'' does not imply any
view by NAS as to whether the scientific evidence establishes a
``positive association'' between herbicide exposure and hypertension
within the meaning of 38 U.S.C. 1116(b). The NAS category of ``limited
or suggestive evidence'' is defined to mean that ``[e]vidence 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.'' Update 2006, at 11. NAS has
explained that, ``[f]or example, a well-conducted study with strong
findings in accord with less compelling results from populations with
similar exposures could constitute such evidence.'' Id. In contrast,
the ``positive association'' standard in 38 U.S.C. 1116(b)(1) and (3)
directs VA to determine whether ``the credible evidence for the
association is equal to or outweighs the credible evidence against the
association.'' In making that determination, VA must consider the NAS
reports and any other available evidence and must consider, with
respect to scientific studies, ``whether the results are statistically
significant, are capable of replication, and withstand peer review.''
38 U.S.C. 1116(b)(2). As NAS noted in a 2007 report, ``the IOM limited/
suggestive category covers a broad range of epidemiological evidence
from relatively weak to strongly suggestive,'' and the NAS
characterization thus cannot be viewed as determinative of the
``positive association'' determination VA is required to make.
Institute of Medicine, Improving the Presumptive Disability Decision-
Making Process for Veterans, at 98 (National Academies Press 2007).
VA has carefully reviewed the NAS findings and analyses in Update
2006 and prior reports. For the reasons explained below, VA has
determined that a positive association does not currently exist between
herbicide exposure and hypertension, but that Update 2006 does identify
significant new evidence that warrants careful consideration of
hypertension on an ongoing basis.
The finding in Update 2006 of ``limited or suggestive evidence''
for hypertension is based primarily upon one new Vietnam Veteran study,
which NAS found to be significant and consistent with results of other
lower quality studies. NAS also noted, however, that findings in other
studies suggested that hypertension is not associated with herbicide
exposure.
NAS found that a 2006 study by Kang et al. supported an association
between herbicide exposure and hypertension. That study assessed the
incidence of hypertension among 1,499 U.S. Army Chemical Corps (ACC)
Veterans who handled or sprayed Agent Orange in Vietnam and a control
group of 1,428 Veterans from the same era who did not serve in Vietnam.
The study found no significant difference in the rates of hypertension
between the two groups. However, when analysis was restricted to ACC
Veterans who served in Vietnam, Veterans who reported having sprayed
herbicides had a higher incidence of hypertension than those who did
not report spraying herbicides. Because there is some evidence that
type 2 diabetes, a condition that may cause hypertension, is associated
with herbicide exposure, the researchers separately evaluated the risk
of hypertension in only non-diabetic ACC Veterans and found that
hypertension was associated with herbicide spraying in non-diabetic
Veterans.
[[Page 32550]]
NAS found that this study had several strengths, including its
focus on one of the most highly exposed Vietnam Veteran cohorts. NAS
noted that exposure to TCDD was directly measured in one subset of the
ACC cohort. It also concluded that the study had the merit of
controlling for established risk factors for hypertension. NAS further
stated that, although the increased incidence of hypertension among ACC
sprayers was not large, it was consistent with the existence of several
other well-established contributors to the development of hypertension.
NAS noted that one limitation of this study is the potential for
information bias, inasmuch as the data on hypertension and on herbicide
spraying were self-reported. The study relied upon information provided
in telephone interviews in which the Veterans were asked whether a
physician had ever diagnosed them with hypertension and also requested
information as to whether they had sprayed or handled herbicides in
service. NAS felt that the potential information bias was diminished,
in part, because a patient is more likely to report accurately a
chronic disorder that requires continuing management, including
hypertension and diabetes. NAS noted that the researchers did not
attempt to verify self-reported hypertension by medical-record review,
but that they did seek to verify self-reports of diabetes and found the
self-reports verified in 79 percent of cases. NAS also noted the
potential for misclassification among exposure groups and the possible
recall bias that could lead to over-reporting of herbicide spraying
among men who have serious health conditions. NAS noted that, although
there is evidence that ex-sprayers were more likely to report several
health conditions besides hypertension, comparison within the ex-
sprayer subgroup according to serum TCDD concentration suggests that
recall bias does not fully explain the associations.
