Veterans and Agent Orange 2014 - Parkinson Disease & Parkonsonism

8/16/2019 Veterans and Agent Orange 2014 - Parkinson Disease & Parkonsonism

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Copyright © National Academy of Sciences. All rights reserved.

Veterans and Agent 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

V eteransand AgentOrangeUpdate 2014


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743

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 specificity 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 clarifies that the finding for PD should

be interpreted by VA to include all diseases with Parkinson-like symptoms unless

those symptoms can be definitively 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 find any new significant associations between the relevant exposures

and neurological disorders. Current evidence supports the findings of earlier

studies that:

There is limited or suggestive evidence of an association between thechemicals of interest and PD and diseases that present with Parkinson-

like symptoms.

There is inadequate or insufficient evidence to determine whether there

is an association between the chemicals of interest and any of the other

adverse neurologic outcomes.


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NEUROLOGIC DISORDERS 751

Previous VAO reports have not identified 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 ad-

dition 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, al-

though its confidence 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 specific 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 first described as a single

entity in 1817 by James Parkinson. In recent years, many nonmotor manifesta-

tions 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 specific environmental risk factors remain largely

unknown. The diagnosis of PD is based primarily on clinical examination, al-

though in recent years, magnetic resonance imaging and functional brain imaging

have become increasingly useful. PD is difficult to distinguish from a variety

of Parkinsonian syndromes, including drug-induced Parkinsonism, and neuro-

degenerative diseases, such as atrophy of multiple systems, that present with

Parkinsonian features combined with other abnormalities. Ultimately, a diagnosisof PD can be confirmed with postmortem pathology examination of brain tissue

for the characteristic loss of neurons from the substantia nigra and telltale Lewy

body intracellular inclusions. Pathology findings 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 person-

years, while its prevalence ranges from 18 to 182 per 100,000 persons. It affects


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752 VETERANS AND AGENT ORANGE: UPDATE 2014

about 1 percent of all persons over 60 years old and up to 5 million people world-

wide. PD is the second-most common neurodegenerative disease (after AD).

Research on the genetic, epigenetic, and environmental causes of PD sug-

gests that it has multiple risk factors, including aging, environmental exposure,

and genetic predisposition (Gao and Hong, 2011; Kwok, 2010). The peak inci-

dence and prevalence of PD are consistently found in people 60–80 years old. A

consensus statement from a 2007 meeting of PD experts (Bronstein et al., 2009)

concluded that, in addition to firm evidence that the toxicant 1-methyl-4-phenyl-

1,2,4,6-tetrahydropyridine (MPTP) can induce PD, there is substantial evidence

that men are at greater risk and that smoking and coffee consumption are associ-

ated 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 first-degree relative who

has PD. At least 13 gene mutations have been identified in autosomal dominantPD, including mutations in parkin and α-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 insufficient information to determine whether there is an associa-

tion between exposure to the COIs and PD. Five case-control studies reviewed by

those committees had investigated association between PD and “herbicide” expo-

sure without providing further specificity. Two of these did not find 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 significant associations with herbicide exposure (Butterfield et al.,

1993; Gorell et al., 1998; Semchuk et al., 1992).

Two new studies reviewed by the committee responsible for Update 2008

examined association specifically 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

significance (OR = 2.07, 95% CI 0.69–6.23), while increases for the chemical

class of chlorophenoxy acids or esters noted by Brighina et al. (2008) reached

statistical significance only in the quartile of cases who were youngest at diag-

nosis (OR = 1.52, 95% CI 1.04–2.22). In the prospective Agricultural Health

Study (AHS), incident PD was related in a dose–response manner to increasing


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NEUROLOGIC DISORDERS 753

days of pesticide use (Kamel et al., 2007b). On the basis of the evidence summa-

rized 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 affirm this

conclusion.

The findings 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 women—4,734 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, officer status, and nursing status was not elevated in those de-

ployed to Vietnam versus the non-deployed cohort (relative risk [RR] = 1.25, 95%CI = 0.34–4.59), and there was no suggestion of an increase when this compari-

son was made for the subsets of only nurses (RR = 0.78, 95% CI 0.17–3.50).

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 prox-

imity of his unit to herbicide-sprayed areas. No association was found between

PD (International Classification of Diseases, Revision 10 [ICD-10] G20-G21)

mortality and the individual EOI scores (HR = 1.01, 95% CI 0.83–1.22) or when

the high-exposure group was compared to the low-exposure group (HR = 0.88,

95% CI 0.40–1.95).

