[Federal Register Volume 79, Number 70 (Friday, April 11, 2014)]
[Notices]
[Pages 20308-20313]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-07950]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF VETERANS AFFAIRS
Determinations Concerning Illnesses Discussed in National Academy
of Sciences Report: Veterans and Agent Orange: Update 2012
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: As required by law, the Department of Veterans Affairs (VA)
hereby gives notice that the Secretary of Veterans Affairs, under the
authority granted by the Agent Orange Act of 1991, codified at 38
U.S.C. 1116, has determined that there is no basis to establish a
presumption of service connection at this time, based on exposure to
herbicide agents, including the substance commonly known as Agent
Orange, for several health effects discussed in the December 4, 2013,
National Academy of Sciences (NAS) report titled: Veterans and Agent
Orange: Update 2012 (hereinafter, ``Update 2012''). This determination
does not in any way preclude VA from granting service connection for
any disease, including those specifically discussed in this notice, nor
does it change any existing rights or procedures.
FOR FURTHER INFORMATION CONTACT: Michael Ford, Regulatory Specialist
(10B4), Office of Regulatory and Administrative Affairs, Veterans
Health Administration, Department of Veterans Affairs, 810 Vermont
Avenue NW., Washington, DC 20420, email [email protected].
SUPPLEMENTARY INFORMATION:
I. Statutory Requirements
The Agent Orange Act of 1991, Public Law 102-4 (codified in part at
38 U.S.C. 1116), directed the Secretary to seek to enter into an
agreement with the National Academy of Sciences (NAS) to conduct a
comprehensive review of scientific and medical literature on potential
health effects of exposure to Agent Orange. Congress mandated that NAS
determine, to the extent possible: (1) Whether there is a statistical
association between suspect diseases and herbicide exposure, taking
into account the strength of the scientific evidence and the
appropriateness of the scientific methodology used to detect the
association; (2) the increased risk of disease among individuals
exposed to the herbicides during service in the Republic of Vietnam
during the Vietnam era; and (3) whether a plausible biological
mechanism or other evidence of a causal relationship exists between
exposure to herbicides and suspect disease.
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.
Although 38 U.S.C. 1116 does not define ``credible,'' it does
instruct the Secretary to ``take into consideration whether the results
[of any study] are statistically significant, are capable of
replication, and withstand peer review.'' The Secretary reviews studies
that report a positive relative risk and studies that report a negative
relative risk of a particular health outcome. He then determines
whether the weight of evidence supports a finding that there is or is
not a positive association between herbicide exposure and the
subsequent health outcome. The Secretary does this by taking into
account the statistical significance, capability of replication, and
whether that study will withstand peer review. Because of differences
in statistical significance, confidence levels, control for confounding
factors, bias, and other pertinent characteristics, some studies are
more credible than others. The Secretary gives weight to more credible
studies in evaluating the overall evidence concerning specific health
outcomes.
II. Prior NAS Reports
NAS has issued ten previous biennial reports under the Agent Orange
Act. Based on those reports and the requirements of the Agent Orange
Act, VA has established presumptions of service connection for 14
categories of disease, which are listed at 38 CFR 3.309(e).
Additionally, following each prior NAS report, VA has published a
notice explaining the Secretary's determination that presumptions of
service connection are not warranted for several diseases discussed in
those reports. Those notices are published at: 59 FR 341 (Jan. 4,
1994), 61 FR 41442 (Aug. 8, 1996), 64 FR 59232 (Nov. 2, 1999), 67 FR
42600 (June 4, 2002), 68 FR 27630 (May 30, 2003), 72 FR 32395 (May 20,
2007), 75 FR 32540 (June 8, 2010), 75 FR 81332 (Dec. 27, 2010), and 77
FR 47924 (Aug. 10, 2012). 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 prior NAS reports, as
discussed in VA's prior Federal Register notices, and upon the
additional information and analysis in Update 2012, as discussed below.
III. Veterans and Agent Orange: Update 2012
On December 4, 2013, NAS publicly released Veterans and Agent
Orange: Update 2012, which describes the relevant scientific and
medical evidence identified subsequent to the last prior NAS review,
Veterans and Agent Orange: Update 2010 (hereinafter, ``Update 2010'').
