Veterans and Agent Orange 2014 - Parkinson Disease & Parkonsonism

Veterans and Agent Orange: Update 2014
Veterans
Agent
and
Orange
Update 2014
Committee to Review the Health Effects in

Vietnam Veterans of Exposure to Herbicides
(Tenth Biennial Update)
Board on the Health of Select Populations
Institute of Medicine
Copyright National Academy of Sciences. All rights reserved.
11
Neurologic Disorders
Chapter Overview
The Department of Veterans Affairs (VA) gave the committee for Update 2014 the
special task to address whether various diagnoses with Parkinsonian symptoms
should be included in the presumptive service related category for Parkinson
disease (PD). Because diagnostic specicity is improbable in both the studies
upon which the conclusion of limited or suggestive association with exposure to
military herbicides were based and in the documentation for the claims submitted
to VA by Vietnam veterans, the committee claries that the nding for PD should
be interpreted by VA to include all diseases with Parkinson-like symptoms unless
those symptoms can be denitively attributed to be secondary to an external agent
other than the herbicides sprayed in Vietnam.
Based on new evidence and a review of prior studies, the committee for Update
2014 did not nd any new signicant associations between the relevant exposures
and neurological disorders. Current evidence supports the ndings of earlier
studies that:
s There is limited or suggestive evidence of an association between the
chemicals of interest and PD and diseases that present with Parkinsonlike symptoms.
s There is inadequate or insufcient evidence to determine whether there
is an association between the chemicals of interest and any of the other
adverse neurologic outcomes.
743
NEUROLOGIC DISORDERS
751
Previous VAO reports have not identied epidemiologic results for multiple
sclerosis (MS) in relation to exposure to the COIs, so this committee notes
that two studies new to this update reported on MS without providing enough
substance to justify developing a section for this health outcome. MS is already
eligible for service-connected consideration for all veterans who experienced
symptoms while in the military or within 7 years of honorable discharge. In addition to reporting on the deaths from PD and ALS in the female Vietnam-era
veterans, Kang HK et al. (2014) found an elevated risk of death from MS, although its condence interval (CI) was wide due to a small number of cases, but
no suggestion of increased risk of death from other nervous system diseases.
In addition to reporting on the prevalence of PD, ALS, and AD, Yi et al. (2014a)
found no association with herbicide exposure for the prevalence of MS, but the
substantial power of this very large study did identify associations for a number
of neurological conditions (paroxysmal disorders, nerve/plexus disorders, and
paralytic syndromes), which are considerably more specic than the outcomes
evaluated in previous VAO updates.
Parkinson Disease and Parkinsonism

PD is a progressive neurodegenerative disorder that affects millions of people
worldwide. Its primary clinical manifestations are bradykinesia, resting tremor,
cogwheel rigidity, and gait instability. These signs were rst described as a single
entity in 1817 by James Parkinson. In recent years, many nonmotor manifestations of PD have been described, and they can be the presenting symptoms of
the disease. These include cognitive dysfunction that often progresses to frank
dementia, sleep disturbances, hallucinations, psychosis, mood disorders, fatigue,
and autonomic dysfunction (Langston, 2006).
In the nearly two centuries since its initial description, much has been
learned about the genetic predisposition and pathophysiology of PD, but its
etiology in most patients and specic environmental risk factors remain largely
unknown. The diagnosis of PD is based primarily on clinical examination, although in recent years, magnetic resonance imaging and functional brain imaging
have become increasingly useful. PD is difcult to distinguish from a variety
of Parkinsonian syndromes, including drug-induced Parkinsonism, and neurodegenerative diseases, such as atrophy of multiple systems, that present with
Parkinsonian features combined with other abnormalities. Ultimately, a diagnosis
of PD can be conrmed with postmortem pathology examination of brain tissue
for the characteristic loss of neurons from the substantia nigra and telltale Lewy
body intracellular inclusions. Pathology ndings in other forms of Parkinsonism
show different patterns of brain injury.
The incidence of PD is estimated to range from 2 to 22 per 100,000 personyears, while its prevalence ranges from 18 to 182 per 100,000 persons. It affects
752
VETERANS AND AGENT ORANGE: UPDATE 2014
about 1 percent of all persons over 60 years old and up to 5 million people worldwide. PD is the second-most common neurodegenerative disease (after AD).
Research on the genetic, epigenetic, and environmental causes of PD suggests that it has multiple risk factors, including aging, environmental exposure,
and genetic predisposition (Gao and Hong, 2011; Kwok, 2010). The peak incidence and prevalence of PD are consistently found in people 6080 years old. A
consensus statement from a 2007 meeting of PD experts (Bronstein et al., 2009)
concluded that, in addition to rm evidence that the toxicant 1-methyl-4-phenyl1,2,4,6-tetrahydropyridine (MPTP) can induce PD, there is substantial evidence
that men are at greater risk and that smoking and coffee consumption are associated with reduced risk. Further evidence of environmental exposures playing a
role in the development of PD has continued to accrue (Chin-Chan et al., 2015;
Tanner et al., 2014).
Heredity has long been suspected of being an important risk factor for PD; as
many as 25 percent of all PD patients have at least one rst-degree relative who
has PD. At least 13 gene mutations have been identied in autosomal dominant
PD, including mutations in parkin and -synuclein (Klein and Lohmann-Hedrich,
2007). Mutations associated with an autosomal recessive inheritance pattern have
also been described. Complex genetics may be found to account for an increasing
number of PD cases in coming years, but environmental risk factors clearly are
also important.
Conclusions from VAO and Previous Updates
The committees responsible for VAO, Update 1996, Update 1998, Update
2000, Update 2002, Update 2004, and Update 2006 concluded that there was
inadequate or insufcient information to determine whether there is an association between exposure to the COIs and PD. Five case-control studies reviewed by
those committees had investigated association between PD and herbicide exposure without providing further specicity. Two of these did not nd associations
with herbicide exposure (Stern et al., 1991; Taylor et al., 1999), but they were
limited because their subjects had experienced little actual herbicide exposure.
Three found signicant associations with herbicide exposure (Buttereld et al.,
1993; Gorell et al., 1998; Semchuk et al., 1992).
Two new studies reviewed by the committee responsible for Update 2008
examined association specically with chlorophenoxy acid and the esters and
found increased odds ratios (ORs) (Brighina et al., 2008; Hancock et al., 2008).
The doubling in risk observed by Hancock et al. (2008) did not achieve statistical
signicance (OR = 2.07, 95% CI 0.696.23), while increases for the chemical
class of chlorophenoxy acids or esters noted by Brighina et al. (2008) reached
statistical signicance only in the quartile of cases who were youngest at diagnosis (OR = 1.52, 95% CI 1.042.22). In the prospective Agricultural Health
Study (AHS), incident PD was related in a doseresponse manner to increasing
753
days of pesticide use (Kamel et al., 2007b). On the basis of the evidence summarized above, Update 2008 concluded that there was limited/suggestive evidence
associating exposure to the COIs with PD. Additional studies considered by the
committees responsible for Update 2010 and Update 2012 led them to afrm this
conclusion.
The ndings of the literature reviewed are summarized in Table 11-1.
Update of the Epidemiologic Literature
Vietnam-Veteran Studies Since the previous update, Kang HK et al. (2014)
performed a retrospective study of mortality through 2010 in three cohorts of
Vietnam-era military women4,734 deployed to the theater of the war, 2,062 who
served in countries near Vietnam, and 5,313 who were not deployed and served
primarily in the United States. PD mortality, adjusted for age, race, duration of
military service, ofcer status, and nursing status was not elevated in those deployed to Vietnam versus the non-deployed cohort (relative risk [RR] = 1.25, 95%
CI = 0.344.59), and there was no suggestion of an increase when this comparison was made for the subsets of only nurses (RR = 0.78, 95% CI 0.173.50).
In the Korean Veterans Health Study (Yi et al., 2014b), 180,639 Korean
veterans were followed up for vital statistics and cause of death. An Exposure
Opportunity Index (EOI) score was assigned to each veteran based on the proximity of his unit to herbicide-sprayed areas. No association was found between
PD (International Classication of Diseases, Revision 10 [ICD-10] G20-G21)
mortality and the individual EOI scores (HR = 1.01, 95% CI 0.831.22) or when
the high-exposure group was compared to the low-exposure group (HR = 0.88,
95% CI 0.401.95).
When Yi et al. (2014a) compared the high- and low-exposure groups with
respect to the prevalence data for primary PD (ICD-10 G20) and secondary
Parkinsonism (ICD-10 G21), the results for both adjusted for age, rank, smoking,
drinking, physical activity, domestic use of herbicides, education, income, and
body mass index (BMI) were less suggestive of an association with herbicide exposure (OR = 1.18, 95% CI 0.991.42 and OR = 1.26, 95% CI 0.931.69, respectively) than were the unadjusted results (p = 0.002 and p = 0.014, respectively).
Occupational Studies No occupational studies addressing exposure to the
COIs and PD have been published since Update 2012.
Environmental Studies Blood samples were drawn from 40,221 individuals
between 1968 and 1972 in the course of the Finnish Mobile Clinic Health Examination Survey. From among those who were 20 to 79 years of age and had not
been diagnosed with PD or psychosis at the time of sampling, Weisskopf et al.
(2012) identied 196 individuals certied before 1994 to receive medication for
PD from the national reimbursement program; hospital records were obtained
101 PD cases 349 (186