NAS noted that selection bias could arise from the cross-sectional
nature of the study, which accounts for disease prevalence only among
people in the original deployed and non-deployed ACC cohorts who were
still alive and participated. NAS concluded, however, that concern for
that type of selection bias is tempered by the high and nearly equal
rates of participation by deployed Veterans (72 percent) and non-
deployed Veterans (69 percent), and by the fact that the prevalence of
hypertension among the non-deployed Veterans (30 percent) was similar
to that among U.S. men of comparable age (32 percent). NAS stated that,
despite those data, it remains unknown whether the observed
relationship of spraying to the prevalence of hypertension is
equivalent to what one would have observed if the cohort had been
followed longitudinally. Nonetheless, because the primary population of
concern to VA is the current living cohort of Vietnam Veterans, the
findings from the study are particularly relevant.
NAS stated that the results of the Kang study are consistent with
those of other studies of Vietnam Veterans, including the other most
highly exposed cohort composed of Vietnam Veterans who served in
Operation Ranch Hand. NAS stated that multiple examination cycles of
the Air Force Health Study (AFHS) of those Veterans have consistently
reported an increase in the prevalence of hypertension with a doubling
of serum dioxin concentration. NAS stated that the analyses controlled
for the major risk factors for hypertension, and diagnosis was
confirmed with medical-record review. NAS noted that limitations of the
AFHS studies include the potential for selection bias and the variation
in the comparison group over examination cycles, but that selection
bias is reduced, in part, by the relatively high participation rates
across certain cycles. NAS stated that the Kang study is also
consistent with three other Veteran studies--a 1996 study of Australian
Veterans by O'Toole et al., a 1988 study of American Legion Vietnam
Veterans by Stellman et al., and a 1988 Vietnam experience study (VES)
by the Centers for Disease Control (CDC)--which NAS characterized as
reporting ``significant increases'' in the incidence of hypertension.
NAS noted, however, that only the Kang study controlled for potential
confounding variables and used an index of herbicide-related exposure.
NAS noted that there was also evidence weighing against an
association between herbicide exposure and hypertension. Specifically,
NAS noted that the key Vietnam Veteran ACC study was not consistent
with a previous study of herbicide factory workers exposed to TCDD that
failed to identify a significant association between measured TCDD and
hypertension after controlling for hypertension risk factors. NAS
stated that ``[t]he negative findings argue against an association
between TCDD exposure and hypertension,'' although it noted some
limitations in the study. Similarly, NAS noted that the ACC study was
not consistent with another recent environmental study examining the
prevalence of hypertension in relation to serum concentrations of PCDDs
and PCDFs in persons residing near a municipal waste dump. NAS stated
that this study ``showed that serum concentrations of dioxin-like PCDDs
and PCDFs are not associated with an increased incidence of
hypertension when major risk factors are adjusted for,'' although NAS
again noted certain limitations in the study. Accordingly, the report
identifies significant evidence both for and against an association
between herbicide exposure and hypertension.
We agree with NAS that the recent Kang study is a significant
addition to the scientific literature concerning herbicide exposure and
hypertension. However, we also note that a number of factors relating
to that and other positive studies cited by NAS limit the strength of
the evidence. The Kang study is limited in part because it is based on
unconfirmed self-reports of hypertension diagnoses. In other reports
provided to VA, NAS has noted the inherent limitations of studies based
on self-reports. For example, in a 2007 study of health effects of
deployment-related stress, NAS noted that some studies had found an
increase in hypertension related to deployment but that ``because most
are based on self-reports, not much reliance can be placed on them.''
Institute of Medicine, Gulf War and Health, Volume 6, Deployment-
Related Stress and Health Outcomes, at 193 (National Academies Press
2007).
