1. Occupational and Environmental Exposures: Associations with Parkinsonism Bradley Evanoff, MD, MPH Department of Medicine

2. 2 Disclosure: Bradley Evanoff Research Support / GrantsNIEHS, NCI, NCATS, NIOSH Stock/Equity (any amount)None Consulting / Employment Monsanto Speakers Bureau / HonorariaNone OtherNone

3. 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.

4. 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

5. Variance in PD Incidence Due to Known Risk Variables Willis and Racette, unpublished. 13% 7% 4%

6. M.M. Finkelstein, M. Jerrett / Environmental Research, 2007. Air Pollution in Canada and Risk of PD 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 Spatial distribution of manganese in TSP in Hamilton Cumulative hazard of a physician’s diagnosis of in relation age in 1999 and Mn exposure.

7. PD Non-randomly Distributed in US z test statistic for nonrandom clustering p<0.00001 Willis AW, et al. Neuroepidemiology, 2010.

8. US Heavy Metal Emitting Facilities: 1988-1998 Willis AW, et al. Am J Epi, 2010.

9. Cumulative onsite copper, manganese or lead release, 1988-1998 (as reported to the EPA) TRI NAICS Code, Industry Description Cumulative Reported Onsite Metal Release (in metric tons) CopperLeadManganese 311 Food/Beverages/Tobacco 722.1659.0896.09 313 Textiles 7.0669.370.12 315 Apparel 0.00No facilities 316 Leather 0.91No facilities4.49 321 Wood Products 17.105.993.84 322 Paper 15.931.372193.05 323 Printing and Publishing 77.772.520.50 324 Petroleum 32.68196.82189.49 325 Chemicals 1362.061192.2422141.09 326 Plastics and Rubber 108.3931.622.98 327 Stone/Clay/Glass 79.40284.18764.19 3273 Cement 7.331069.831373.26 331 Primary Metals 73190.8435041.4083602.23 332 Fabricated Metals 1841.601140.724732.29 333 Machinery 657.33111.741493.45 334 Computers/Electronic Products 285.16112.4813.97 335 Electrical Equipment 966.052492.98466.27 336 Transportation Equipment 946.58318.191448.89 337 Furniture 9.042.8819.28 339 Miscellaneous Manufacturing 112.3544.3633.41 562 Hazardous Waste 1549.8711074.033759.13 2121 Coal Mining 0.00 0.68 2122 Metal Mining 250837.24399.805364.49 2211 Electric Utilities 354.29193.17975.20 4246 Chemical Wholesalers 0.120.010.24 4247 Petroleum Bulk Terminals 0.00 No TRI NAICS code 635.01527.12226.22 Cumulative onsite copper, manganese or lead release, 1988-1998 Willis AW, et al. Am J Epi, 2010.

10. * less than 100lbs. reported Increased Risk of PD Associated with Metal Emissions Willis AW, et al. Am J Epi, 2011.

11. 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

12. 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

13. VariablePercent Alive (n) Risk of Death * OR (95%CI) Geographical Region** Northeast34.9 (10769)REF. Midwest34.9 (12114)1.04 (1.03-1.07) South34.5 (17515)1.06 (1.05-1.08) West39.5 (8041)0.93 (0.91-0.95) Population Density† Completely Urban (>1,000,000)35.3 (37631)REF. Completely Rural (<2,500)37.6 (3361)0.91 (0.88-0.94) Urban Heavy Metal emission ‡ Low Manganese38.1 (1853)REF. High Manganese33.8 (3054)1.19 (1.10-1.29) Low Copper35.5 (2236)REF. High Copper37.1 (2919)1.01 (0.96-1.07) NS PD Mortality According to Geographical Variables Willis et al, Arch Neurol, 2012

14. 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

15. History of Mn Neurotoxicity 1955 – Rodier describes 115 cases of fulminant neurological disorder in Mn miners: with dystonia, neuropsychiatric symptoms, “masque manganifique”

16. Metals and PD Gorell et al., 1997

17. Younger Age of PD Onset in Mn Exposed Welders Racette et al. Neurology, 2001

18. 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

19. Science 2003 Metals

20. 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.

21. Rodier et al., 1957 Exposures then and now…. Clinical syndrome then and now….

22. Luccini 2009, NeuroMol Med 11:311-322

23. Prevalence ratios of parkinsonism in Alabama welders Racette et al. Neurology, 2005.

24. Danish Welder Hospitalization Rate for PD Fryzek J et al, JOEM 2005 Swedish Welder Incidence Rate for PD Fored et al, OEM 2006

25. Epidemiology of Parkinsonism in Welders Study Procedures Direct examination by movement disorders specialist blinded to occupational history Validated welding exposure questionnaire (Hobsen et al. 2009) Derived cumulative Mn/m 3 years (Hobson et al., 2010) PDQ39 Cohort Worksite based shipyard and fabrication workers exposed to welding fumes in upper Midwest, USA

26. 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

27. 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

28. Racette, et al. unpublished Clinical Feature Parkinsonian Welders (n=112) Idiopathic PD patients (n=118) 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 signs a 4.3 (2.5)*6.3 (4.9) UPDRS3 score, mean (sd) 19.8 (4.6)22.9 (13.7) Comparison of Parkinsonian Signs in Welders and Newly Diagnosed, Untreated PD Patients

29. Imaging Biomarkers of Parkinsonism in Welders Structural MPRAGE/T1 DWI Molecular FDOPA DTBZ Functional MR Rs-fcMRI Region definition Exposure metric Structural damage ApplicationsImaging Modality Synaptic function Toxic mechanism Clinical correlation Brain connectivity Toxic mechanism Clinical correlation(?)

30. Brain deposition Influx Efflux Mn Transport in Blood: -80% bound to  1-globulin and albumin -small fraction transferrin Mn Transport across Blood-Brain Barrier: -not completely understood -multiple carrier-mediated transport process (active, facilitated, transferrin-dependent: Mn 3+, DMT1: Mn 2+ ) -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

31. MRI and Manganese Toxicity ↑ T1-Weighted MRI Normal T2-Weighted MRI Bowler R,et al. Neurotoxicology 2006; 27: 327-332.

32. Intensity Indices in Asymptomatic Welders * different from controls, p<0.05 Controls (n = 18) Welders (n = 18) p value Pallidal Index (mean + SD) 112.75 + 3.83120.17 + 7.960.04* Caudate Index 86.70 + 2.5689.03 + 2.690.01* Anterior Putamen Index 88.71 + 2.5692.52 + 4.190.002* Posterior Putamen Index 96.39 + 2.73100.80 + 4.710.002* Basal Ganglia Index 96.13 + 2.77100.6 + 4.330.001* Caudate Ant. Post. Globus Basal Putamen Putamen Pallidus Ganglia Criswell et al, JOEM 2012

33. Correlations between Regional Intensity Indices and Cumulative Exposure Hours Intensity IndexExposure Correlationp value Pallidal Indexr = 0.4840.175* Caudate Indexr= 0.6450.004* Anterior Putamen Indexr= 0.5950.009* Posterior Putamen Indexr= 0.5710.013* Basal Ganglia Indexr= 0.6100.042* *Spearman’s correlation Criswell et al, JOEM, 2012.

34. Average FDOPA PET Ki by region Criswell et al, Neurology, 2011

35. 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

36. 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

37. 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/age- matched non Mn miners)

38. 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

39. Exposure limits to Mn OSHA PEL5 mg/m3 NIOSH REL1 mg/m3 ACGIH TLV0.2 mg/m3 Swedish limit0.1 mg/m3 “How long must a useful truth be known, before it is generally received and acted upon?” - Benjamin Franklin