matched
controls)
474 PD cases VV with low

exposure
(69,305) vs
VV with high
exposure
(42,421)
Yi et al.,
2014a
Korean Vietnam
veteransprevalence
data obtained from Korea
National Health Insurance
claims (01/200009/2005)
AO (based on self-report
and proximity of veterans
military unit to AO-sprayed
area)
Mono-ortho dioxin-like
PCBs (PCBs 105, 118, 156,
157, 167, 189)
JEM group (medium)

JEM group (high)
AHS-algorithm group
(medium)
AHS-algorithm group (high)
2,4-D (low)
2,4-D (high)
JEM and an algorithm

derived from the AHS
were used to derive
cumulative exposure
to herbicides; a cropbased method was used
to estimate exposure to
particular pesticides
PCBs analyzed in serum
876 matched
controls
Exposure(s)a
Vietnam veterans
All COIs
information obtained from
death certicates, VA
records, Social Security
Death Master File, NCHS
National Death Index
Exposure Assessment
5,313 nondeployed US
female VV
Weisskopf
et al., 2012
Kang et al., 10 PD deaths

2014
(2,260 in
Vietnam
cohort and
1,781 in
near-Vietnam
cohort)
van der
444 cases
Mark et al.,
2014
Reference
Cases in
Comparison
and Country Study Group Group
213
cases
with high
exposure;
261
cases
with low
exposure
10 PD
cases
(8 PD
cases in
nurses)
Neurologist review of
medical records
Diagnosis from death

records
Diagnosis of
Neurologic Dysfunction
PCB 118:
Neurologist review of
0.4 (0.41.0)
medical records
Dioxin-like PCBs;
0.3 (0.10.9)
PD and high vs low Insurance claim data
exposure:
HR = 1.2 (1.01.4)
Log EOI scores:
HR = 1.0 (1.01.1)
Secondary PD and
high vs low exposure:
HR = 1.3 (0.91.7)
Log EOI scores:
HR = 1.0 (0.91.1)
1.2 (0.62.3)
1.5 (0.83.0)
1.1 (0.52.4)
1.7 0.83.5)
1.3 (0.72.4)
0.3 0.62.5)
Vietnam cohort:
1.3 (0.34.6)
Nurses only:
0.8 (0.23.5)
OR (95% CI)
TABLE 11-1 Epidemiologic Studies of Herbicidea Exposure and Parkinson Disease and Parkinson-Like Conditions (Shaded
entries are new information for this update)
754
Initial screening phoneinterview followed by