NAS reviewed, evaluated, and summarized scientific and medical
literature addressing several conditions and the health status of
Veterans.
Consistent with its prior reviews, NAS concentrated its review on
epidemiologic studies to fulfill its charge of assessing whether
specific human health effects are associated with exposure to at least
one of the herbicides utilized or to a chemical
[[Page 20309]]
component of herbicides, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-
dioxin; referred to as TCDD to represent a single--and the most toxic--
congener of the tetrachlorodibenzo-p-dioxins, also commonly referred to
as dioxin). NAS also considered controlled laboratory investigations
that provided information on whether the association between the
chemicals of interest and a given effect is biologically plausible.
In Update 2012, NAS endeavored to emphasize and clarify the
relationship among the succession of publications that have provided
ever increasing insight into the health responses of particular exposed
populations that have been studied for many years. The information that
the present Committee reviewed was identified through a comprehensive
search of relevant databases, including databases covering biologic,
medical, toxicologic, chemical, historical, and regulatory information.
NAS conducted a comprehensive search of all medical and scientific
studies on health effects of herbicides used in the Vietnam War,
including more than 6,800 potentially relevant studies. Of this group,
NAS selected 1,100 studies for careful review. It ultimately identified
61 epidemiologic studies as well as several score of toxicologic
studies and exposure evaluations that contributed new information.
Relevant animal studies, as with previous biennial ``Agent Orange
Updates,'' were also reviewed to determine biological plausibility and
possible mechanisms of action.
The epidemiologic information evaluated in Update 2012 was
integrated with that previously assembled including Veterans studies,
occupational studies, and environmental studies. NAS noted that few
studies concerning the health of Vietnam Veterans were identified as
having been published since the studies evaluated in Update 2010, and
almost all addressed mental health issues that are not within the scope
of its report. There were no new studies of Vietnam Veterans and only a
single case-control study on Vietnam era South Korean Veterans with
cardiac disease, some of whom had served in Vietnam. This study
examined whether a history of Vietnam service is associated with the
clinical course of coronary disease, not with the occurrence of
coronary disease itself.
Since Update 2010, several occupational studies have been published
which may show potential health effects of herbicide exposure. For
instance, studies focused on cancer mortality in pentachlorophenol
(PCP) workers who are part of the National Institute for Occupational
Safety and Health (NIOSH) cohort, and cancer incidence in a NIOSH
subcohort of chemical workers in a Dow Chemical Company plant in
Michigan. Another study investigated plasma dioxin concentrations and
cause-specific mortality in German production workers in a plant
included in the International Agency for Research on Cancer (IARC)
cohort in Hamburg, Germany. Three new studies of IARC subcohorts in the
Netherlands that collectively reported on cancer mortality, ischemic
heart disease, humoral immunity, atopic disease, and immune suppression
in herbicide workers. The incidence of gliomas in pesticide appliers in
participants in the Upper Midwest Health Study was reviewed. Also,
eight reports from the Agricultural Health Study (AHS) examined cancer
incidence, body-mass index, amyotrophic lateral sclerosis, and
mortality in private pesticide applicators (farmers), their spouses,
and commercial pesticide applicators in Iowa and North Carolina.
Since Update 2010, numerous studies on environmental exposures to
chemicals of interest have been published. Researchers reported on
cancer incidence and reproductive factors in people who lived near the
site of the industrial accident in Seveso, Italy. Five new studies
published by the Prospective Investigations of the Vasculature in
Uppsala Seniors (PIVUS) group reported on stroke, atherosclerosis,
diabetes, and obesity. Several new studies from Taiwan examined
hypertension, cardiovascular disease, and insulin resistance in people
who lived in the vicinity of a closed PCP factory. Other studies looked
at hypertension, bone mineral density, and environmental exposures via
the National Health and Nutrition Examination Survey, and diabetes and
hypertension in the Anniston (Alabama) Community Health Survey. Another
study focused on reproductive outcomes in mother-infant pairs exposed
to TCDD and other chemicals that have dioxin-like biologic activity in
Japan, Finland, the Netherlands, United States, and Vietnam. New case-
control studies examined environmental exposures to the chemicals of
interest and several types of cancer, myelodysplastic syndromes,
endometriosis, menstrual cycles, and Parkinson's disease.