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 ex-

posure (OR = 1.18, 95% CI 0.99–1.42 and OR = 1.26, 95% CI 0.93–1.69, respec-

tively) 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 Ex-

amination 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) identified 196 individuals certified before 1994 to receive medication for

PD from the national reimbursement program; hospital records were obtained


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R e f e r e n c e

a n d C o u n t r y

C a s e s i n

S t u d y G r o u p

C o m p a r i s o n

G r o u p

E x p o s u r e A s s e s s m e n t

E x p o s u r e ( s ) a

n

O R ( 9 5 % C I )

D i a g n

o s i s o f

N e u r o

l o g i c D y s f u n c t i o n

K a n g e t a l . ,

2 0 1 4

1 0 P D d e a

t h s

( 2 , 2

6 0 i n

V i e t n a m

c o h o r t a n d

1 , 7 8 1 i n

n e a r - V i e t n

a m

c o h o r t )

5 , 3 1 3 n o n -

d e p l o y e d U S

f e m a l e V V

V i e t n a m v e t e r a n s —

i n f o r m a t i o n o b t a i n e d f r o m

d e a t h c e r t i fi c a t e s , V

A

r e c o r d s , S o c i a l S e c

u r i t y

D e a t h M a s t e r F i l e ,

N C H S

N a t i o n a l D e a t h I n d

e x

A l l C O I s

1 0 P D

c a s e s

( 8 P D

c a s e s i n

n u r s e s )

V i e t n a m c o h o r t :

1 . 3 ( 0 . 3 – 4 . 6

)

N u r s e s o n l y :

0 . 8 ( 0 . 2 – 3 . 5

)

D i a g n

o s i s f r o m d e a t h

r e c o r d

s

v a n d e r

M a r k e t a l . ,

2 0 1 4

4 4 4 c a s e s

8 7 6 m a t c h e d

c o n t r o l s

J E M a n d a n a l g o r i t h m

d e r i v e d f r o m t h e A H S

w e r e u s e d t o d e r i v e

c u m u l a t i v e e x p o s u r e

t o h e r b i c i d e s ; a c r o

p -

b a s e d m e t h o d w a s u s e d

t o e s t i m a t e e x p o s u r e t o

p a r t i c u l a r p e s t i c i d e

s

J E M g r o u p ( m e d i u m )

1 . 3 ( 0 . 7 – 2 . 4

)

N e u r o

l o g i s t r e v i e w o f

m e d i c

a l r e c o r d s

J E M g r o u p ( h i g h )

0 . 3 0 . 6 – 2 . 5 )

A H S - a l g o r i t h m g r o u p

( m e d i u m )

1 . 2 ( 0 . 6 – 2 . 3

)

A H S - a l g o r i t h m g r o u p ( h i g h )

1 . 5 ( 0 . 8 – 3 . 0

)

2 , 4 - D ( l o w )

1 . 1 ( 0 . 5 – 2 . 4

)

2 , 4 - D ( h i g h )

1 . 7 0 . 8 – 3 . 5 )

W e i s s k o p f

e t a l . ,

2 0 1 2

1 0 1 P D c a

s e s 3 4 9 ( 1 8 6

m a t c h e d

c o n t r o l s )

P C B s a n a l y z e d i n s e r u m

M o n o - o r t h o d i o x i n - l i k e

P C B s ( P C B s 1 0 5 , 1 1 8 , 1 5 6 ,

1 5 7 , 1 6 7 , 1 8 9 )

P C B 1 1 8 :

0 . 4 ( 0 . 4 – 1 . 0

)

D i o x i n - l i k e P C B s ;

0 . 3 ( 0 . 1 – 0 . 9

)

N e u r o

l o g i s t r e v i e w o f

m e d i c

a l r e c o r d s

Y i e t a l . ,

2 0 1 4 a

4 7 4 P D c a

s e s V V w i t h l o w

e x p o s u r e

( 6 9 , 3 0 5 ) v s

V V w i t h h i g h

e x p o s u r e

( 4 2 , 4 2 1 )

K o r e a n V i e t n a m

v e t e r a n s — p r e v a l e n

c e

d a t a o b t a i n e d f r o m

K o r e a

N a t i o n a l H e a l t h I n s u r a n c e

c l a i m s ( 0 1 / 2 0 0 0 – 0 9 / 2 0 0 5 )

A O ( b a s e d o n s e l f - r e p o r t

a n d p r o x i m i t y o f v e t e r a n ’ s

m i l i t a r y u n i t t o A O - s p r a y e d

a r e a )

2 1 3

c a s e s

w i t h h i g h

e x p o s u r e ;

2 6 1

c a s e s

w i t h l o w

e x p o s u r e

P D a n d h i g h v s l o w

e x p o s u r e :

H R = 1 . 2 ( 1 . 0 – 1 . 4

)

L o g E O I s c o r e s :

H R = 1 . 0 ( 1 . 0 – 1 . 1

)

S e c o n d a r y P D a n d

h i g h v s l o w e x p o s u r e :

H R = 1 . 3 ( 0 . 9 – 1 . 7

)


H R = 1 . 0 ( 0 . 9 – 1 . 1

)

I n s u r a

n c e c l a i m d a t a

754

T A B L E

1 1 - 1

E p i d e m i o l o g i c S t u d i e s o f H e r b i c i d e

a E

x p o s u r e a n d P a r k i n s o n D i s e

a s e a n d P a r k i n s o n - L i k e C o n d i t i o n s ( S h a d e d

e n t r i e s a r e n e w i n f o

r m a t i o n f o r t h i s u p d a t e )