an in-person physical
assessment employing a
checklist and record of
symptoms, reviewed by a
neurologist specializing in
movement disorders
Firestone
Enrolled
526 unrelated Structured face-to-face
et al., 2010 cases
controls
interviews; demographic
(updates
increased
information collected, job
and expands from 250
descriptions (if held for
Firestone
(in original
more than 6 mos), and
et al., 2005); study) to 404
workplace exposures to
Washington,
various industrial toxicants
US
identied from a checklist
were recorded
405 matched
controls
VV (Korean Veterans
Health Study)cause of
death ascertained from
National Statistical Ofce
(19922005)
Rugbjerg at 403 PD
al., 2011;
cases from
Canada
pharmacy
database
VV with low
exposure
(7,973) vs
VV with high
exposure
(9,556)
Incidence of Hospital diagnosis of PD
PD in general between 19772008
population of
Denmark
25 PD
deaths; total
population
17,529
Kenborg
28 PD cases
et al., 2012; from male
Denmark
members
of Danish
Union of
Gardeners (n
= 3,124)
Yi et al.,
2014b
33
35
2,4-D
28
11
16
1
13 highexposure
deaths;
12 lowexposure
deaths
Herbicides
Neurotoxic pesticides
(including 2,4-D, 2,4,5-T)
Pesticides (including
phenoxy herbicides)
AO (based on self-report
and proximity of veterans
military unit to AO-sprayed
area)
0.8 (0.32.0)
Hospitalization:
1.1 (0.81.7)
Born before 1915:
1.6 (0.82.8)
Born 19151934:
1.2 (0.71.9)
Born 1935 or later:
0.3 (0.01.6)
1.8 (0.973.4)
1.8 (0.953.3)
1.8 (0.973.4)
1.8 (0.953.3)
continued
2 of 4 cardinal signs;
must have bradykinesia
or resting tremor, may
have cogwheel rigidity,
or postural reex
impairment
Parkinsonian tremor,
rigidity, bradykinesia,
masked facies,
micrographia, or
postural imbalance
Not specied
PD and high vs low Diagnosis from death

exposure:
records
HR = 0.9 (0.42.0)
Log EOI scores:
HR = 1.0 (0.81.2)
755
Dhillon
et al.,
2008; US
(University
of Texas)
Brighina
et al., 2008;
US (Mayo
Clinic)
833 PD
sequential
cases from
clinic;
median age =
67.7 yrs, 208
cases 59.8
yrs
100 PD cases
recruited
from a
medical
centers
neurological
Tanner et al., 519 cases;

2009; US
consecutively
eligible
subjects
between July
1, 2004, and
May 31,
2007
Exposure Assessment
84 controls
without PD
recruited
from the
same medical
center
Professionally
administered questionnaire
used to determine military
history (including spraying
herbicides/pesticides),
personal use/mixing
Initial self-assessment,
plus individual interview
with occupational
specialist
521 controls Telephone interviewers
frequency
collected information
matched
about exposures before the
to cases by
reference age; employment
age, sex, and historyindustry,
location
location, processes,
materials, and job tasks
Toxicant exposure
collected for some jobs
472
Self-report down to
unaffected
specic herbicides;
siblings and 2,4-D said to be most
361 unrelated prevalent in cases, but
controls
published analysis not that
detailed
Elbaz et al., 224 PD cases 557 controls

2009;
France
Reference
Cases in
Comparison
16
na
na
Ever personally used/mixed or applied:

Herbicide use-home or
34
agricultural
2,4-D
17
2,4,5-T
4
Silvex or other 2,4,5-TP
1
For youngest quartile at diagnosis:

Pesticides (ever):
87
Herbicides (ever):
Phenoxy herbicides:
Insecticides (ever):
Fungicides (ever):
2,4-D
Phenoxy herbicides
Age of onset > 65 yrs
Exposure(s)a

1.2 (0.62.8)
0.5 (0.11.6)
0.3 (0.02.7)
0.8 (0.41.4)
1.8 (1.12.9)
2.5 (1.34.5)
1.5 (1.02.2)
1.0 (0.61.7)
1.0 (0.33.2)
2.6 (1.06.5)
1.8 (0.93.3)
2.9 (1.17.3)
OR (95% CI)
PD diagnosed by
neurologist specializing
in movement disorders
using standard clinical/
lab diagnostic criteria
PD diagnosed by
movement disorder
specialist
2 cardinal signs (rest

tremor, bradykinesia,
rigidity, impaired
postural reexes)
Enrolling investigator
determined diagnosis
and type of
Parkinsonism, Unied
Parkinson Disease
Rating Scale score, and
clinical features
Diagnosis of
TABLE 11-1 Epidemiologic Studies of Herbicidea Exposure and Parkinson Disease and Parkinson-Like Conditions,
continued
756
296
unaffected
relatives and
others
and average duration of

exposure to herbicides and
specic pesticides, among
other exposures
All comparisons referent
to those who never applied
any pesticide
products
Pesticide application:
Insecticides:
Botanical:
Organophosphate:
Herbicides:
Chlorophenoxy:
Phosophonoglycine:
Triazine:
Kamel et al., 83 prevalent 79,557
Self-report of individual
For incident cases:
2007b;
cases at
without PD at herbicides (2,4-D;
2,4-D:
US
enrollment; enrollment;
2,4,5-T; 2,4,5-TP) on
2,4,5-T:
(Agricultural 78 incident 55,931
detailed self-administered 2,4,5-TP:
Health
cases during without PD
questionnaires at
Dicamba:
Study)
follow-up
followed up enrollment or telephone
Paraquat:
[Updates
among
interview for follow-up
Trifuralin:
Kamel et al., private
Cyanazine
2005]
applicators
For prevalent cases:
and spouses
2,4-D:
2,4,5-T:
2,4,5-TP:
Dicamba:
Paraquat:
Trifuralin:
Cyanazine
Hancock
319 cases
et al., 2008;
US (Duke)
institute in
East Texas
1.0 (0.52.1)
1.8 (1.03.3)
0.9 (0.41.8)
1.5 (0.82.8)
1.0 (0.51.9)
1.7 (1.03.2)
1.0 (0.51.8)
0.9 (0.51.8)
0.9 (0.51.7)
0.8 (0.31.9)
0.9 (0.51.6)
1.8 (1.03.4)
0.9 (0.51.6)
2.6 (1.44.9)
49
24
7
32
11
32
26
47
16
4
26
14
31
30
15
57
5
7
53
1.6 (1.12.3)
1.8 (1.22.8)
5.9 (0.656)
1.9 (1.13.6)
1.6 (1.02.5)
2.1 (0.76.2)
1.5 (0.92.5)
1.1 (0.33.6)
200
continued
757
Self-administered
questionnaire for
occupational exposure
72
Engel et al., 238