As in its prior reports, NAS placed each health outcome it reviewed
in one of four categories based on the strength of the evidence of
association between herbicide exposure and the health outcome. The four
categories are: Sufficient Evidence of Association; Limited or
Suggestive Evidence of Association; Inadequate or Insufficient Evidence
to Determine Whether an Association Exists; and Limited or Suggestive
Evidence of No Association. VA has established presumptions of service
connection for all diseases NAS placed in the first category and for
most of the diseases NAS placed in the second category. However, VA
will not establish a presumption of service connection for a condition
solely on the basis that NAS has placed the condition in one of the two
highest categories of association used by NAS. Rather, each condition
is considered individually, based on available evidence, and informed
by conclusions and recommendations of NAS. The ``limited or suggestive
evidence'' category used by NAS may encompass a potentially wide range
of evidentiary circumstances, and NAS' placement of a disease in that
category is not intended to express any view on policy matters or on
the outcome of VA's application of the ``positive association''
standard prescribed by 38 U.S.C. 1116(b). This notice explains the
basis for VA's determination that no new presumptions of service
connection are warranted for the diseases discussed in Update 2012.
Limited or Suggestive Evidence of an Association
NAS has defined this category of association to mean that the
``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.''
Hypertension
NAS placed hypertension in the ``Limited or Suggestive Evidence of
Association'' category. Hypertension affects more than 70 million adult
Americans and is a major risk factor for coronary artery disease,
myocardial infarction, stroke, and heart and renal failure. A recent
study of the Framingham cohort (The Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure 2004) showed that in both 55 and 65-year-old
participants, the cumulative lifetime risk for the development of
hypertension (at or above 140/90 mm Hg, regardless of treatment) was 90
percent. The lifetime risk statistic is the probability that an
individual will develop a disease over a lifetime. Major risk factors
are well established and include tobacco use, diet, physical
inactivity, obesity, diabetes mellitus, alcohol, and heredity.
[[Page 20310]]
In its reports prior to 2006, NAS placed hypertension in the
``Inadequate or Insufficient Evidence'' category. In Veterans and Agent
Orange: Update 2006 (hereinafter, ``Update 2006''), Update 2008, and
Update 2010, NAS elevated hypertension to the ``Limited or Suggestive
Evidence'' category, but could not clearly distinguish the possibility
of a small increased risk for hypertension due to herbicide exposure
from more prevalent scientifically established risk factors in
evaluating the risk to individual Veterans. NAS noted the limitations
of the studies regarding hypertension. In the Federal Register of June
8, 2010, December 27, 2010, and August 10, 2012, VA explained why the
studies reviewed in Update 2006, Update 2008, and Update 2010 did not,
in VA's view, warrant a presumption of service connection for
hypertension in Veterans exposed to herbicides in service. 75 FR 32540
(June 8, 2010), 75 FR 81332 (Dec. 27, 2010), and 77 FR 47924 (Aug. 10,
2012).
NAS identified no Vietnam Veteran studies addressing exposure to
the chemicals of interest and hypertension published since Update 2010.
One group of researchers performed a retrospective study of outcomes of
Vietnam-era South Korean Veterans undergoing coronary angiography
because of acute coronary syndrome according to whether they served or
did not serve in Vietnam. This study examined whether a history of
Vietnam service is associated with the clinical course of coronary
disease, not with the occurrence of coronary disease itself. NAS
concluded that this study was not helpful in assessing whether
herbicide exposure was a factor in the development of hypertension.
Medical research studies related to Agent Orange generally fall
into one of three categories--environmental studies, occupational
studies, and case-control studies. Environmental studies focus on
exposure outside of the workplace (i.e., in the surrounding
environment), usually due to an industrial incident or accidental
release of Agent Orange or other related chemicals of interest.