7/24



Y i e t a l . ,

2 0 1 4 b

2 5 P D

d e a t h s ; t o t a l

p o p u l a t i o n

1 7 , 5

2 9

V V w i t h l o w

e x p o s u r e

( 7 , 9

7 3 ) v s

V V w i t h h i g h

e x p o s u r e

( 9 , 5

5 6 )

V V ( K o r e a n V e t e r a

n s

H e a l t h S t u d y ) — c a u s e o f

d e a t h a s c e r t a i n e d f r o m

N a t i o n a l S t a t i s t i c a l O f fi c e

( 1 9 9 2 – 2 0 0 5 )

A O ( b a s e d o n s e l f - r e p o r t

a n d p r o x i m i t y o f v e t e r a n ’ s

m i l i t a r y u n i t t o A O - s p r a y e d

a r e a )

1 3 h i g h -

e x p o s u r e

d e a t h s ;

1 2 l o w -

e x p o s u r e

d e a t h s

P D a n d h i g h v s l o w

e x p o s u r e :

H R = 0 . 9 ( 0 . 4 – 2 . 0

)


H R = 1 . 0 ( 0 . 8 – 1 . 2

)

D i a g n

o s i s f r o m d e a t h

r e c o r d

s

K e n b o r g

e t a l . ,

2 0 1 2 ;

D e n m a r k

2 8 P D c a s e s

f r o m m a l e

m e m b e r s

o f D a n i s h

U n i o n o f

G a r d e n e r s

( n

= 3 , 1 2 4 )

I n c i d e n c e o f

P D i n g e n e r a l

p o p u l a t i o n o f

D e n m a r k

H o s p i t a l d i a g n o s i s

o f P D

b e t w e e n 1 9 7 7 – 2 0 0 8

P e s t i c i d e s ( i n c l u d i n g

p h e n o x y h e r b i c i d e s )

2 8 1 1 1 6 1

H o s p i t a l i z a t i o n :

1 . 1 ( 0 . 8 – 1 . 7

)

B o r n b e f o r e 1 9 1 5 :

1 . 6 ( 0 . 8 – 2 . 8

)

B o r n 1 9 1 5 – 1 9 3 4 :

1 . 2 ( 0 . 7 – 1 . 9

)

B o r n 1 9 3 5 o r l a t e r :

0 . 3 ( 0 . 0 – 1 . 6

)

1 . 8 ( 0 . 9

7 – 3 . 4 )

1 . 8 ( 0 . 9

5 – 3 . 3 )

N o t s p e c i fi e d

R u g b j e r g a t

a l . ,

2 0 1 1 ;

C a n a d a

4 0 3 P D

c a s e s f r o m

p h a r m a c y

d a t a b a s e

4 0 5 m a t c h e d

c o n t r o l s

I n i t i a l s c r e e n i n g p h

o n e -

i n t e r v i e w f o l l o w e d

b y

a n i n - p e r s o n p h y s i c a l

a s s e s s m e n t e m p l o y

i n g a

c h e c k l i s t a n d r e c o r d o f

s y m p t o m s , r e v i e w e

d b y a

n e u r o l o g i s t s p e c i a l i z i n g i n

m o v e m e n t d i s o r d e r s

H e r b i c i d e s

N e u r o t o x i c p e s t i c i d e s

( i n c l u d i n g 2 , 4 - D , 2 , 4 , 5 - T )

3 3 3 5

1 . 8 ( 0 . 9

7 – 3 . 4 )

1 . 8 ( 0 . 9

5 – 3 . 3 )

P a r k i n

s o n i a n t r e m o r ,

r i g i d i t y , b r a d y k i n e s i a ,

m a s k e

d f a c i e s ,

m i c r o g r a p h i a , o r

p o s t u r a l i m b a l a n c e

F i r e s t o n e

e t a l . ,

2 0 1 0

( u p d a t e s

a n d e x p a n d s

F i r e s t o n e

e t a l . ,

2 0 0 5 ) ;

W a s h i n g t o n ,

U S

E n r o l l e d

c a s e s

i n c r e a s e d

f r o m 2 5 0

( i n o r i g i n a

l

s t u d y ) t o 4

0 4 5 2 6 u n r e l a t e d

c o n t r o l s

S t r u c t u r e d f a c e - t o - f a c e

i n t e r v i e w s ; d e m o g r a p h i c

i n f o r m a t i o n c o l l e c t e d , j o b

d e s c r i p t i o n s ( i f h e l d f o r

m o r e t h a n 6 m o s ) , a n d

w o r k p l a c e e x p o s u r e s t o

v a r i o u s i n d u s t r i a l t o x i c a n t s

i d e n t i fi e d f r o m a c h e c k l i s t

w e r e r e c o r d e d

2 , 4 - D

8

0 . 8 ( 0 . 3 – 2 . 0

)

≥ 2

o f

4 c a r d i n a l s i g n s ;

m u s t h a v e b r a d y k i n e s i a

o r r e s t i n g t r e m o r , m a y

h a v e c

o g w h e e l r i g i d i t y ,

o r p o s

t u r a l r e fl e x

i m p a i r m e n t

755

c o n t i n u e d


8/24



756

R e f e r e n c e

a n d C o u n t r y

C a s e s i n

S t u d y G r o u p

C o m p a r i s o n

G r o u p



n

O R ( 9 5 % C I )

