Occupational and Environmental
Exposures:
Associations with Parkinsonism
Bradley Evanoff, MD, MPH
Department of Medicine
Disclosure: Bradley Evanoff
Research Support / Grants
NIEHS, NCI, NCATS, NIOSH
Stock/Equity (any amount)
None
Consulting / Employment
Monsanto
Speakers Bureau / Honoraria
None
Other
None
2
Acknowledgements
• Epidemiology
– Harvey Checkoway, PhD
– Bradley Evanoff, M.D., MPH
– Jessica Lundlin
• Neuroimaging
– Susan Criswell, M.D., MSCI
– Joel Perlmutter, M.D.
– Johanna Hartlein, RN
• Movement Disorders
– Brad Racette, M.D.
– Samer Tabbal, M.D.
– Susan Criswell, M.D.
– Allison Willis, M.D., MSCI
• Pathology
– Jing Zhang, M.D.
– Jill Murray, M.D.
– Gill Nelson, MSc
•
•
•
•
Industrial Hygiene
– Noah Seixas, PhD
– Angela Hobsen, MPH
– David Sterling, PhD
Research Coordinators
– Laura Good
– Angela Birke
– Karen McDonell
– Rachel Harris
Industry Consultants
– Milan Racic
– Leonard Gunderson
– Bill Kojola
– Mark Garrett
Funding
– NINDS, NIEHS, APDA, Michael J.
Fox Foundation
– No researcher associated with
these studies has received any
money personally related to this
research.
Parkinson’s Disease:
Risk Factors
Non-modifiable




Age
Gender (Men)
Race (Caucasians)
Genetics









Modifiable
Well water
Farming
Rural residence
Wood pulp mills
Steel/alloy industries
Herbicides/Pesticides
Trauma
Metals (manganese, iron)
Tobacco
Variance in PD Incidence Due to Known
Risk Variables
4%
13%
7%
7%
Willis and Racette, unpublished.
Air Pollution in Canada and Risk of PD
Spatial distribution of manganese in TSP in Hamilton
Cumulative hazard of a physician’s diagnosis
of in relation age in 1999 and Mn exposure.
OR for physician’s diagnosis of PD = 1.034 (1.00–1.07) per 10 ng/m3 increase in Mn in TSP.
Estimated “doubling exposure” was 150 ng/m3
M.M. Finkelstein, M. Jerrett / Environmental Research, 2007.
PD Non-randomly Distributed in US
z test statistic for nonrandom clustering p<0.00001
Willis AW, et al. Neuroepidemiology, 2010.
US Heavy Metal Emitting Facilities: 1988-1998
Willis AW, et al. Am J Epi, 2010.
Cumulative onsite copper, manganese or lead
release, 1988-1998
Cumulative onsite copper, manganese or lead release, 1988-1998 (as reported to the EPA)
Cumulative Reported Onsite Metal Release
(in metric tons)
TRI NAICS Code, Industry Description
Copper
311 Food/Beverages/Tobacco
Lead
722.16
Manganese
59.08
96.09
313 Textiles
7.06
69.37
0.12
315 Apparel
0.00
No facilities
No facilities
4.49
316 Leather
0.91
No facilities
321 Wood Products
17.10
5.99
3.84
322 Paper
15.93
1.37
2193.05
323 Printing and Publishing
77.77
2.52
0.50
324 Petroleum
32.68
196.82
189.49
325 Chemicals
1362.06
1192.24
22141.09
326 Plastics and Rubber
108.39
31.62
2.98
79.40
284.18
764.19
7.33
1069.83
1373.26
73190.84
35041.40
83602.23
1841.60
1140.72
4732.29
333 Machinery
657.33
111.74
1493.45
334 Computers/Electronic Products
285.16
112.48
13.97
335 Electrical Equipment
966.05
2492.98
466.27
336 Transportation Equipment
946.58
9.04
318.19
2.88
1448.89
19.28
327 Stone/Clay/Glass
3273 Cement
331 Primary Metals
332 Fabricated Metals
337 Furniture
339 Miscellaneous Manufacturing
562 Hazardous Waste
2121 Coal Mining
2122 Metal Mining
2211 Electric Utilities
112.35
44.36
33.41
1549.87
11074.03
3759.13
0.00
0.00
0.68
250837.24
399.80
5364.49
354.29
193.17
975.20
4246 Chemical Wholesalers
0.12
0.01
0.24
4247 Petroleum Bulk Terminals
0.00
0.00
0.00
635.01
527.12
226.22
No TRI NAICS code
Willis AW, et al. Am J Epi, 2010.
Increased Risk of PD Associated with Metal Emissions
* less than 100lbs. reported
Willis AW, et al. Am J Epi, 2011.
