I have nothing to disclose Advances Roberto Lucchini, MD Division - PDF document

2/27/2017 Manganese Toxicity: Recent Research I have nothing to disclose Advances Roberto Lucchini, MD Division Occupational Medicine Selikoff Centers for Occupational Health New York, USA Total attendees (417) 261 Webcast Participants Australia Belgium 155 In-person Attendees Bahia Belgium Canada Brazil Costa Rica Ecuador Canada France China Germany Costa Rica Greece France Indonesia Germany Italy Greece Jamaica Italy Morocco Mexico Mexico Netherlands Mongolia Nepal Morocco Norway Netherlands Peru Norway Puerto Rico South Africa Russia South Korea Sweden Sweden Sri Lanka United Kingdom Tanzania United Kingdom United Sates United States UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 4 1

2/27/2017 Documentary Film: Le manganisme ( circa 1953 ) Plenaries Film by Jean Rodier, J. Boyer and Richard Chenay. Made possible by Centre National du Cinema, Paris  Health Risk Assessment and Protective Standards  Health Effects of Community and Workplace Exposures  Children’s Health and Development  New Aspects of Toxicology in Animal Models and Cellular Functions  Genetic and Mechanistic Influences  Imaging and Biomarkers UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 Harry A. Roels, Université Catholique de Louvain, Belgium 1 st Preventive measure for Mn-air exposure Workplace exposure and Study in 75 Pennsylvania plants ( Tanaka & Lieben, 1969) standards ▶ 144 workers: air Mn dust/fumes > 5 mg/m 3 7 cases & 15 borderline cases of manganism ▶ 48 workers: air Mn dust/fumes < 5 mg/m 3 0 cases 1970: 1 st Industrial hygiene measure for air-Mn US-OSHA & ACGIH: ceiling value of 5 mg Mn/m³ UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 2

2/27/2017 2 nd Preventive measure for Mn-air exposure 3 rd Preventive measure for Mn-air exposure 1980s-1990s: Belgium, Canada, Italy & Sweden Independent epidemiologic investigations  Application of particle size-selective criteria  Mn-air exposures < 1 mg Mn/m³ for inhalation of airborne particulate matter (PM)  Findings of sub/preclinical CNS changes: on industrial aerosol containing Mn particles: decreased neuropsychological and psychomotor performances, - inhalable fraction : PM < 100 µm cognitive deficits, and mood disturbances - respirable fraction: PM < 10 µm 1995: 2 nd Industrial hygiene measure for air-Mn Inhalable Respirable* to prevent sub/preclinical CNS manifestaions EU-SCOEL (2011): 0.2 mg/m³ 0.05 mg/m³ ACGIH (TLV-TWA 8h , 1995) : 5 0.20 mg/m 3 (total dust) ACGIH (2012/13): 0.2 0.1 mg/m³ 0.02 mg/m³ no change *Higher neurotoxic potential of fine particles (e.g., welding fume ) US-OSHA (Ceiling, 1970) 5 mg/m³ US-NIOSH (REL-TWA) 1 mg/m³ UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 William Perry, Occupational Safety and Health Administration Results of OSHA Compliance Monitoring for I ndustry Sectors Where Mn Exposures Have Been Commonly Found Manganese, 2012-2016 40  Commercial Industrial Machinery Repair Percent of Detectable Samples 35  Transportation Equipment Manufacturers N = 1,886 total N = 62 (3%) > 1 mg/m 3 30  Auto, Light Duty Vehicle Manufacture N = 8 (0.4%) > 5 mg/m 3 25  Machinery Manufacturing Majority are welders, millwrights, blasters 20  Fabricated Metal Products 15  Primary Metals Manufacture 10  Specialty Trade Contractors 5  Heavy and Civil Engineering Construction 0 >0.1 >1 >5 Mn Exposure (mg/m 3) UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 3