D i a g n

o s i s o f

N e u r o


E l b a z e t a l . ,

2 0 0 9 ;

F r a n c e

2 2 4 P D c a

s e s 5 5 7 c o n t r o l s

I n i t i a l s e l f - a s s e s s m

e n t ,

p l u s i n d i v i d u a l i n t e

r v i e w

w i t h o c c u p a t i o n a l

s p e c i a l i s t

P h e n o x y h e r b i c i d e s

n a

1 . 8 ( 0 . 9 – 3 . 3

)

≥ 2

c a

r d i n a l s i g n s ( r e s t

t r e m o r , b r a d y k i n e s i a ,

r i g i d i t y , i m p a i r e d

p o s t u r a l r e fl e x e s )

A g e o f o n s e t > 6 5 y r s

n a

2 . 9 ( 1 . 1 – 7 . 3

)

T a n n e r e t a l . ,

2 0 0 9 ; U S

5 1 9 c a s e s ;

c o n s e c u t i v

e l y

e l i g i b l e

s u b j e c t s

b e t w e e n J u l y

1 , 2 0 0 4 , a n d

M a y 3 1 ,

2 0 0 7

5 2 1 c o n t r o l s

f r e q u e n c y

m a t c h e d

t o c a s e s b y

a g e , s e x , a n d

l o c a t i o n

T e l e p h o n e i n t e r v i e w e r s

c o l l e c t e d i n f o r m a t i o n

a b o u t e x p o s u r e s b e

f o r e t h e

r e f e r e n c e a g e ; e m p

l o y m e n t

h i s t o r y — i n d u s t r y ,

l o c a t i o n , p r o c e s s e s ,

m a t e r i a l s , a n d j o b t a s k s

T o x i c a n t e x p o s u r e

c o l l e c t e d f o r s o m e

j o b s

2 , 4 - D

1 6

2 . 6 ( 1 . 0 – 6 . 5

)

E n r o l l i n g i n v e s t i g a t o r

d e t e r m

i n e d d i a g n o s i s

a n d t y

p e o f

P a r k i n

s o n i s m , U n i fi e d

P a r k i n

s o n D i s e a s e

R a t i n g S c a l e s c o r e , a n d

c l i n i c a l f e a t u r e s

B r i g h i n a

e t a l . ,

2 0 0 8 ;

U S ( M a y o

C l i n i c )

8 3 3 P D

s e q u e n t i a l

c a s e s f r o m

c l i n i c ;

m e d i a n a g e =

6 7 . 7 y r s , 2

0 8

c a s e s 5 9 . 8

y r s

4 7 2

u n a f f e c t e d

s i b l i n g s a n d

3 6 1 u n r e l a t e d

c o n t r o l s

S e l f - r e p o r t d o w n t o

s p e c i fi c h e r b i c i d e s ;

2 , 4 - D s a i d t o b e m o s t

p r e v a l e n t i n c a s e s , b u t

p u b l i s h e d a n a l y s i s

n o t t h a t

d e t a i l e d

F o r y o u n g e s t q u a r t i l e a t d i a g n

o s i s :

P D d i a g n o s e d b y

m o v e m e n t d i s o r d e r

s p e c i a

l i s t

P e s t i c i d e s ( e v e r ) :

8 7

1 . 8 ( 1 . 1 – 2 . 9

)

H e r b i c i d e s ( e v e r ) :

2 . 5 ( 1 . 3 – 4 . 5

)

P h e n o x y h e r b i c i d e s :

1 . 5 ( 1 . 0 – 2 . 2

)

I n s e c t i c i d e s ( e v e r ) :

1 . 0 ( 0 . 6 – 1 . 7

)

F u n g i c i d e s ( e v e r ) :

1 . 0 ( 0 . 3 – 3 . 2

)

D h i l l o n

e t a l . ,

2 0 0 8 ; U S

( U n i v e r s i t y

o f T e x a s )

1 0 0 P D c a

s e s

r e c r u i t e d

f r o m a

m e d i c a l

c e n t e r ’ s

n e u r o l o g i c

a l 8 4 c o n t r o l s

w i t h o u t P D

r e c r u i t e d

f r o m t h e

s a m e m e d i c a l

c e n t e r

P r o f e s s i o n a l l y

a d m i n i s t e r e d q u e s t i o n n a i r e

u s e d t o d e t e r m i n e m i l i t a r y

h i s t o r y ( i n c l u d i n g s p r a y i n g

h e r b i c i d e s / p e s t i c i d e s ) ,

p e r s o n a l u s e / m i x i n g

E v e r p e r s o n a l l y u s e d / m i x e d o

r a p p l i e d :

P D d i a g n o s e d b y

n e u r o l o g i s t s p e c i a l i z i n g

i n m o v e m e n t d i s o r d e r s

u s i n g

s t a n d a r d c l i n i c a l /

l a b d i a g n o s t i c c r i t e r i a

H e r b i c i d e u s e - h o m e o r

a g r i c u l t u r a l

3 4

0 . 8 ( 0 . 4 – 1 . 4

)