Occupational studies focus on workplace exposure to Agent Orange or
related chemicals of interest. Case-control studies identify
individuals with the health outcome of interest (cases) and individuals
without the health outcome (controls), then compare the exposure
experience (often self-reported) of the two groups.
NAS did not identify any occupational studies or case-control
studies of exposure to chemicals of interest and hypertension published
since Update 2010.
In Update 2012, NAS identified three environmental studies
published since Update 2010 focusing on environmental exposure to
chemicals of interest and hypertension. Researchers reported findings
from the cross-sectional sample of residents of Taiwan living in an
area with a high level of industrial contamination from various
compounds including dioxins, furans, and mercury. This study updated
and extended an earlier report discussed in Update 2010. The updated
report extended the survey period for an additional 7 months increasing
the number of surveyed residents from 1,478 to 1,812. Data were
reviewed using factor analysis and multivariate models. Factor analysis
was used to determine which components of metabolic syndrome appeared
to be most strongly associated with dioxin toxic equivalency
concentrations, based on serum dioxin and furan levels. The authors of
the study concluded that dioxin toxic equivalencies were more strongly
associated with blood pressure than other syndrome components. Based on
multivariate analysis, the researchers concluded that there was a
highly statistically significant association between toxic equivalency
concentrations and diastolic blood pressure but not systolic blood
pressure after adjustment for age, sex, obesity, smoking status,
alcohol use, and family history of hypertension or diabetes.
NAS considered the strengths and weaknesses of the study. It stated
that the strengths of the study are the large number of potential
confounding variables addressed and the clear exposure to the chemicals
of interest. The weaknesses are that it is a cross-sectional survey
which precludes making a strong causal inference since the temporal
relationship between exposure and the outcome is unknown. Additionally,
NAS noted that surveys are prone to selection factors that may bias
relationships between exposures and outcomes.
Another study examined data on 394 residents of Anniston, Alabama,
who were living in an area with high levels of polychlorinated
biphenyls (PCB). The purpose of the study was to determine the
relationship between blood pressure and serum concentrations of 35 PCBs
and nine chlorinated pesticides. Individuals taking antihypertensive
medications were excluded from the study. The authors concluded that,
other than age, total serum PCB concentrations were the strongest
correlate of blood pressure after adjustment for age, body mass index,
sex, race, smoking status, and exercise. They saw a weak, not
statistically significant, association between blood pressure and mono-
ortho PCBs. PCBs with more potent dioxin-like activity were not
measurable within the limits of the assay used. NAS concluded that this
study shares strengths and weaknesses with the Taiwanese survey, but
exposures to chemicals of interest and specifically TCDD were lower in
the Alabama sample.
A study examining urinary arsenic concentrations and hypertension
in the 2003-2008 National Health and Nutrition Examination Survey
showed no statistically significant association. NAS stated that it did
not consider this study because the relationship between urinary
arsenic and the arsenic-containing chemical that the Veterans were
exposed to, cacodylic acid, is unclear.
Based on its analysis of these studies published since Update 2010,
NAS concluded that the new relevant data are consistent with a
relationship between the chemicals of interest and blood pressure, and
continued its placement of hypertension in the limited or suggestive
category.
VA has reviewed this additional information in relation to the
information in prior NAS reports analyzing studies concerning
hypertension. Based on this review, the Secretary has determined that
the available evidence is not sufficient to establish a new presumption
of service connection for hypertension in Veterans exposed to
herbicides. As noted in VA's evaluation of prior NAS reports, 75 FR
32540 (June 8, 2010), 75 FR 81332 (Dec. 27, 2010), and 77 FR 47924
(Aug. 10, 2012), the evidence overall includes a wide variety of
results. While some Veteran studies have reported increased incidence
of hypertension, others have found no increase. Similarly, numerous
environmental and occupational studies have found no significant
increased risk of hypertension. Two environmental studies published
since Update 2010 examining environmental exposures in Taiwan and
Alabama suggested a possible association between serum concentration of
dioxin-like compounds and elevated blood pressure. Based on this
limited amount of new information, NAS reaffirmed its decision to place
hypertension in ``limited or suggestive evidence of an association''
category. The two studies that provide evidence of an increased risk
are limited by the design of the study or the type of assay used to
measure exposure. Accordingly, the Secretary has determined that the
available evidence does not at this time establish a positive
association between herbicide exposure and hypertension
[[Page 20311]]
that would warrant a presumption of service connection.