2001;
US (crosssectional,
but
otherwise
fairly
high-quality
design)
Interview determining
occupational and homebased pesticide exposure
characterized by chemical
name or brand, duration,
and frequency
Structured interview
250 (156
388 (241
men) newly men)
diagnosed
19922002 at
Group Health
Cooperative
Exposure Assessment
Behari et al., 377

377 matched
2001;
(301 men, 76 for age ( 3
India
women)
yrs), but not
sex
Firestone
et al., 2005;
Washington,
US
(Updated by
Firestone
et al., 2010)
Reference
Cases in
Comparison
n
OR (95% CI)
Occupational, men only

Pesticides:
19
1.0 (0.51.9)
Insecticides:
15
0.9 (0.41.8)
Fungicides:
2
0.4 (0.13.9)
Herbicides:
9
1.4 (0.53.9)
Paraquat:
2
1.7 (0.212.8)
Home use, all subjects
Pesticides:
178
1.0 (0.71.4)
Insecticides:
141
0.8 (0.61.1)
Fungicides:
14
0.6 (0.31.1)
Herbicides:
116
1.1 (0.81.5)
McNemar chi-square:
Herbicides:
p = 0.010
(protective effectnot conrmed by multivariate analysis)
Insecticide:
p = 0.169
Rodenticide:
p = 0.662
[prevalence ratios]
Any pesticide:
0.8 (0.51.2)
Herbicides:
0.9 (0.61.3)
Insecticides:
0.9 (0.61.5)
Fungicides:
0.8 (0.61.3)
Exposure(s)a
Neurologic exam by
trained nurse
Controlled for age, sex,

smoking
Diagnosis of
continued
758
120
Seidler
380 (age <
et al., 1996; 66 yrs with
Germany
PD after
1987)
Liou et al.,
1997;
Taiwan
Taylor et al., 140

1999;
Boston
Medical
Center
Gorell et al., 144 (age >
1998;
50 yrs)
US
Kuopio
123 (onset
et al., 1999; of PD before
Finland
1984; 63
men, 60
women)
Interviewdose-years
= years of application
weighted by use
39
26
13
33
20
13
1.0 (0.61.7)
1.2 (0.72.0)
0.7 (0.31.3)
1.4 (0.82.5)
1.7 (0.93.2)
0.8 (0.41.7)
Pesticides:
Herbicideshigh dose:
Dose trend
vs neighbor controls
vs regional controls
Insecticideshigh dose:
Dose trend
vs neighbor controls
vs regional controls

p = 0.12
p < 0.001
p = 0.06
p < 0.001
2.1 (0.94.8)
2.1 (1.62.6)
2.4 (1.06.0)
2.9 (2.33.7)
2.2 (0.95.6)
4.7 (2.012))
3.2 (2.44.3)
All occupations contributing exposure to:

Herbicides:
4.1 (1.412.2)
Insecticides:
3.6 (1.87.2)
Fungicides:
1.6 (0.55.5)
Logistic analysis adjusted for age, sex, family history,

education, smoking, water source, head injury, depression
Pesticides:
1.0 (0.91.2)
Herbicides:
1.1 (0.71.7)
Pesticide use:
Occasional use:
Regular use:
Herbicide use:
Occasional use:
Regular use:
Interviewoccupational Pesticides vs no pesticides:

exposures to herbicides or But no paraquat use:
pesticides
Paraquat use:
Paraquat use vs no paraquat:
Interviewherbicide
and insecticide use while
working on a farm or
gardening
464
240 hospital
controls
matched for
age ( 2 yrs)
and sex
755 (379
neighborhood,
376 regional;
neighborhood
controls
may be
over-matched)
Interviewexposure
recorded as total days for
lifetime
147 controls
referred by
cases
246 matched Interviewpesticides or

on sex, age
herbicides regularly or
( 2 yrs), and occasionally used
urban/rural
continued
Neurologic exam
Neurologic exam
Standard criteria of PD
by history
Neurologic exam
Neurologic exam
759
Buttereld 63 young
et al., 1993; onset cases
US
(age < 50
yrs)
Semchuk
130 living
et al., 1992; cases from
Calgary,
register of
Alberta,
Calgary
Canada
residents
(populationbased)
260
community
controls
matched for
age ( 2.5
yrs) and sex,
identied by
RDD
68
Hertzman
127
245
et al., 1994; (71 men and (121 with
Canada
56 women) cardiac
disease; 124
voters)
Reference
Cases in
Comparison
Exposure(s)a
Interviewself-report of Pesticides:
exposure for each job held Herbicides:
> 1 mo
Exposed during age interval:
1625 yrs
2635 yrs
3645 yrs
4655 yrs
Insecticides:
Fungicides:
Cases vs votersamong
men
Pesticides:
Herbicides:
Chlorophenoxys:
Paraquat:
Insecticides:
Fungicides:
Questionnairepesticide Herbicides:
or insecticide use 10 times Insecticides:
in any year
Dwelling fumigated:
Interviewoccupation
with probable pesticide
exposure
Exposure Assessment
2.3 (1.34.0)
3.1 (1.37.0)
1.4 (0.54.3)
4.8 (1.515.0)
3.8 (1.213.0)
4.9 (1.319.0)
2.1 (1.04.1)
1.6 (0.83.3)
17
16
2.3 (1.14.9)
1.2 (0.62.5)
1.2 (0.62.4)
1.3 (0.34.6)
0.3 (0.10.9)
3.2 (p = 0.033)
5.8 (p < 0.001)
5.3 (p = 0.45)
OR (95% CI)
32
17
Neurologic exam
conrming idiopathic
PD without dementia
(average 7.8 yrs from
diagnosis)
Standard criteria of PD
by history
Neurologic exam
Diagnosis of
continued
760
Interviewself-report of
insecticide and pesticide
use by self or others in
home or garden
122 aged 50 Questionnaireever