2 , 4 - D

1 7

1 . 2 ( 0 . 6 – 2 . 8

)

2 , 4 , 5 - T

4

0 . 5 ( 0 . 1 – 1 . 6

)

S i l v e x o r o t h e r 2 , 4 , 5 - T P

1

0 . 3 ( 0 . 0 – 2 . 7

)

T A B L E

1 1 - 1


a E


a s e a n d P a r k i n s o n - L i k e C o n d i t i o n s ,

c o n t i n u e d


9/24



757

i n s t i t u t e i n

E a s t T e x a s

a n d a v e r a g e d u r a t i o n o f

e x p o s u r e t o h e r b i c i d e s a n d

s p e c i fi c p e s t i c i d e s ,

a m o n g

o t h e r e x p o s u r e s

p r o d u c t s

H a n c o c k

e t a l . ,

2 0 0 8 ;

U S ( D u k e )

3 1 9 c a s e s

2 9 6

u n a f f e c t e d

r e l a t i v e s a n d

o t h e r s

A l l c o m p a r i s o n s r e

f e r e n t

t o t h o s e w h o n e v e r

a p p l i e d

a n y p e s t i c i d e

P e s t i c i d e a p p l i c a t i o n :

2 0 0

1 . 6 ( 1 . 1 – 2 . 3

)

I n s e c t i c i d e s :

1 . 8 ( 1 . 2 – 2 . 8

)

B o t a n i c a l :

7

5 . 9 ( 0 . 6 – 5 6 )

O r g a n o p h o s p h a t e :

5 3

1 . 9 ( 1 . 1 – 3 . 6

)

H e r b i c i d e s :

1 . 6 ( 1 . 0 – 2 . 5

)

C h l o r o p h e n o x y :

1 5

2 . 1 ( 0 . 7 – 6 . 2

)

P h o s o p h o n o g l y c i n e :

5 7

1 . 5 ( 0 . 9 – 2 . 5

)

T r i a z i n e :

5

1 . 1 ( 0 . 3 – 3 . 6

)

K a m e l e t a l . ,

2 0 0 7 b ;

U S

( A g r i c u l t u r a l

H e a l t h

S t u d y )

[ U p d a t e s

K a m e l e t a l . ,

2 0 0 5 ]

8 3 p r e v a l e

n t

c a s e s a t

e n r o l l m e n t ;

7 8 i n c i d e n

t

c a s e s d u r i n g

f o l l o w - u p

a m o n g

p r i v a t e

a p p l i c a t o r s

a n d s p o u s e s

7 9 , 5

5 7

w i t h o u t P D a t

e n r o l l m e n t ;

5 5 , 9

3 1

w i t h o u t P D

f o l l o w e d u p

S e l f - r e p o r t o f i n d i v

i d u a l

h e r b i c i d e s ( 2 , 4 - D ;

2 , 4 , 5 - T ; 2 , 4 , 5 - T P ) o n

d e t a i l e d s e l f - a d m i n

i s t e r e d

q u e s t i o n n a i r e s a t

e n r o l l m e n t o r t e l e p

h o n e

i n t e r v i e w f o r f o l l o w

- u p

F o r i n c i d e n t c a s e s :

2 , 4 - D :

4 9

1 . 0 ( 0 . 5 – 2 . 1

)

2 , 4 , 5 - T :

2 4

1 . 8 ( 1 . 0 – 3 . 3

)

2 , 4 , 5 - T P :

7

0 . 9 ( 0 . 4 – 1 . 8

)

D i c a m b a :

3 2

1 . 5 ( 0 . 8 – 2 . 8

)

P a r a q u a t :

1 1

1 . 0 ( 0 . 5 – 1 . 9

)

T r i f u r a l i n :

3 2

1 . 7 ( 1 . 0 – 3 . 2

)

C y a n a z i n e

2 6

1 . 0 ( 0 . 5 – 1 . 8

)

F o r p r e v a l e n t c a s e s :

2 , 4 - D :

4 7

0 . 9 ( 0 . 5 – 1 . 8

)

2 , 4 , 5 - T :

1 6

0 . 9 ( 0 . 5 – 1 . 7

)

2 , 4 , 5 - T P :

4

0 . 8 ( 0 . 3 – 1 . 9

)

D i c a m b a :

2 6

0 . 9 ( 0 . 5 – 1 . 6

)

P a r a q u a t :

1 4

1 . 8 ( 1 . 0 – 3 . 4

)

T r i f u r a l i n :

3 1

0 . 9 ( 0 . 5 – 1 . 6

)

C y a n a z i n e

3 0

2 . 6 ( 1 . 4 – 4 . 9

)

c o n t i n u e d


10/24



758

R e f e r e n c e

a n d C o u n t r y

C a s e s i n

S t u d y G r o u p

C o m p a r i s o n

G r o u p



n

O R ( 9 5 % C I )

D i a g n

o s i s o f

N e u r o


F i r e s t o n e

e t a l . ,

2 0 0 5 ;

W a s h i n g t o n ,

U S

( U p d a t e d b y

F i r e s t o n e

e t a l . ,

2 0 1 0 )