Neurologist care in Parkinson disease: a utilization,
outcomes, and survival study (Willis 2011)
• Determine if neurologist treatment of PD is
associated with improved clinical outcomes
• National sample of 138,000 Medicare
beneficiaries with PD in 2002; followed 6 yrs
• Compared risk of death, hip fx and nursing
home placement between PD cases treated by
neurologist vs. primary care physicians
• Adjusted for multiple demographic factors and
medical co-morbidities
• Neurologist treated
patients with PD
had lower:
– Mortality
– Nursing home
placement
– Hip fractures
Limitations:
- Diagnostic uncertainty
- Can’t directly measure disease severity
- Can only study what Medicare collects
PD Mortality According to Geographical Variables
Variable
Percent Alive (n)
Risk of Death *
OR (95%CI)
Geographical Region**
Northeast
34.9 (10769)
REF.
Midwest
34.9 (12114)
1.04 (1.03-1.07)
South
34.5 (17515)
1.06 (1.05-1.08)
West
39.5 (8041)
0.93 (0.91-0.95)
Completely Urban (>1,000,000)
35.3 (37631)
REF.
Completely Rural (<2,500)
37.6 (3361)
0.91 (0.88-0.94)
Low Manganese
38.1 (1853)
REF.
High Manganese
33.8 (3054)
1.19 (1.10-1.29)
Low Copper
35.5 (2236)
REF.
High Copper
37.1 (2919)
1.01 (0.96-1.07) NS
Population Density†
Urban Heavy Metal emission ‡
Willis et al, Arch Neurol, 2012
History of Mn Neurotoxicity
• 1837 – Crouper
describes 5 cases of
disease in workers
heavily exposed to
Mn oxide.
Characterized by
bradykinesia, masked
facies, postural
instability
History of Mn Neurotoxicity
• 1955 – Rodier
describes 115 cases of
fulminant neurological
disorder in Mn
miners: with dystonia,
neuropsychiatric
symptoms, “masque
manganifique”
Metals and PD
Gorell et al., 1997
Younger Age of PD Onset in Mn
Exposed Welders
Racette et al. Neurology, 2001
Occupational Welding: A Model for
Human Mn Exposure
• 361,970 welders in U.S.
in 2002
• 800,000 full-time welders
worldwide
• >2 million workers perform
welding as part of work
duties
Bureau of Labor Statistics, 2002;
NIOSH, 1998
Metals
Science 2003
The Controversy of
Defining Manganese Toxicity
• “The clinical, imaging, and
pathologic features of
manganese-induced
parkinsonism are so
characteristic that the
differentiation of this
syndrome should pose no
problem for the experienced
clinician.”
Jankovic J. Searching of a relationship between manganese and
welding and Parkinson’s disease. Neurology 2005; 64:2021-2028.
Exposures then and now….
Clinical syndrome then and now….
Rodier et al., 1957
Luccini 2009, NeuroMol Med 11:311-322
Prevalence ratios of parkinsonism in
Alabama welders
Racette et al. Neurology, 2005.
Swedish Welder Incidence Rate for PD
Fored et al, OEM 2006
Danish Welder Hospitalization Rate for PD
Fryzek J et al, JOEM 2005
Epidemiology of Parkinsonism in Welders
Cohort
Worksite based shipyard and
fabrication workers exposed to
welding fumes in upper Midwest,
USA
Study Procedures
• Direct examination by movement
disorders specialist blinded to
occupational history
• Validated welding exposure questionnaire
(Hobsen et al. 2009)
• Derived cumulative Mn/m3 years (Hobson
et al., 2010)
• PDQ39
Case Definitions of Parkinsonism in Welders
• Unified Parkinson Disease Rating Scale
– Most widely used clinical rating scale for Parkinson disease
– Developed to monitor disease progression in PD clinical trials
– Quantifies motor abnormalities on a 0-108 continuous scale
– Higher scores associated with PD specific disability and
reductions in quality of life
• Exams done by movement disorders specialist
• Videotaped exam protocol – allowed scoring of UPDS elements
by external observers, testing of reliability between observers
Effects of parkinsonism on health status in
welding exposed workers (Harris 2011)
• Examined 394 active welders
• Evaluated for parkinsonism using Unified
Parkinson Disease Rating Scale (UPDRS3)
• Completed PDQ 39, a widely used QoL measure
for Parkinson Disease
• Parkinsonism in welders was common, (~15% had
UPDRS3 > 15) and was associated with reduced
QoL across multiple domains including mobility,
emotional well-being, and ADLs
Comparison of Parkinsonian Signs in Welders and Newly
Diagnosed, Untreated PD Patients
Parkinsonian Welders
(n=112)
Clinical Feature
Idiopathic PD patients
(n=118)
Total, mean (sd)
Total, mean (sd)
Upper limb bradykinesia
7.7 (2.6)
6.9 (4.2)
Upper limb rigidity
1.9 (1.4)
2.1 (1.3)
Lower limb bradykinesia
2.0 (1.4)
2.2 (1.8)
Lower limb rigidity
2.2 (1.4)*
1.6 (1.7)
Rest tremor
0.3 (0.8)*
1.9 (2.2)
Action/postural tremor
0.9 (1.2)
0.9 (1.1)
Axial signsa
4.3 (2.5)*
6.3 (4.9)
UPDRS3 score, mean (sd)
19.8 (4.6)
22.9 (13.7)
Racette, et al. unpublished
Imaging Biomarkers of Parkinsonism in Welders
Imaging Modality
Structural
• MPRAGE/T1
• DWI
Molecular
• FDOPA
Applications
Region definition
Exposure metric
Structural damage
• DTBZ
Synaptic function
Toxic mechanism
Clinical correlation
Functional MR
• Rs-fcMRI
Brain connectivity
Toxic mechanism
Clinical correlation(?)