Stroke
NAS placed stroke in the ``Limited or Suggestive Evidence of
Association'' category. Stroke is the third leading cause of death and
the second leading cause of disability among adults in the United
States. The incidence of stroke increases with age and varies according
to ethnicity and gender. The cumulative lifetime risk for development
of stroke is about 1 in 6 for men and 1 in 5 for women. Black and
Latino men are at the highest risk for stroke. The incidence of stroke
for people over 75 years of age is more than twice that of people 55-65
years old. Other factors that increase the risk of stroke include:
Smoking, diabetes, hypertension, and obesity. Based on these factors
alone, some members of the aging Vietnam Veteran cohort can be expected
to experience stroke in their lifetime. A recently completed 25-year
follow up of the National Vietnam Veterans Readjustment Study cohort
found a 0.6 percent mortality rate from stroke, a rate which is
comparable to that of the U.S. general population experience.
In prior reports NAS placed stroke in the ``Inadequate or
Insufficient Evidence'' category. This determination was made based on
its analysis of relevant studies. In Update 2012, NAS identified three
new occupational studies and one environmental study addressing
exposure to chemicals of interest and stroke.
No Vietnam Veteran studies addressing exposure to the chemicals of
interest and cerebrovascular disease and stroke have been published
since Update 2010. No case-control studies of exposure to the chemicals
of interest and cerebrovascular disease or stroke have been published
since Update 2010.
One study reported findings on mortality in 2,122 production
workers engaged in the manufacture of PCP in four midwestern plants.
PCP contains dioxin and furan contaminants that do not include the most
toxic 2,3,7,8-TCDD congener. The cohort was partitioned into a
subcohort of 1,402 workers (PCP-only group) who were employed only in
production of PCP and a separate subcohort of 720 workers (PCP-plus-
TCDD group) who also worked in PCP production and were exposed to TCDD.
The cohort was followed through the end of 2005. The authors did not
observe an increase in cerebrovascular deaths among the workers
compared to the general population. NAS noted that the researchers used
the U.S. population as a referent group, which would tend to understate
associations because of confounding by the healthy-worker effect.
Another study reported an updated mortality analysis of workers
exposed to TCDD at two Dutch chlorophenoxy-herbicide production
facilities. Results of that cohort have been included in previous NAS
Updates. Workers in plant A were exposed to high concentrations of
dioxin both as a contaminant of 2,4,5-Trichlorophenoxyacetic acid
(2,4,5-T) production and through accidental exposure after the
explosion of a kiln. Plant B was involved in 2,4-Dichlorphenoxyacetic
acid (2,4-D) production, but TCDD exposure was assumed to be minimal.
The study followed all male employees of either factory during their
years of operation, which lasted until 1985 for plant A and 1986 for
plant B. Mortality was ascertained through the end of 2006. The authors
did not observe an increase in cerebrovascular deaths among the workers
compared to the general population. NAS concluded that the study has
good exposure measurement, using non-exposed workers in the same plants
as the referent population, and 39 total stroke deaths were observed;
but no association with cerebrovascular death was observed.
Researchers reported on a 23-year follow up of workers exposed to
dioxins in a chemical plant in Hamburg, Germany, that manufactured
herbicides and pesticides, including 2,4,5-T. Results on that cohort
have been included in previous NAS Updates. The study included 1,191
men and 398 women who were employed full-time at the plant for at least
3 months during 1952-1984. Individual cumulative exposure was estimated
from work history on the basis of company records, and the intensity of
TCDD exposure in workplaces was based on previous analyses of serum and
fat-tissue dioxin concentrations. The authors found a statistically
significant higher risk of cerebrovascular-disease mortality than
expected in men, but not in women.