79 yrs who
worked in an orchard
responded
from electoral
rolls
149
nominated
by each case
or picked
from hospital;
matched by
age ( 6 yrs),
sex, and race
Work in orchards:
Paraquat:
4/57
3.7 (1.310.3)
(p = 0.01)
Insecticides:
0.7 (0.31.4)
Onset < 40 yrs:
0.6 (0.21.7)
Onset > 59 yrs:
0.8 (0.32.1)
Herbicides:
1.1 (0.71.7)
Onset < 40 yrs:
0.9 (0.51.7)
Onset > 59 yrs:
1.3 (0.72.4)
Adjusted for smoking, head injury, rural residence:
Insecticides:
0.5 (0.21.1)
Herbicides:
0.9 (0.61.5)
Neurologic exam
conrmed diagnostic
criteria in 55 of 69
cases identied by
asking physicians in
area
Review of medical
records, responsive to
PD medication (under
treatment average of
8.2 yrs), without major
cognitive impairment
NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid or Silvex; AHS,
Agricultural Health Study; AO, Agent Orange; CI, condence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; JEM, jobexposure matrix;
HR, hazard ratio; na, not applicable; NCHS, National Center for Health Statistics; OR, odds ratio; PCB, polychlorinated biphenyl; PD, Parkinson disease; RDD,
random-digit dialing; VA, US Department of Veterans Affairs; VV, Vietnam veteran.
aFor the objective of the VAO review series, only associations with herbicides are of possible relevance; only the phenoxy herbicides, cacodylic acid, and
picloram are of specic interest.
69all
young
onset cases
identied
(age < 40
yrs);
80random
selection of
old onset
cases (age >
59 yrs)
Hertzman
57 prevalent
et al., 1990; PD patients
British
(age <
Columbia, 79 yrs)
Canada
(5054 had
conrmed
PD, not clear
exactly how
many)
Stern et al.,
1991;
NJ and PA,
US
761
762
for 126 of these cases, and from this information neurologists conrmed the PD
diagnosis for all but 25. The 101 established PD cases were matched to controls
without PD by age, sex, municipality, and vital status. The serum samples were
analyzed in 20052007 for 55 PCB congeners, including the dioxin-like PCBs
105, 118, 156, 157, 167, 189. This set of dioxin-like PCBs consists only of
mono-ortho congeners, which have considerably lower TEFs than the four nonortho dioxin-like congeners, which were not covered in the serum analyses. In
addition to analyses on total PCBs and three common nondioxin-like congeners,
results were reported individually for the common PCB 118 and for the measured
set of dioxin-like PCBs. Concentrations (ng/g serum) for each congener group
were partitioned into quintiles. With adjustments for smoking, occupation, BMI,
triglycerides, cholesterol, and serum dieldrin concentration, the number of PD
cases in the highest quintile was compared to the number in the lowest quintile,
and a trend test was performed. Reduced ORs for PD in the highest quintile and
the suggestion of an inverse relationship with increasing concentration were
reported for both PCB 118 (OR = 0.37, 95% CI 0.370.95; p = 0.10) and for
total dioxin-like PCBs (OR = 0.34, 95% CI 0.130.90; p = 0.05). These ndings
are not supportive of an association between dioxin-like activity and PD, but the
committee does not attribute much weight to evidence based only on these monoortho PCBs whose dioxin-like activity is weak. Furthermore, the association
that has been noted for the COIs is based primarily on exposure to the phenoxy
herbicides themselves, rather than the dioxin-like activity of the contaminated
mixtures sprayed in Vietnam.
Case-Control Studies van der Mark et al. (2014) identied PD cases newly
diagnosed in 20062011 at ve hospitals in the Netherlands. For each case, two
controls matched on age and sex were identied from among patients without
neurodegenerative symptoms who had been seen in the respective neurology department in that period. Of the 1,001 PD cases identied, 993 were alive and had
current addresses. Of those, 45 percent completed computer-assisted telephone
interviews addressing occupational histories with especially detailed information
gathered on farming and gardening jobs. Of the matched controls, 35 percent
completed the interview, giving a nal sample for analysis of 444 cases and 876
controls. The responses were processed by a jobexposure matrix (JEM) and by
an algorithm from the AHS to derive cumulative exposure to herbicides (as well
as to insecticides or to fungicides); the exposure estimates were partitioned into
three groups for comparison to those with no reported exposure. A crop-based
method was used to estimate exposures to particular pesticides, with 2,4-D being one of the four herbicides assessed in this fashion; these estimates were
partitioned into high and low groups for comparison to the never-exposed group.
The analyses were adjusted for smoking, coffee consumption, occupational
skill, and estimated endotoxin exposure (the other risk factor investigated in this
study). For the overall herbicide exposure estimates, the medium and high groups
763
consistently showed non-signicantly elevated risks: medium (OR = 1.30, 95%