2 5 0 ( 1 5 6

m e n ) n e w l y

d i a g n o s e d

1 9 9 2 – 2 0 0 2 a t

G r o u p H e a l t h

C o o p e r a t i v e

3 8 8 ( 2 4 1

m e n )

I n t e r v i e w d e t e r m i n i n g

o c c u p a t i o n a l a n d h o m e -

b a s e d p e s t i c i d e e x p

o s u r e

c h a r a c t e r i z e d b y c h

e m i c a l

n a m e o r b r a n d , d u r

a t i o n ,

a n d f r e q u e n c y

O c c u p a t i o n a l , m e n o n l y

C o n t r o l l e d f o r a g e , s e x ,

s m o k i n g

P e s t i c i d e s :

1 9

1 . 0 ( 0 . 5 – 1 . 9

)


1 5

0 . 9 ( 0 . 4 – 1 . 8

)

F u n g i c i d e s :

2

0 . 4 ( 0 . 1 – 3 . 9

)


9

1 . 4 ( 0 . 5 – 3 . 9

)

P a r a q u a t :

2

1 . 7 ( 0 . 2 – 1 2 . 8 )

H o m e u s e , a l l s u b j e c t s


1 7 8

1 . 0 ( 0 . 7 – 1 . 4

)


1 4 1

0 . 8 ( 0 . 6 – 1 . 1

)


1 4

0 . 6 ( 0 . 3 – 1 . 1

)


1 1 6

1 . 1 ( 0 . 8 – 1 . 5

)

B e h a r i e t a l . ,

2 0 0 1 ;

I n d i a

3 7 7

( 3 0 1 m e n ,

7 6

w o m e n )

3 7 7 m a t c h e d

f o r a g e ( ± 3

y r s ) , b u t n o t

s e x

S t r u c t u r e d i n t e r v i e w

M c N e m a r c h i - s q u a r e :


p = 0 . 0 1 0

( p r o t e c t i v e e f f e c t — n o t c o n fi r m e d b y m u l t i v a r i a t e a n a l y s i s )

I n s e c t i c i d e :

p = 0 . 1 6 9

R o d e n t i c i d e :

p = 0 . 6 6 2

E n g e l e t a l . ,

2 0 0 1 ;

U S ( c r o s s -

s e c t i o n a l ,

b u t

o t h e r w i s e

f a i r l y

h i g h - q u a l i t y

d e s i g n )

2 3 8

7 2

S e l f - a d m i n i s t e r e d

q u e s t i o n n a i r e f o r

o c c u p a t i o n a l e x p o s

u r e

[ p r e v a l e n c e r a t i o s ]

A n y p e s t i c i d e :

0 . 8 ( 0 . 5 – 1 . 2

)

N e u r o

l o g i c e x a m b y

t r a i n e d n u r s e


0 . 9 ( 0 . 6 – 1 . 3

)


0 . 9 ( 0 . 6 – 1 . 5

)


0 . 8

( 0 . 6 – 1 . 3

)

T A B L E

1 1 - 1


a E



c o n t i n u e d


11/24



759

K u o p i o

e t a l . ,

1 9 9 9 ;

F i n l a n d

1 2 3 ( o n s e t

o f P D b e f o r e

1 9 8 4 ; 6 3

m e n , 6

0

w o m e n )

2 4 6 m a t c h e d

o n s e x , a g e

( ± 2 y r s ) , a n d

u r b a n / r u r a l

I n t e r v i e w — p e s t i c i d e s o r

h e r b i c i d e s r e g u l a r l y o r

o c c a s i o n a l l y u s e d

P e s t i c i d e u s e :

3 9

1 . 0 ( 0 . 6 – 1 . 7

)

N e u r o

l o g i c e x a m

O c c a s i o n a l u s e :

2 6

1 . 2 ( 0 . 7 – 2 . 0

)

R e g u l a r u s e :

1 3

0 . 7 ( 0 . 3 – 1 . 3

)

H e r b i c i d e u s e :

3 3

1 . 4 ( 0 . 8 – 2 . 5

)

O c c a s i o n a l u s e :

2 0

1 . 7 ( 0 . 9 – 3 . 2

)

R e g u l a r u s e :

1 3

0 . 8 ( 0 . 4 – 1 . 7

)

T a y l o r e t a l . ,

1 9 9 9 ;

B o s t o n

M e d i c a l

C e n t e r

1 4 0

1 4 7 c o n t r o l s

r e f e r r e d b y

c a s e s

I n t e r v i e w — e x p o s u r e

r e c o r d e d a s t o t a l d a y s f o r

l i f e t i m e

L o g i s t i c a n a l y s i s a d j u s t e d f o r

a g e , s e x , f a m i l y h i s t o r y ,

e d u c a t i o n , s m o k i n g , w a t e r s o u r c e , h e a d i n j u r y , d e p r e s s i o n

N e u r o

l o g i c e x a m


1 . 0 ( 0 . 9 – 1 . 2

)


1 . 1 ( 0 . 7 – 1 . 7

)

G o r e l l e t a l . ,

1 9 9 8 ;