NAS relied primarily on the results of research on the PIVUS study
in placing stroke in the limited or suggestive category. The PIVUS
study recruited participants, within 2 months after their 70th
birthdays, randomly from the registry of residents of the community of
Uppsala, Sweden, from April 2001 to June 2004. The primary aim was to
investigate cardiovascular disease in an elderly population with
adjustment for sex. All participants answered a questionnaire about
medical history, medication, diet, and smoking habits. The burden of
persistent organic pollutants (POPs) including several dioxin-like
PCBs, was assessed from blood serum or plasma. The investigators
examined the relationship between POPs in 898 70-year-old residents of
Uppsala, Sweden, and their incidence of stroke 5 years later. The
investigators measured 16 PCBs, Octachlorodibenzodioxin (OCDD), and
four other pollutants. Thirty-five participants developed stroke;
stroke subtype was not determined. All odds ratios discussed below were
adjusted for gender, body mass index, cigarette smoking, exercise,
alcohol consumption, hypertension, diabetes, triglycerides, and serum
cholesterol. Plasma concentrations of OCDD and of most PCBs with fewer
than seven chlorine atoms were positively related to stroke risk. A
total of 35 study participants suffered strokes. Participants in the
highest 25th percentile of OCDD had 3.5 times the odds of developing
stroke compared with those in the lowest 25th percentile. Both
chemicals that had dioxin-like properties and ones that did not were
positively associated with stroke. Total toxic equivalencies, however,
were strongly associated with stroke risk. Those with toxic
equivalencies at or above the 90th percentile had 4.2 times the odds of
developing stroke. Stroke risk was also greater in participants that
had higher concentrations of chlorine-containing pesticides.
NAS also summarized relevant previous studies that addressed stroke
or cerebrovascular disease. It noted that two existing studies found an
increased incidence of cerebrovascular mortality in Vietnam Veterans,
but neither achieved statistical significance, and one of the studies
failed to control for important potential confounders.
NAS discussed an environmental study published in 2008, in which
researchers reported on the 25-year mortality experience of residents
exposed to dioxin through an accidental industrial release in Seveso,
Italy. The mortality from cerebrovascular disease was assessed in
residents of areas of high, medium, and low exposure to TCDD compared
with residents of non-exposed areas in this region of Italy. Because of
the relatively small number of residents in the high-exposure zone and
the rarity of stroke, NAS noted that the precision of the estimate for
that zone was quite low. However, the study did show an increase in
stroke mortality in medium-exposure and low-exposure zones. NAS
concluded that the strengths of the study are the documented exposure
to a chemical of interest and measured TCDD concentrations that support
the geographic exposure
[[Page 20312]]
classification. The associations were adjusted for age, sex, and time
but were not adjusted for other stroke risk factors.
NAS also discussed a 1998 IARC study, in which researchers pooled
data on 36 populations of workers involved in the manufacture of
chemicals associated with dioxin contamination. There were 263 stroke
deaths among the 21,863 included phenoxy herbicide or chlorophenol
workers. Workers who were exposed to dioxin had 54 percent higher
cerebrovascular-disease mortality than workers who were not. However,
the study's finding was not statistically significant at the 95 percent
confidence interval.
NAS reviewed data that updated results from several of the
populations included in the IARC report. In addition to the Dutch and
Hamburg chemical-worker studies, two articles published before Update
2010 provided updated information on stroke mortality in cohorts that
had been included in the IARC analysis. Neither publication reported a
significant increase in stroke mortality in exposed workers compared
with the general population. None of the studies could adjust for
relevant risk factors, such as smoking and body mass index.
VA has reviewed this additional information in relation to the
information in prior NAS reports analyzing studies concerning stroke.