CI 0.702.39) and high (OR = 1.25, 95% CI 0.622.53) JEM groups; medium
(OR = 1.21, 95% CI 0.622.33) and high (OR = 1.52, 95% CI 0.782.97) AHSalgorithm groups. However, only the product-specic results of the crop-based
exposure estimation model provided ndings fully informative for the VAO task;
the two exposure groups for 2,4-D versus the never-exposed group had ndings
similar to those for herbicides overall: low (OR = 1.13, 95% CI 0.492.364) and
high (OR = 1.68, 95% CI 0.813.49) groups. The only statistically signicant
nding was for the group with high exposure to the fungicide benomyl.
Biologic Plausibility
McDowell and Chesselet (2012) recently reviewed the literature on the ability of both toxicant-induced (6-hydroxydopamine, MPTP, rotenone, cycad) and
genetically based animal models to reproduce the nonmotor symptoms of PD.
The very clear PD-like toxicity resulting from human exposure to MPTP has indicated that select chemicals can result in the same type of damage to dopaminergic
neurons as occurs in classical PD, and MPTP has become an important toxicant
in studies that use animal and in vitro models. It is notable that MPTPs bioactive
metabolite, MPP+, is similar in chemical structure to Paraquat (a commonly used
herbicide, but not one that was used in Vietnam), but structurally unrelated to
any of this reports COIs. Pesticides shown to produce PD-like toxicity in animal
models include Paraquat, rotenone, maneb, and dieldrin. Substantial research has
gone into understanding the molecular mechanisms responsible for the toxicity,
especially in connection with Paraquat and rotenone (Blandini and Armentero,
2012; Di Monte et al., 2002; Drechsel and Patel, 2008; Duty and Jenner, 2011;
Hatcher et al., 2008; Moretto and Colosio, 2013; Nunomura et al., 2007; Sherer
et al., 2002; Yadav et al., 2012). The damage done to dopaminergic neurons in
PD is probably caused by oxidative stress and inammation and may well also
involve damage to mitochondria in the target cells (Anderson and Maes, 2014:
Janda et al., 2012; Liang et al., 2007; Littleljohn et al., 2011; Sarnico et al.,
2008).
The COIs to this committee are known to be distributed to the CNS.
Bongiovanni et al. (2007) found that rat cerebellar granule cells in culture (an in
vitro model using cells not involved in PD pathology) produce increased concentrations of ROSs when exposed to 2,4-D. The COIs have not been investigated,
however, in experimental systems such as those that have shown that compounds,
such as Paraquat, cause inammation and oxidative stress, so it is not known
whether any of the COIs could produce these responses.
Research on the neurotoxicity of 2,4-D has been going on for a number of
years, but most of it has focused on its effects on the developing rodent nervous
system. The studies have often used high doses of 2,4-D that have resulted in
adverse changes in the developing nervous systemboth neurochemical (such as
764
changes in D2 receptors, tyrosine hydroxylase, and dopamine beta-hydroxylase)

and behavioral (for example, Bortolozzi et al., 1999, 2002, 2003, 2004; Duffard
et al., 1996; Evangelista de Duffard et al., 1990, 1995; Garcia et al., 2004, 2006;
Rosso et al., 2000a,b). The injection of 2,4-D directly into the rat brain yields
toxicity in the basal ganglia (Bortolozzi et al., 2001), but this route of administration is highly articial. Postpartum dietary exposure of females to 2,4-D results
in adverse alterations in maternal behavior and neurochemical changes, including increases in dopamine and its metabolites 3,4-dihydroxyphenylacetic acid
and homovanillic acid (Strtz et al., 2008). Such an increase in dopamine is the
reverse of what is seen in PD, in which a degradation of the dopaminergic system
occurs. In addition, a study of mice and 2,4-D yielded no evidence of neurochemical damage to the dopaminergic system (Thiffault et al., 2001). One study
indicated that 2,4-D, among a variety of pesticides and metals, causes brillation
of -synuclein in vitro, but the study used puried protein and reported only a
generalized result rather than data on 2,4-D (Uversky et al., 2002), so little condence can be placed in it. Because most of the studies were on the developing
nervous system, not the mature nervous system, and some studies yielded evidence of a lack of a role of 2,4-D in the development of PD, the existing studies
do not support a role for the COIs in the etiology of PD.
A general summary of the biologic plausibility of neurologic effects arising
from exposure to the COIs is presented at the beginning of this chapter.
Synthesis
The committee responsible for Update 2014 reviewed two new epidemiologic studies that examined herbicide exposure and PD mortality in Vietnam
veterans that did not nd an association (Kang HK et al., 2014; Yi et al., 2014b).
When investigating the prevalence of PD among the Korean Vietnam veterans,
however, Yi et al. (2014a) found indications of an elevation. While the Finnish
study of environmental exposures was not particularly informative for the committee, its ndings on exposure to herbicides, and 2,4-D in particular, are consistent with the conclusion that exposure to the phenoxy herbicides sprayed in
Vietnam may be associated with the development of PD. A biologic mechanism
by which the COIs may cause PD has not been demonstrated. Nevertheless, the
overall epidemiologic evidence continues to support an association between herbicide exposure and PD and to be consistent with an association with exposure
to the phenoxy herbicides specically.
For this update, VA added a special task to the committees charge to evaluate the evidence of any association between neurodegenerative diseases with
Parkinson-like symptoms and herbicide exposure. Strictly speaking, genuine or
primary PD is a diagnosis of exclusion, and a patient with Parkinson-like symptoms would be diagnosed as having Secondary Parkinsonism if his condition
were known to have been caused by exposure to herbicides, as indicated by the
765
TABLE 11-2 Correspondence of ICD-9 and ICD-10 Codes for Parkinson

Disease and Other Extrapyramidal Disease and Abnormal Movement Disorders
ICD-9 Code
Description of Condition
ICD-10 Code
332
332.0
Parkinson Disease
Paralysis agitans
G20
Parkinson disease
Paralysis agitans
Hemiparkinsonism
Idiopathic Parkinsonism or PD
Parkinsonism or PD NOS
Primary Parkinsonism or PD
Secondary Parkinsonism
Malignant neuroleptic
syndrome
Other drug-induced secondary
Parkinsonism
G21.11Neuroleptic induced
Parkinsonism
G21.19Other drug
induced secondary
Parkinsonism
Secondary Parkinsonism due
to other external agents
Postencephalitic Parkinsonism
Vascular Parkinsonism
Other Secondary Parkinsonism
Secondary Parkinsonism,
unspecied
332.1
Idiopathic Parkinsonism or PD
Parkinsonism or PD NOS
Primary Parkinsonism or PD
Secondary Parkinsonism
Parkinsonism attributable to a
drug or identied toxicant
G21
G21.0
G21.1
G21.2
G21.3
G21.4
G21.8
G21.9
333
333.0
Other extrapyramidal disease

and abnormal movement
disorders
Other degenerative diseases of
the basal ganglia
Atrophy or degeneration:
olivopontocerebellar (DjrineThomas syndrome)
pigmentary pallidal
(Hallervorden-Spatz disease)
striatonigral
Parkinsonian syndrome
associated with:
idiopathic orthostatic
hypotension
symptomatic orthostatic
hypotension
Progressive supranuclear
ophthalmoplegia
Shy-Drager syndrome
G23
G23.0
G23.1
G23.2
G23.8
G23.9
Other degenerative diseases of

basal ganglia
Hallervorden-Spatz disease
Progressive supranuclear
ophthalmoplegia
Striatonigral degeneration
Other specied degenerative
diseases of basal ganglia
Degenerative disease of basal
ganglia, unspecied
continued
766
TABLE 11-2 Continued