In Update 2006, NAS noted that the potential bias of self-reports
was tempered because people are more likely to accurately recall and
report a chronic disease requiring continuous management, such as
hypertension and diabetes, and because the researchers had verified the
accuracy of 79 percent of the self-reported diagnoses of diabetes. The
seemingly conflicting views concerning the reliability of self-reported
hypertension present some difficulty in interpreting the evidence. We
note that there is some reason to believe that the potential error rate
in self-reported hypertension may be significant enough to impact the
study's findings. In its 1994 report on Veterans and Agent Orange, NAS
explained that in the CDC's 1988 VES study comparing hypertension
incidence in Vietnam Veterans and non-deployed Vietnam-era Veterans
``[a] significant difference in self-reported hypertension between the
groups was reported,'' but that ``there was no significant difference
in hypertension measured as part of a physical examination in the
study.'' Institute of Medicine, Veterans and Agent Orange; Health
Effects of
[[Page 32551]]
Herbicides Used in Vietnam, at 702 (National Academies Press 1994).
As noted above, the Kang study did find that 79 percent of self-
reported diabetes diagnoses were confirmed by medical record research,
and it is reasonable to believe that a similar verification rate would
exist for self-reported hypertension. That finding suggests that most
self-reports are accurate, but also acknowledges a potentially
significant margin of misreported diagnoses. The NAS report does not
address the potential impact that such misreported diagnoses could have
on the study.
We note also that the Kang study found no significant difference in
hypertension between Veterans who served in Vietnam and non-deployed
Vietnam era Veterans. This factor does not undermine the study's
finding of an increased risk of hypertension in the most highly exposed
group, although it might suggest that any association between herbicide
exposure and hypertension would be limited to certain high levels of
exposure.
The other Vietnam Veteran studies cited as consistent with the Kang
study also have a number of limitations. As noted above, NAS noted that
several cycles of the AFHS study have consistently reported an increase
in the prevalence of hypertension with a doubling of serum dioxin
concentration. However, the AFHS findings as reported in Update 2006
report increased risks that are relatively small and in most instances
are not statistically significant. Although the consistent findings of
increased risk may weigh in favor of an association, the low magnitude
of the findings and the general lack of statistical significance may
argue against an association or at least may be viewed as
indeterminate.
NAS indicated that the CDC's 1988 VES study found a significant
increase in the incidence of hypertension in Vietnam Veterans. As noted
above, however, that finding existed only with respect to self-reported
hypertension diagnoses, and was not supported by physical examinations.
Accordingly, in another recent report, NAS characterized the CDC study
as finding that the prevalence of hypertension was ``not significantly
higher'' in Vietnam Veterans as compared to non-deployed Vietnam-era
Veterans. Institute of Medicine, Gulf War and Health, Volume 6,
Deployment-Related Stress and Health Outcomes at 185 (National
Academies Press 2007).
NAS discussed the 1996 O'Toole study in Veterans and Agent Orange:
Update 1998. The study involved a simple random sample of Australian
Vietnam Veterans' self-reported health status information in relation
to the Australian public. The study found a significant increase in
self-reported hypertension among the Vietnam Veterans. Because the
study was based on self-reports, it is subject to some of the same
concerns discussed above in relation to the Kang study. More
significantly, the results apparently do not control for confounding
factors. In fact, the study found that the Veterans were significantly
more likely than the control population to be current or former smokers
and to report high alcohol consumption. The lack of controls for
potentially significant risk factors known to exist in the study
population significantly limits the weight of this study for present
purposes.
NAS discussed the 1988 Stellman study in its 1994 Veterans and
Agent Orange report. That study was also based on self-reports of
hypertension diagnoses. The report found no significant differences in
the prevalence of hypertension in Vietnam Veterans and non-deployed
Vietnam-era Veterans. It did, however, find a significant increase in
self-reported hypertension in Vietnam Veterans who handled herbicides
as compared to Vietnam Veterans who did not. NAS noted that the
conclusions to be drawn from the study are limited by the potential for
misclassification of exposure and the lack of validation of self-
reported diagnoses. As noted above, the potential for misreporting of
hypertension diagnoses limits the strength of the reported data on
association.