Based on this review, the Secretary has determined that the available
evidence is not sufficient to establish a new presumption of service
connection for stroke in Veterans exposed to herbicides. In prior
reports NAS placed stroke in the Inadequate or Insufficient Evidence to
Determine Whether an Association Exists category. It moved stroke to
the ``limited or suggestive'' category based largely on the results of
the PIVUS study. Although VA agrees with NAS that the PIVUS study is
generally well designed, it also has a number of limitations for
purposes of evaluating the potential health effects of exposure to
herbicides used in Vietnam. As noted by the authors of the study, there
were only 35 cases of strokes documented and the confidence intervals
were wide, so interpretation of the results should be cautious and
associations might be chance findings. NAS noted that follow up for the
incidence of stroke was incomplete (about 80 percent), which
potentially could bias the results. NAS also noted that the study
methodology theoretically could have led to some exposure
misclassification. Additionally, the study analyzed nearly 60 data
comparisons and, with that large number of comparisons, one would
expect at least three to reach statistical significance at the 95
percent confidence level by chance alone.
Conclusions based on the PIVUS study are further limited because
the chemicals being measured in the serum levels of PIVUS study
participants are not those found in Agent Orange, and there is
significant uncertainty as to whether the associations found for the
chemicals studied can support any conclusions regarding the health
effects of dioxin or other chemicals in herbicides used in Vietnam. The
assumption underlying comparison of those chemicals (primarily PCBs) to
dioxin is that both are capable of binding to the ``Ah'' receptor found
on the surface of vascular endothelial cells and that this binding can
be measured in the form of a total Toxic Equivalency. However, the
authors of the PIVUS study noted that their data indicated that the
associations found were not clearly related to this dioxin-like
activity of the chemicals studied. Thus, because the associations
detected in the PIVUS study were not clearly related to the dioxin-like
properties of the chemicals studied, the study has limited value for
determining the extent to which dioxin may be associated with stroke.
On consideration of the available scientific and medical evidence,
including the PIVUS study, VA has determined that the evidence does not
currently establish a positive association between herbicide exposure
and stroke. Of the five studies previously identified by NAS relating
to stroke or cerebrovascular disease in Vietnam Veterans, only one
study published in 1985 showed a statistically significant increase in
risk for stroke mortality. However, that study did not control for
important potential confounders. Of the 12 relevant occupational
studies identified by NAS, only one showed a statistically significant
higher risk of cerebrovascular-disease mortality and that finding is
limited somewhat by the fact that the increased risk was observed only
in exposed men, while no increased risk was observed in exposed women.
Thus, most of the relevant studies do not provide statistically
significant evidence of an association between exposure to chemicals of
interest and stroke, and the few studies that provide such evidence are
limited by methodological concerns and other factors as discussed
above. Accordingly, the Secretary has determined that the available
evidence does not at this time establish a positive association between
herbicide exposure and stroke that would warrant a presumption of
service connection.
Inadequate or Insufficient Evidence To Determine an Association
NAS has defined this category of association to mean that available
epidemiologic studies are of insufficient quality, consistency, or
statistical power to permit a conclusion regarding the presence or
absence of an association. For example, these studies may fail to
control for confounding factors, have inadequate exposure assessment,
or fail to address latency.
Consistent with its findings in Update 2010, NAS in Update 2012,
found inadequate or insufficient evidence to determine whether an
association exists between herbicide exposure and the following
conditions: (1) Cancers of the oral cavity (including lips and tongue),
pharynx (including tonsils), and nasal cavity (including ears and
sinuses); (2) cancers of the pleura, mediastinum, and other unspecified
sites within the respiratory system and intrathoracic organs; (3)
cancers of the digestive organs (esophageal cancer; stomach cancer;
colorectoral cancer (including small intestine and anus), hepatobiliary
cancers (liver, gallbladder, and bile ducts), and pancreatic cancer);
(4) bone and joint cancer; (5) melanoma; (6) nonmelanoma skin cancer
(basal cell and squamous cell); (7) breast cancer; (8) cancers of the
reproductive organs (cervix, uterus, ovary, testes, and penis;
excluding prostate); (9) urinary bladder cancer; (10) renal cancer
(kidney and renal pelvis); (11) cancers of the brain and nervous system
(including eye); (12) endocrine cancers (including thyroid and thymus);
(13) leukemia (other than all chronic B-cell leukemias including
chronic lymphocytic leukemia and hairy cell leukemia); (14) cancers at
other and unspecified sites (other than those as to which the Secretary
has already established a presumption); (15) reproductive effects
(including infertility; spontaneous abortion other than after paternal
exposure to TCDD; and--in offspring of exposed people--neonatal death,
infant death, stillborn, low birth weight, birth defects [other than
spina bifida], and childhood cancer [including acute myeloid
leukemia]); (16) neurobehavioral disorders (cognitive and
neuropsychiatric); (17) neurodegenerative diseases (including
amyotrophic lateral sclerosis (ALS) but excluding Parkinson's disease);
(18) chronic peripheral nervous system disorders (other than early-
onset peripheral neuropathy); (19) respiratory disorders (wheeze or
asthma, chronic obstructive pulmonary disease, and farmer's lung); (20)
gastrointestinal, metabolic, and digestive disorders (including changes
in liver enzymes,
[[Page 20313]]
lipid abnormalities, and ulcers); (21) immune system disorders (immune
suppression, allergy, and autoimmunity); (22) circulatory disorders
(other than hypertension, ischemic heart disease, and stroke); (23)
endometriosis; (24) effects on thyroid homeostasis; (25) hearing loss;
(26) eye problems; and (27) bone conditions.