ICD-9 Code
333.1
Essential and other specied

forms of tremor
Monoclonus
Tics of organic origin
Huntington chorea
Other choreas
Idiopathic torsion dystonia
Symptomatic torsion dystonia
Fragments of torsion dystonia
Other and unspecied
Restess legs
Stiffman syndrome
333.2
333.3
333.4
333.5
333.6
333.7
333.8
333.9
ICD-10 Code
G90.3
Multi-system degeneration of the

autonomic nervous system
NOTE: ICD, International Classication of Diseases; NOS, not otherwise specied; PD, Parkinson
disease.
SOURCE: Excerpted from CDCs ICD-10-CM (http://www.cdc.gov/nchs/icd/icd9cm.htm; http://
www.cdc.gov/nchs/icd/icd10cm.htm#icd2016, accessed November 11, 2015).
description of ICD-9 332.1 in Table 11-2. For some patients with Parkinson-like
symptoms, the details of their medical records may establish that their condition
is denitively attributable to a specic genetic syndrome or to some identied
external agent (other than possible exposure to herbicides in Vietnam). Contemporary sophisticated techniques and a thorough knowledge of a patients history
may permit making distinctions among conditions having characteristics of PD
with some degree of condence, but in practice clinicians would not be expected
to uniformly settle on the same diagnostic code for a given patient. Such variations in diagnostic specicity are factors that extend to the epidemiology studies supporting the conclusion of prior VAO committees that there is limited or
suggestive evidence of association between PD and exposure to the herbicides
sprayed in Vietnam.
In the ICD coding system, several codes are allocated to conditions with
constellations of symptoms that are Parkinson-like, but their assignments differ somewhat between the ICD-9 and the ICD-10 classications, as shown in
Table 11-2. The revised coding system has progressed by providing individual
codes for specic types of secondary Parkinsonism, which should facilitate VAs
processing of claims submitted since the ICD-10 codes became effective on October 1, 2015. Because the veteran is to be given the benet of the doubt in the
claims process, the current committee does not judge it reasonable to exclude
from coverage for this presumptively service-related condition any Vietnam veterans with Parkinsonian symptoms unless VA can denitively establish, on a
767
case-by-case basis, that those symptoms are secondary to an external agent other
than the herbicides sprayed in Vietnam or to a specic genetic condition.
Conclusions
On the basis of the evidence reviewed here and in previous VAO reports, the
committee concludes that there is limited or suggestive evidence of an association between exposure to the COIs and PD, including Parkinson-like conditions
such as Parkinsonism, in the setting of dementia, multiple system atrophy, and
progressive supranuclear palsy.
Amyotrophic Lateral Sclerosis
ALS is a progressive, adult-onset, motor neuron disease that presents with
muscle atrophy, weakness, and fasciculations and with signs that indicate the involvement of motor neuron pathways in the CNS. The incidence of sporadic ALS is
12 per 100,000 person-years, and the incidence of ALS peaks at the ages of 5575
years (Brooks, 1996). The diagnosis of ALS is made through clinical examination
and electrodiagnostic testing and has a high degree of accuracy when performed by
experienced neurologists (Rowland, 1998; Rowland and Shneider, 2001).
The cause of most cases of ALS is unknown, but about 510 percent of cases
are recognized as resulting from inheritance of autosomal dominant or recessive genes (Wood, 2014). One-fth of familial-ALS patients have mutations in
the gene that encodes superoxide dismutase-1 (Rosen et al., 1993). Many other
possible etiologic factors have been investigated (Breland and Currier, 1967;
Gallagher and Sander, 1987; Hanisch et al., 1976; Kang H et al., 2014; Kurtzke
and Beebe, 1980; Mitchell and Borasio, 2007; Roelofs-Iverson et al., 1984;
Sutedja et al., 2009a,b; Wang et al., 2014), including military service (Weisskopf
et al., 2005), but they have not found conclusive evidence of association with any
of the environmental exposures addressed.
Summary of Previous Updates
ALS was rst evaluated as a disease that might be associated with the COIs
by the committee for Update 2002.
Pesticide or herbicide exposure has been associated with an increased risk
of ALS, including a doubling of the risk after long-term occupational exposure
to pesticides (Deapen and Henderson, 1986) and a tripling after exposure to
agricultural chemical products (Savettieri et al., 1991) and herbicides (McGuire
et al., 1997), but none of the risk estimates was statistically signicant. A
population-based case-control study demonstrated associations between exposure to agricultural chemical products and ALS in men, with an OR of 2.4 and a
trend with duration of exposure that were both statistically signicant (McGuire
The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution
to advise the nation on issues related to science and technology. Members are
elected by their peers for outstanding contributions to research. Dr. Ralph J.
Cicerone is president.
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to advising the nation. Members are elected by their peers for extraordinary
contributions to engineering. Dr. C. D. Mote, Jr., is president.
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established in 1970 under the charter of the National Academy of Sciences to
advise the nation on medical and health issues. Members are elected by their
peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau
is president.
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Learn more about the National Academies of Sciences, Engineering, and Medicine at www.national-academies.org.
COMMITTEE TO REVIEW THE HEALTH EFFECTS