Influx
Brain deposition
Mn Transport in Blood:
-80% bound to b1-globulin and albumin
-small fraction transferrin
Mn Transport across Blood-Brain Barrier:
-not completely understood
-multiple carrier-mediated transport process
(active, facilitated, transferrin-dependent: Mn3+, DMT1: Mn2+)
-competition with other metals, especially Fe
Fe-deficiency = increased Mn in CNS
Fe-overload = decreased Mn in CNS
-slow efflux (not carrier-mediated) = brain Mn accumulation
Aschner, Environ Health Perspect 108, 2000
MRI and Manganese Toxicity
↑ T1-Weighted MRI
Normal T2-Weighted MRI
Bowler R,et al. Neurotoxicology 2006; 27: 327-332.
Intensity Indices in Asymptomatic Welders
Controls
(n = 18)
Welders
(n = 18)
p value
Pallidal
Index (mean
+ SD)
112.75 + 3.83
120.17 + 7.96
0.04*
Caudate
Index
86.70 + 2.56
89.03 + 2.69
0.01*
Anterior
Putamen
Index
88.71 + 2.56
92.52 + 4.19
0.002*
Posterior
Putamen
Index
96.39 + 2.73
100.80 + 4.71
0.002*
Basal
Ganglia
Index
96.13 + 2.77
100.6 + 4.33
0.001*
Caudate
Ant.
Post.
Globus
Putamen Putamen Pallidus
Basal
Ganglia
* different from controls, p<0.05
Criswell et al, JOEM 2012
Correlations between Regional Intensity Indices
and Cumulative Exposure Hours
Intensity Index
Exposure Correlation
p value
Pallidal Index
r = 0.484
0.175*
Caudate Index
r= 0.645
0.004*
Anterior Putamen Index
r= 0.595
0.009*
Posterior Putamen Index
r= 0.571
0.013*
Basal Ganglia Index
r= 0.610
0.042*
*Spearman’s correlation
Criswell et al, JOEM, 2012.
Average FDOPA PET Ki by region
Criswell et al, Neurology, 2011
Conclusions
• Mn exposed welders have a clinical syndrome that
overlaps substantially with PD
• Heterogeneity of disease manifestations, possibly
related to intensity and time course of exposure
• Asymptomatic Mn exposed welders demonstrate
dopaminergic dysfunction but in a pattern that
appears to be unique from IPD
• Parkinsonism in welders is associated with
reduction in “PD specific” quality of life
Conclusions
• PD incidence and prevalence are higher in areas
with high Mn emissions
• PD patients with Mn exposure may have younger
onset and atypical course with higher mortality
• Role of sub-clinical liver disease?
• Gene-environment interactions
Neuropathology of Chronic Mn Exposure
• SA produces 80% world’s Mn
• Occupational Diseases in Mines and
Works Act of 1973
• Deaths notified by local medical
practitioners
• Case (Mn miners): referents (race/agematched non Mn miners)
Preliminary Results
• 90% of families approached consented to the removal of the
brain
• 60 study participants ; mean autopsy interval = 7 days
• Gross pathology: excellent tissue quality of brains using
modified protocol.
• High quality conventional histology ( i.e. H&E, and GPAP)
• Greater PI in Mn miners compared to non-Mn miners
• Persistence of T1 signal up to 19 years after working in Mn
mine (Nelson et al, Neurotoxicology, 2012)
• Detailed histopathology, tissue Mn levels in progress
Exposure limits to Mn
“How long must a useful truth be
known, before it is generally received
and acted upon?”
- Benjamin Franklin
OSHA PEL
5 mg/m3
NIOSH REL
1 mg/m3
ACGIH TLV
0.2 mg/m3
Swedish limit
0.1 mg/m3