With respect to the 27 categories of disease considered in its
prior reports, NAS identified no new Vietnam Veteran studies,
occupational studies, environmental studies, or case studies published
since Update 2010 addressing the potential relationship between the
chemicals of interest and basal cell carcinoma, squamous cell
carcinoma, and chronic lymphocytic leukemia. It identified 31 studies
published since Update 2010 that addressed the relationship between the
chemicals of interest and at least one of the remaining types of cancer
listed above. It identified no new Vietnam Veteran studies,
occupational studies, environmental studies, or case studies published
since Update 2010 addressing the potential relationship between the
chemicals of interest and thyroid homeostasis, eye problems, hearing
loss, or chronic peripheral nervous system disorders. A total of 27
studies were published since Update 2010 that addressed the
relationship between the chemicals of interest and the remaining non-
cancer conditions list above. After analyzing the results of research
published since the last update, NAS found that the studies published
since Update 2010 generally did not contain statistically significant
findings or other significant evidence of association between herbicide
exposures and those health outcomes.
In notices following prior NAS reports, cited in section II above,
VA has explained the basis for the Secretary's determination that a
positive association does not exist between herbicide exposure and the
health conditions identified in Update 2012 in the ``inadequate or
insufficient evidence'' category. For the reasons explained above, VA
has determined that the additional studies discussed in Update 2012 do
not change the Secretary's determination that a positive association
does not currently exist between herbicide exposure and those health
conditions.
Limited or Suggestive Evidence of No Association
NAS has previously concluded that there is limited or suggestive
evidence of no association between paternal herbicide exposure and
spontaneous abortion. In Update 2012, NAS identified no new studies
relevant to that health outcome. Accordingly, the Secretary has
determined that there is no positive association between paternal
herbicide exposure and spontaneous abortion.
Detailed information on NAS' findings may be found at http://www.iom.edu/Reports/2013/Veterans-and-Agent-Orange-Update-2012.aspx.
After selecting the link titled: ``Read Report Online for Free,''
report findings, organized by category, may be found under the heading,
``Table of Contents.''
Conclusion
After careful review of the findings of the 2012 NAS report,
Veterans and Agent Orange: Update 2012, the Secretary has determined
that based on the scientific evidence presented in this report and
prior NAS reports, no new presumptions of service connection are
warranted at this time for any of the conditions discussed in this
notice.
Signing Authority
The Secretary of Veterans Affairs, or designee, approved this
document and authorized the undersigned to sign and submit the document
to the Office of the Federal Register for publication electronically as
an official document of the Department of Veterans Affairs. Jose D.
Riojas, Chief of Staff, Department of Veteran Affairs, approved this
document on March 25, 2014, for publication.
Dated: April 4, 2014.
William F. Russo,
Deputy Director, Regulation Policy and Management, Office the General
Counsel, Department of Veterans Affairs.
[FR Doc. 2014-07950 Filed 4-10-14; 8:45 am]
BILLING CODE P