IN VIETNAM VETERANS OF EXPOSURE TO
HERBICIDES (TENTH BIENNIAL UPDATE)
KENNETH S. RAMOS (Chair), Associate Vice President for Precision Health
Sciences and Professor of Medicine, Arizona Health Sciences Center,
University of Arizona
ILIR AGALLIU, Assistant Professor, Department of Epidemiology and
Population Health, Albert Einstein College of Medicine, New York, New
York
ERIN M. BELL, Associate Professor, Department of Environmental Health
Sciences, School of Public Health, University at Albany, New York
MAARTEN BOSLAND, Professor of Pathology, College of Medicine,
University of Illinois at Chicago
ROBERT CANALES, Assistant Professor, Community, Environment and
Policy Department, Mel & Enid Zuckerman College of Public Health,
University of Arizona
MICHAEL J. CARVAN, Shaw Professor, School of Freshwater Sciences,
University of WisconsinMilwaukee
MELISSA GONZALES, Associate Professor, Department of Internal
Medicine, University of New Mexico
KARL T. KELSEY, Professor, Epidemiology and Pathology and Laboratory
Medicine, Brown University, Providence, Rhode Island
KEVIN E. KIP, Executive Director of the Research Center, Professor of
Epidemiology and Biostatistics, College of Nursing, University of South
Florida
STEPHEN KRITCHEVSKY, Director, J. Paul Sticht Center on Aging, Wake
Forest School of Medicine, Wake Forest University, Winston-Salem, North
Carolina
ELAN D. LOUIS, Chief, Division of Movement Disorders and Professor of
Neurology and Epidemiology, Yale School of Medicine and Yale School of
Public Health, Yale University, New Haven, Connecticut
DAVID RICHARDSON, Associate Professor, Department of Epidemiology,
Gillings School of Global Public Health, University of North Carolina at
Chapel Hill
MITCHELL TURKER, Senior Scientist, Oregon Institute of Occupational
Health Sciences, Professor of Molecular and Medical Genetics, School of
Medicine, Oregon Health & Science University
LORI WHITE, Associate Professor, Department of Biochemistry and
Microbiology, School of Environmental and Biological Sciences, Rutgers
University, New Brunswick, New Jersey
Study Staff
MARY BURR PAXTON, Study Co-Director
JENNIFER A. COHEN, Study Co-Director
HEATHER L. CHIARELLO, Research Associate
NICOLE FREID, Senior Program Assistant
JULIE WILTSHIRE, Financial Ofcer
ROBERT POOL, Editor
FREDERICK (RICK) ERDTMANN, Director, Board on the Health of Select
Populations
vi
Reviewers
This report has been reviewed in draft form by individuals chosen for their
diverse perspectives and technical expertise. The purpose of the independent
review is to provide candid and critical comments that will assist the institution
in making its published report as sound as possible and to ensure that the report
meets institutional standards of objectivity, evidence, and responsiveness to the
study charge. The review comments and draft manuscript remain condential to
protect the integrity of the deliberative process. We thank the following for their
review of the report:
Cande V. Ananth, Columbia University
Frederick R. Appelbaum, Fred Hutchinson Cancer Research Center
Margit L. Bleecker, Center for Occupational and Environmental Neurology
Linda S. Birnbaum, National Institute of Environmental Health Sciences
and National Toxicology Program
David E. Cohen, New York University School of Medicine
David L. Eaton, University of Washington
Warren G. Foster, Michael G. DeGroote School of Medicine and McMaster
University
Michael Gochfeld, Rutgers Robert Wood Johnson Medical School Environmental and Occupational Health Sciences Institute
Robert G. Holloway, University of Rochester
Linda A. McCauley, Emory University
Michael D. McClean, Boston University School of Public Health
Gail S. Prins, University of Illinois at Chicago
David Strogatz, Bassett Research Institute
vii
viii
REVIEWERS
Elizabeth A. Stuart, Johns Hopkins Bloomberg School of Public Health

Grace Wahba, University of WisconsinMadison
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the nal draft of the report before its release. The
review of the report was overseen by Kristine M. Gebbie, Flinders University
School of Nursing and Midwifery, Australia. She was responsible for making
certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully
considered. Responsibility for the nal content of this report rests entirely with
the authoring committee and the institution.

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Veterans and Agent Orange: Update 2014

Committee to Review the Health Effects in

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Veterans and Agent Orange: Update 2014

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Veterans and Agent Orange: Update 2014

Parkinson Disease and Parkinsonism

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Veterans and Agent Orange: Update 2014

VETERANS AND AGENT ORANGE: UPDATE 2014

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Veterans and Agent Orange: Update 2014

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101 PD cases 349 (186

474 PD cases VV with low

JEM group (medium)

JEM and an algorithm

Kang et al., 10 PD deaths

Diagnosis from death

Veterans and Agent Orange: Update 2014

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Initial screening phoneinterview followed by

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PD and high vs low Diagnosis from death

Veterans and Agent Orange: Update 2014

Tanner et al., 519 cases;

Elbaz et al., 224 PD cases 557 controls

Ever personally used/mixed or applied:

For youngest quartile at diagnosis:

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2 cardinal signs (rest

Veterans and Agent Orange: Update 2014

and average duration of

Veterans and Agent Orange: Update 2014

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Engel et al., 238

Behari et al., 377

Occupational, men only

Controlled for age, sex,

Veterans and Agent Orange: Update 2014

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Taylor et al., 140

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All occupations contributing exposure to:

Logistic analysis adjusted for age, sex, family history,

Interviewoccupational Pesticides vs no pesticides:

246 matched Interviewpesticides or

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Veterans and Agent Orange: Update 2014

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122 aged 50 Questionnaireever

Veterans and Agent Orange: Update 2014

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Veterans and Agent Orange: Update 2014

VETERANS AND AGENT ORANGE: UPDATE 2014

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Veterans and Agent Orange: Update 2014

consistently showed non-signicantly elevated risks: medium (OR = 1.30, 95%

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Veterans and Agent Orange: Update 2014

VETERANS AND AGENT ORANGE: UPDATE 2014

changes in D2 receptors, tyrosine hydroxylase, and dopamine beta-hydroxylase)

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Veterans and Agent Orange 2014 - Parkinson Disease & Parkonsonism

Veterans and Agent Orange 2014 - Parkinson Disease & Parkonsonism