Occupational and Environmental Exposures: Associations with Parkinsonism Bradley

Occupational and Environmental Exposures: Associations with Parkinsonism Bradley

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.

Parkinsons 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, unpublishe ir Pollution in Canada and Risk of PD Spatial distribution of manganese in TSP in Hamilton Cumulative hazard of a physicians

diagnosis of in relation age in 1999 and Mn exposure. OR for physicians diagnosis of PD = 1.034 (1.001.07) per 10 ng/m3 increase in Mn in TSP. Estimated doubling exposure was 150 ng/m3 M.M. Finkelstein, M. Jerrett / Environmental PD Non-randomly Distributed in US z test statistic for nonrandom clustering p<0.00 Willis AW, et al. Neuroepidemiology, 201 US Heavy Metal Emitting Facilities: 19881998 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 Manganese 722.16 59.08 313 Textiles 7.06 69.37 0.12 315 Apparel 0.00

No facilities No facilities 4.49 316 Leather 96.09 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 22141.09 108.39 31.62 2.98 326 Plastics and Rubber 327 Stone/Clay/Glass 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 337 Furniture 339 Miscellaneous Manufacturing 946.58 9.04 318.19 2.88

1448.89 19.28 3273 Cement 331 Primary Metals 332 Fabricated Metals 562 Hazardous Waste 2121 Coal Mining 2122 Metal Mining 2211 Electric Utilities 4246 Chemical Wholesalers 4247 Petroleum Bulk Terminals No TRI NAICS code 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 0.12

0.01 0.24 0.00 0.00 0.00 635.01 527.12 226.22 Willis AW, et al. Am J Epi, 2010. eased Risk of PD Associated with Metal Emissi * 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 - Cant directly measure disease severity - Can only study what Medicare

PD Mortality According to Geographical Variables Percent Alive (n) Risk of Death * OR (95%CI) 34.9 (10769) 34.9 (12114) 34.5 (17515) 39.5 (8041) REF. 1.04 (1.03-1.07) 1.06 (1.05-1.08) 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 High Manganese 38.1 (1853) 33.8 (3054) REF. 1.19 (1.10-1.29) Low Copper High Copper 35.5 (2236) 37.1 (2919) REF. 1.01 (0.96-1.07) NS Variable

Geographical Region** Northeast Midwest South West 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 Parkinsons 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. unpublishe 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 Effl Brain deposition u x

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 Gangli * 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* *Spearmans 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% worlds 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

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