Further, in update 2006, NAS acknowledged that the CDC, O'Toole,
and Stellman studies did not control for potentially confounding
variables. These variables may include alcohol or tobacco use, body
mass index or obesity, and type 2 diabetes. The failure to control for
confounding factors renders it difficult to draw significant
conclusions from the reported data. In Update 2006, for example, NAS
noted that a 2006 environmental study by Chen et al. based on self-
reported data initially found a more than five-fold increase in the
risk of hypertension associated with elevated serum PCDD and PCDF
concentrations in persons who lived near municipal-waste incinerators;
however, when the results were controlled for age, sex, smoking status,
and body mass index, the results showed that the study population
actually had a decreased risk of hypertension.
NAS identified a number of studies finding no association between
herbicide exposure and hypertension. Among Vietnam Veteran studies, a
2005 study by Ketchum and Michalek of mortality of Ranch Hand Veterans
found no significant increase in mortality from hypertension. As noted
above, although the CDC's 1988 Vietnam Experience Study found a
significant increase in self-reports of hypertension, physical
examinations did not show any differences in increased blood pressures,
which argues against an association.
The two environmental studies cited by NAS showed no increased risk
of hypertension. As noted above, the 2006 study by Chen et al. found
that persons residing for at least 5 years near a municipal-waste
incinerator and who had elevated serum PCDD and PCDF concentrations did
not have any increased risk of hypertension. This study has the
strength of controlling for confounding factors, although NAS noted a
potential limitation in the lack of information on the criteria for
diagnosing hypertension. A 2001 study by Bertazzi et al. of mortality
among persons exposed to TCDD as the result of an accident in Seveso,
Italy, found no increased mortality due to hypertension.
Occupational studies identified by NAS generally found no increased
risk of hypertension in exposed populations. A 2005 study by `t
Mannetje et al. of mortality rates among New Zealand workers exposed to
phenoxy herbicides and dioxins found no increased mortality due to
hypertension. A 1998 study by Calvert et al. of workers exposed at two
U.S. herbicide factories did not find any significant increase in the
risk of hypertension. This study controlled for risk factors and
included exposure information based on serum TCDD levels, although NAS
noted potential limitations in that some of the information on
hypertension was based on self-reports and the overall response rate
was low, which could contribute to selection bias. A 1984 study by
Suskind and Hertzberg of circulatory disorders among workers at an
herbicide production plant found no significant differences in rates of
self-reported hypertension associated with exposure. A 2000 study by
Kitamura et al. of workers at a municipal-waste incinerator found no
significant increase in self-reported hypertension associated with
elevated serum PCDD levels. Several other studies found no significant
increase in circulatory disorders, including hypertension, in persons
occupationally exposed to herbicides, but these studies are less
helpful because they do not specifically isolate findings concerning
hypertension.
[[Page 32552]]
The consistently negative findings in the occupational studies
identified to date is of interest because, as NAS has noted (Update
2006 at 38), at least in studies of chemical-production workers, the
magnitude and duration of exposures in occupational studies generally
would be greater than in Vietnam Veteran studies. Accordingly, if the
increase in self-reported hypertension observed in the recent Kang
study is attributable to herbicide exposure, one would expect similar
findings in occupational studies of herbicide-production workers.
In summary, the available occupational and environmental studies to
date have consistently failed to detect a significant association
between herbicide exposure and hypertension. The available Vietnam
Veteran studies have produced a mixture of positive and negative
findings, as well as findings that are essentially indeterminate in
that they report low-magnitude increases that are not statistically
significant. The primary evidence in favor of an association is the
recent study by Kang et al. Other Vietnam Veteran studies reporting a
significant increased risk of hypertension are limited primarily by
concern of control for confounding factors. Viewing the evidence as a
whole and taking into account the considerations discussed above, the
Secretary has determined that the credible evidence for an association
between hypertension and herbicide exposure is not equal to nor does it
outweigh the credible evidence against an association. Therefore, he
has determined that a positive association does not exist. In view of
the suggestive findings in the recent Kang study, VA will continue to
closely monitor further developments regarding the possible association
between herbicide exposure and hypertension.