U S

1 4 4 ( a g e >

5 0 y r s )

4 6 4

I n t e r v i e w — h e r b i c i d e

a n d i n s e c t i c i d e u s e

w h i l e

w o r k i n g o n a f a r m

o r

g a r d e n i n g

A l l o c c u p a t i o n s c o n t r i b u t i n g e x p o s u r e t o :

S t a n d a r d c r i t e r i a o f P D

b y h i s

t o r y


4 . 1 ( 1 . 4 – 1 2 . 2 )


3 . 6 ( 1 . 8 – 7 . 2

)


1 . 6 ( 0 . 5 – 5 . 5

)

L i o u e t a l . ,

1 9 9 7 ;

T a i w a n

1 2 0

2 4 0 h o s p i t a l

c o n t r o l s

m a t c h e d f o r

a g e ( ± 2 y r s )

a n d s e x

I n t e r v i e w — o c c u p a t i o n a l

e x p o s u r e s t o h e r b i c

i d e s o r

p e s t i c i d e s

P e s t i c i d e s v s n o p e s t i c i d e s :

2 . 9 ( 2 . 3 – 3 . 7

)

N e u r o

l o g i c e x a m

B u t n o p a r a q u a t u s e :

2 . 2 ( 0 . 9 – 5 . 6

)

P a r a q u a t u s e :

4 . 7 ( 2 . 0 – 1 2 ) )

P a r a q u a t u s e v s n o p a r a q u a t :

3 . 2 ( 2 . 4 – 4 . 3

)

S e i d l e r

e t a l . ,

1 9 9 6 ;

G e r m a n y

3 8 0 ( a g e <

6 6 y r s w i t h

P D a f t e r

1 9 8 7 )

7 5 5 ( 3 7 9

n e i g h b o r h o o d ,

3 7 6 r e g i o n a l ;

n e i g h b o r h o o d

c o n t r o l s

m a y b e

o v e r - m a t c h e d )

I n t e r v i e w — d o s e - y e a r s

= y e a r s o f a p p l i c a t i o n

w e i g h t e d b y u s e


2 . 1 ( 1 . 6 – 2 . 6

)

N e u r o

l o g i c e x a m

H e r b i c i d e s — h i g h d o s e :

2 . 4 ( 1 . 0 – 6 . 0

)

D o s e t r e n d

v s n e i g h b o r c o n t r o l s

p = 0 . 0 6

v s r e g i o n a l c o n t r o l s

p < 0 . 0 0 1

I n s e c t i c i d e s — h i g h d o s e :

2 . 1 ( 0 . 9 – 4 . 8

)

D o s e t r e n d

v s n e i g h b o r c o n t r o l s

p = 0 . 1 2

v s r e g i o n a l c o n t r o l s

p < 0 . 0 0 1

c o n t i n u e d


12/24



760

R e f e r e n c e

a n d C o u n t r y

C a s e s i n

S t u d y G r o u p

C o m p a r i s o n

G r o u p



n

O R ( 9 5 % C I )

D i a g n

o s i s o f

N e u r o


H e r t z m a n

e t a l . ,

1 9 9 4 ;

C a n a d a

1 2 7

( 7 1 m e n a n d

5 6 w o m e n

)

2 4 5

( 1 2 1 w i t h

c a r d i a c

d i s e a s e ; 1 2 4

v o t e r s )

I n t e r v i e w — o c c u p a t i o n

w i t h p r o b a b l e p e s t i c i d e

e x p o s u r e

C a s e s v s v o t e r s — a m o n g

m e n

N e u r o

l o g i c e x a m



2 . 3 ( 1 . 1 – 4 . 9

)

C h l o r o p h e n o x y s :

1 . 2 ( 0 . 6 – 2 . 5

)

P a r a q u a t :

1 . 2 ( 0 . 6 – 2 . 4

)


1 . 3 ( 0 . 3 – 4 . 6

)


0 . 3 ( 0 . 1 – 0 . 9

)

B u t t e r fi e l d

e t a l . ,

1 9 9 3 ;

U S

6 3 y o u n g

o n s e t c a s e s

( a g e < 5 0

y r s )

6 8

Q u e s t i o n n a i r e — p e s t i c i d e

o r i n s e c t i c i d e u s e 1

0 t i m e s

i n a n y y e a r


3 . 2 ( p = 0 . 0 3 3 )

S t a n d a r d c r i t e r i a o f P D

b y h i s

t o r y


5 . 8 ( p < 0 . 0 0 1 )

D w e l l i n g f u m i g a t e d :

5 . 3 ( p = 0 . 4 5 )

S e m c h u k

e t a l . ,

1 9 9 2 ;

C a l g a r y ,

A l b e r t a ,

C a n a d a

1 3 0 l i v i n g

c a s e s f r o m

r e g i s t e r o f

C a l g a r y

r e s i d e n t s

( p o p u l a t i o n -

b a s e d )

