Determinations Concerning Illnesses Discussed in National Academy of Sciences Report: Veterans and Agent Orange: Update 2012, 20308-20313 [2014-07950]

Agencies

• DEPARTMENT OF VETERANS AFFAIRS

[Federal Register Volume 79, Number 70 (Friday, April 11, 2014)]
[Notices]
[Pages 20308-20313]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-07950]


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DEPARTMENT OF VETERANS AFFAIRS


Determinations Concerning Illnesses Discussed in National Academy 
of Sciences Report: Veterans and Agent Orange: Update 2012

ACTION: Notice.

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SUMMARY: As required by law, the Department of Veterans Affairs (VA) 
hereby gives notice that the Secretary of Veterans Affairs, under the 
authority granted by the 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 michael.ford2@va.gov.

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 https://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]
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