Circulatory Disorders
NAS found that circulatory diseases constitute a group of diverse
conditions, of which hypertension (addressed above), coronary heart
disease, and stroke are the most prevalent, that account for 75 percent
of mortality from circulatory diseases in the United States. The major
quantifiable risk factors for circulatory diseases are similar to those
for hypertension and include age, race, smoking, serum cholesterol, BMI
or percentage of body fat, and diabetes.
NAS found that reported results of new morbidity and mortality
studies of the most highly exposed Vietnam-Veteran cohorts (ACC and
Operation Ranch Hand) were not entirely consistent. NAS noted that ACC
Veterans who sprayed Agent Orange reported a significant increase in
the prevalence of heart disease, primarily ischemic heart disease, but
that the AFHS did not find the prevalence of heart disease, myocardial
infarction, or stroke to be significantly associated with either
current or back-extrapolated serum TCDD concentrations in Ranch Hand
Veterans. NAS stated that one study found a significant increase in
mortality due to atherosclerotic heart disease in Ranch Hand ground
crew personnel, but the increase in mortality from circulatory disease
among all Ranch Hand Veterans based on back-extrapolated serum TCDD was
not significant.
NAS also noted that several new occupational studies reported no
significant increase in risk of circulatory disorders, including
ischemic heart disease, associated with herbicide exposure; in fact,
two new studies found that the risk of certain circulatory disorders
was significantly lower in the exposed populations.
NAS noted that some previously reviewed studies of herbicide
factory workers occupationally exposed to TCDD reported findings
supporting an association between herbicide exposure and heart disease.
Those findings came primarily from mortality studies in which the
researchers did not have access to information concerning the impact of
potentially confounding risk factors. NAS noted that, in the studies
that did have information on potential confounders, the cardiovascular
health endpoints were described imprecisely and did not clearly
distinguish ischemic heart disease from other conditions. Viewing those
prior studies in relation to the new findings from the studies of ACC
and Ranch Hand Veterans, some members of the NAS committee felt that
there was limited/suggestive evidence of an association between
herbicide exposure and ischemic heart disease. Other members of the
committee, however, felt that the lack of information on potential
confounders limited the strength of many of the studies and that the
evidence remained inadequate or insufficient to determine whether an
association exists between herbicide exposure and ischemic heart
disease. For all other types of circulatory disease, the committee
agreed that the evidence is inadequate or insufficient to determine
whether there is an association with exposure to the compounds of
interest.
Upon consideration of Update 2006 and prior NAS reports, the
Secretary in May 2008 determined that the then-existing credible
evidence for an association between circulatory disorders and herbicide
exposure was not equal to nor did it outweigh the credible evidence
against an association. Therefore, he determined that a positive
association was not established at that time. Although Update 2006
found some evidence supporting an association between herbicide
exposure and ischemic heart disease, there was also significant
evidence against an association, including several studies that found
no significant increased risk of the disease and at least one that
found a significantly decreased risk. Further, a number of the studies
reporting a significant increase in mortality due to ischemic heart
disease were unable to consider potential confounding factors, a
concern that limits the strength of the reported data.
As stated previously, based upon the NAS report ``Veterans and
Agent Orange: Update 2008,'' the Secretary, on October 13, 2009,
announced his decision to establish a presumption of service connection
between exposure to herbicides and the subsequent development of hairy
cell leukemia (HCL) and other chronic B cell leukemias, Parkinson's
disease, and ischemic heart disease. See 75 FR 14391 (Mar. 25, 2010).
Endometriosis
In prior reports, NAS evaluated five studies relevant to
endometriosis. It found that three environmental studies reported no
increased incidence of endometriosis associated with herbicide exposure
and that two case-control studies reported elevated odds ratios but had
very wide confidence intervals that precluded statistical significance.
In Update 2006, NAS identified two new environmental studies, both of
which reported significant increases in the incidence of endometriosis
in the populations exposed to dioxin-like PCBs. NAS noted, however,
that one of the studies was limited because it was unable to
differentiate the effects of the dioxin-like PCBs and non-dioxin-like
PCBs to which the subjects were exposed.
On the basis of its evaluation of the evidence reviewed in Update
2006 and previous reports, NAS concluded that there is inadequate or
insufficient evidence to determine whether there is an association
between herbicide exposure and endometriosis.