2 6 0

c o m m u n i t y

c o n t r o l s

m a t c h e d f o r

a g e ( ± 2 . 5

y r s ) a n d s e x ,

i d e n t i fi e d b y

R D D

I n t e r v i e w — s e l f - r e p

o r t o f

e x p o s u r e f o r e a c h j o b h e l d

> 1 m o


3 2

2 . 3 ( 1 . 3 – 4 . 0

)

N e u r o

l o g i c e x a m

c o n fi r m i n g i d i o p a t h i c

P D w i t h o u t d e m e n t i a

( a v e r a

g e 7 . 8 y r s f r o m

d i a g n o s i s )


1 7

3 . 1 ( 1 . 3 – 7 . 0

)

E x p o s e d d u r i n g a g e i n t e r v a l :

1 6 – 2 5 y r s

1 . 4 ( 0 . 5 – 4 . 3

)

2 6 – 3 5 y r s

4 . 8 ( 1 . 5 – 1 5 . 0 )

3 6 – 4 5 y r s

3 . 8 ( 1 . 2 – 1 3 . 0 )

4 6 – 5 5 y r s

4 . 9 ( 1 . 3 – 1 9 . 0 )


1 7

2 . 1 ( 1 . 0 – 4 . 1

)


1 6

1 . 6 ( 0 . 8 – 3 . 3

)

T A B L E

1 1 - 1


a E



c o n t i n u e d


13/24



S t e r n e t a l . ,

1 9 9 1 ;

N J a n d P A ,

U S

6 9 — a l l

y o u n g

o n s e t c a s e s

i d e n t i fi e d

( a g e < 4 0

y r s ) ;

8 0 — r a n d o

m

s e l e c t i o n o

f

o l d o n s e t

c a s e s ( a g e

>

5 9 y r s )

1 4 9

n o m i n a t e d

b y e a c h c a s e

o r p i c k e d

f r o m h o s p i t a l ;

m a t c h e d b y

a g e ( ± 6 y r s ) ,

s e x , a n d r a c e

I n t e r v i e w — s e l f - r e p

o r t o f

i n s e c t i c i d e a n d p e s t i c i d e

u s e b y s e l f o r o t h e r s i n

h o m e o r g a r d e n


0 . 7 ( 0 . 3 – 1 . 4

)

R e v i e w o f m e d i c a l

r e c o r d

s , r e s p o n s i v e t o

P D m e d i c a t i o n ( u n d e r

t r e a t m

e n t a v e r a g e o f

8 . 2 y r s ) , w

i t h o u t m a j o r

c o g n i t i v e i m p a i r m e n t

O n s e t < 4 0 y r s :

0 . 6 ( 0 . 2 – 1 . 7

)

O n s e t > 5 9 y r s :

0 . 8 ( 0 . 3 – 2 . 1

)


1 . 1 ( 0 . 7 – 1 . 7

)

O n s e t < 4 0 y r s :

0 . 9 ( 0 . 5 – 1 . 7

)

O n s e t > 5 9 y r s :

1 . 3 ( 0 . 7 – 2 . 4

)

A d j u s t e d f o r s m o k i n g , h e a d i n j u r y , r u r a l r e s i d e n c e :


0 . 5 ( 0 . 2 – 1 . 1

)


0 . 9 ( 0 . 6 – 1 . 5

)

H e r t z m a n

e t a l . ,

1 9 9 0 ;

B r i t i s h

C o l u m b i a ,

C a n a d a

5 7 p r e v a l e n t

P D p a t i e n t s

( a g e <

7 9 y r s )

( 5 0 – 5 4 h a d

c o n fi r m e d

P D , n o t c l e a r

e x a c t l y h o w

m a n y )

1 2 2 a g e d 5 0 –

7 9 y r s w h o

r e s p o n d e d

f r o m e l e c t o r a l

r o l l s

Q u e s t i o n n a i r e — e v e r

w o r k e d i n a n o r c h a

r d

W o r k i n o r c h a r d s :

3 . 7 ( 1 . 3 – 1 0 . 3 )

N e u r o

l o g i c e x a m

c o n fi r m e d d i a g n o s t i c

c r i t e r i a i n 5 5 o f 6 9

c a s e s i d e n t i fi e d b y

a s k i n g

p h y s i c i a n s i n

a r e a

P a r a q u a t :

4 / 5 7

( p = 0 . 0 1 )

N O T E : 2 , 4 - D , 2 , 4 - d i c h l o r o p h e n o x y a c e t i c a c i d ; 2 , 4 , 5 - T , 2 , 4 , 5 - t r i c h l o r o p h e n o x y a c e t i c a c i d ; 2 , 4 , 5 - T P , 2

- ( 2 , 4 , 5 - t r i c h l o r o p h e n o x y ) p r o p i o n i c a c i d o r S i l v e x ; A H S ,

A g r i c u l t u r a l H e a l t h S t u d

y ; A O , A g e n t O r a n g e ; C I , c o n fi d e n c e i n

t e r v a l ; C O I , c h e m i c a l o f i n t e r e s t ; E O I ,

E x p o s u r e O p p o r t u n i t y I n d e x ; J E M , j o b

– e x p o s u r e m a t r i x ;

H

Documents

Veterans and Agent Orange 2014 - Parkinson Disease & Parkonsonism