2/27/2017 John Howard John Howard Asphalt Tank, Respirable Mn (µg/m 3 ) Welders exposure according to Mn Director, NIOSH Director, NIOSH forms/ valence Five Welders Highest Full-shift TWA Breathing Zone Exposure 400 to Total Mn Inhalable Fractions (µg/m 3 ) 350 Oil Refinery Construction: 300 1 250 Job Process Sol. 0, 2+ 3+ , 4+ Sum 2 200 3 Tank Stick, CS 28 74 250 380 150 TLV= 100 µg/m 3 4 100 Piping Stick, CS 3.3 38 18 57 TLV 5 50 20 ug/ m3 Vessels Stick, CS 26 210 52 320 0 Sol Mn Mn (0,+ 2) Mn (+ 3,+ 4) Mn (sum) Welders exposure warrant effective exposure control Ventilation improvements May require respiratory protection – high efficiency filtering face-piece (?); PAPR welding helmets UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 Nail Clippings Surrogate: Biomonitoring John Howard John Howard Nail Clips for Biomonitoring of Director, NIOSH Director, NIOSH Welding-Mn Exposure Welding-related Mn Exposure Manganese (percent control) Experimental rats were exposed (2mg/rat; 1/week x 28 weeks) to different welding fumes or manganese chloride by intra-tracheal instillation (to overcome superficial contamination of nails that could occur by whole-body inhalation). Brain regions (striatum and midbrain) and nail clippings were collected and subjected to analysis of manganese content. Experimental rats were exposed (2mg/rat; 1/week x 28 weeks) to different welding fumes or manganese chloride by intra-tracheal instillation (to overcome superficial contamination of nails that could occur by whole- body inhalation). Brain (striatum), blood and nail clippings were collected and subjected to elemental analysis. Manganese was detected in striatum and nail clippings but not in blood. UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 4

2/27/2017 Updating the NIOSH REL!  NIOSH quantitative risk assessment : Brain I maging in welders - Conducted using best available data - On subclinical neurobehavioral changes - Provides an array of risk levels - With two-tier REL (inhalable/respirable)? - Peer-reviewed - Public input encouraged - Considers analytical achievability  NIOSH topic page: Welding and manganese www.cdc.gov/niosh/topics/welding/ UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 Brad A. Racette FDOPA PET including Symptomatic Susan R. Criswell Increase in UPDRS3 Score Due to Welding Washington U Saint Louis Washington U Fume Exposure by Years as a Welder Saint Louis Welders and Mn-Exposed Workers Control Mn-Exposed Workers Average Ki Value, Adjusted for Age 0.014 Mn-Exposed Welders 0.012 * 0.010 0.008 0.006 0.004 0.002 0.000 Caudate Anterior Posterior Putamen Putamen Average FDOPA PET K i by region for controls, welders, and workers . * = different from controls, p < 0.01 Criswell et. al, in submission Criswell SR, Perlmutter JS, Videen TO. Neurology. 2011;76:1296-301. UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 5

2/27/2017 Ulrike Dydak, Purdue University A: Recruitment of welders and controls: •  Cumulative Mn exposure to welding fume at estimated Mn concentrations From same local truck trailer manufacturer, male only • Welders: more than 3 years of welding history Controls: no exposure history (0.14 mg Mn/m 3 ) near some regulatory thresholds appeared to increase progression of parkinsonism in a dose-dependent manner. Indiana cohort Mean airborne Mn  Workers performing Flux-cored arc welding (FCAW) may be at (Lafayette, IN, US) Number Mean years of exposure Mean age [mg/m 3 ] particularly greater risk of developing progressive parkinsonism. Controls 22 0.007 ± 0.001 0 35 ± 11  More stringent workplace monitoring of Mn exposures, greater use of Welders (low exp) 17 0.09 ± 0.03 12 ± 7 39 ± 10 personal protective equipment and ventilation, and systematic worker Welders (high exp) 15 0.23 ± 0.19 15 ± 9 43 ± 11 assessment may be indicated to reduce morbidity.  What do we call this syndrome? B: Recruitment of PD patients and controls: • Patients: Mild PD, recruited from neurological clinic; male and female • 12 hours off medication, some patients drug naiive • Controls: usually spouses or friends of patients, no exposure history, no neurol or Racette et al. psych. history Dose-dependent progression of parkinsonism in manganese- Range of disease onset Mean age PD cohort Number Males / females exposed welders. Neurology. 2016 Dec 28. (years) (years) PD patients 19 9 F 0.75- 11 63.7 ± 9.1 controls 18 59.7 ± 10.2 7 F N/A UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 Eric Ward, Frank Rosenthal Mn Toe Nail Levels Exposure versus Toe Nail Mn Purdue University Past year exposure Cumulative exposure p = 0.002 p = 0.006 *P = 0.0018  Mn in Toe nail clippings may serve as reliable biomarker of exposure  It gives information about exposure over the past year, but also on lifetime cumulative exposure  Correlations were adjusted for age, sex, race, cigarette smoking and dietary Mn intake UCSF_CME/ Presentation Slide / March 10, 2017 UCSF_CME/ Presentation Slide / March 10, 2017 6