Effects on Thyroid Homeostasis
NAS noted that numerous animal experiments and several
epidemiologic studies have shown that TCDD and dioxin-like compounds
appear to exert an influence on thyroid homeostasis. Specifically,
those compounds may
[[Page 32553]]
affect the secretion of thyroid-stimulating hormone (TSH), which
governs the function of the thyroid gland in secreting the hormones T3
and T4. In prior reports, NAS noted that several human studies observed
an increase in TSH levels associated with TCDD exposure, but without a
corresponding increase in T4 levels, suggesting that the human body was
able to adapt to any effect on TSH production. In Update 2006, NAS
noted that, in the newly identified studies of adults, there was lack
of correlation between dioxin-like compounds and TSH concentrations.
Likewise, NAS noted that, in the newly identified studies of changes in
thyroid homeostasis in relation to fetal and infant development, there
were not significant associations between magnitude of exposure to
dioxin or dioxin-like compounds and measures of thyroid function. NAS
concluded that the studies continue to suggest that people were able to
adapt to changes in thyroid status that might have been induced by
exposure to TCDD and other dioxin-like compounds.
NAS concluded that there is inadequate or insufficient evidence of
an association between exposure to the compounds of interest and
clinical or overt adverse effects on thyroid homeostasis. Although some
effects have been observed in humans, the functional importance of the
changes reported in the studies reviewed remains unclear, because
adaptive capacity could be adequate to accommodate them.
AL Amyloidosis
In Update 2006, the NAS found there was limited or suggestive
evidence of an association between herbicide exposure and AL
amyloidosis. We are not addressing AL amyloidosis in this Notice
because a presumption of service connection has been established for
this disease. VA published a final rule providing a presumption of
service connection for AL amyloidosis for any Veteran exposed in
service to an herbicide agent who develops the disease at any time
after separation from service in the Federal Register on May 7, 2009,
at 74 FR 21258.
Conclusion
NAS reviewed scientific and medical articles published since the
publication of its first report as an integral part of the process that
resulted in ``Veterans and Agent Orange: Update 2006.'' The
comprehensive review and evaluation of the available literature that
NAS conducted in conjunction with its report has permitted VA to
identify all conditions for which the current body of knowledge
supports a finding of a positive association with herbicide exposure.
The Secretary's determinations regarding the diseases discussed in
Update 2006 are based upon the NAS's identification and analysis of the
relevant scientific and medical literature in Update 2006, as
summarized above, and the additional analyses set forth in this notice,
viewed in relation to prior relevant NAS reports and VA's prior notices
addressing these matters.
Taking account of the available evidence and NAS's analysis, the
Secretary in May 2008 found that the evidence and analysis available to
VA at that time did not warrant a presumption of service connection for
cancers of the oral cavity (including lips and tongue), pharynx
(including tonsils), or 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; cancers of brain and nervous
system (including eye); endocrine cancers (thyroid, thymus, and other
endocrine); leukemia (other than CLL); cancers at other and unspecified
sites; neurobehavioral disorders (cognitive and neuropsychiatric);
movement disorders (including Parkinson's disease and ALS); chronic
peripheral nervous system disorders; respiratory disorders;
gastrointestinal, metabolic, and digestive disorders (changes in liver
enzymes, lipid abnormalities and ulcers); immune system disorders
(immune suppression, allergy and autoimmunity); ischemic heart disease;
circulatory disorders (including hypertension); endometriosis; effects
on thyroid homeostasis; certain reproductive effects, 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, childhood cancer (including acute
myelogenous leukemia) in offspring of exposed people; and any other
condition for which the Secretary has not specifically determined a
presumption of service connection is warranted. That determination was
based on a finding that the then-existing credible evidence against an
association between herbicide exposure and the cited conditions
outweighed the credible evidence for such an association and that a
positive association therefore did not exist.
Approved: May 28, 2010.
John R. Gingrich,
Chief of Staff, Department of Veterans Affairs.
[FR Doc. 2010-13653 Filed 6-7-10; 8:45 am]
BILLING CODE 8320-01-P