Anthony Almazan MD Occupational Medicine Residency Program Department of Environmental Health

1. Is Manganese Exposure a Risk Factor for Hearing Loss?Environmental Manganese Exposure and Auditory Function in Children Anthony Almazan MD Occupational Medicine Residency Program Department of Environmental Health University of Cincinnati College of Medicine

2. Outline • Manganese • Hearing Loss • Significance to Occupational/Environmental Health • Field Investigation • Discussion • Future Directions

3. Manganese • Essential element that is neurotoxic with overexposure • Crosses blood-brain barrier & placenta • Accumulates in basal ganglia • Neuromotor and neuropsych effects • Parkinsonian syndrome with chronic overexposure Levy BS, Nassetta WJ. Neurologic effects of manganese in humans: a review. Int J Occup Environ Health 2003;9(2):153 Nordberg G et al. Handbook on the Toxicology of Metals 3rd Ed. 2007 Erickson KM et al. Manganese inhalation by rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity. Toxicol Sci 2007;97(2):459-66 Aschner M et al. Manganese: Recent advances in understanding its transport and neurotoxicity. Toxicol App Pharm 2007;221:131-47. Dobson A et al. Manganese Neurotoxicity. Ann NY Acad Sci 2004:1012:115-28.

4. Mn-Hearing Connection • Mn associated with hearing loss alone and when combined with noise but relationship is unclear • Mn-exposed workers reported auditory and vestibular symptoms • Hemodialysis pts had elevated Mn and hearing loss • Increased latency in event-related auditory potentials in Mn-exposed workers Nikolov Z. Hearing reduction caused by manganese and noise. JFORL J. Fr. Otorhinolaryngol Audiophonol Chir Maxillofac 1974;23:231-4 Khalkova Zh, Kostadinova G. [Auditory-vestibular changes in workers in ferrous metallurgy manufacture]. [Article in Bulgarian] Probl Khig 1986;11:134-8 Bouchard M et al. Manganese cumulative exposure and symptoms: A follow-up study. NeuroToxicol 2008;29:577-83 Roels H et al. Epidemiological survey among workers exposed to manganese: effects on lung, central nervous symptoms, and some biological indices. Am J Ind Med1987;11(3):307-27 da Silva CJ, et al. A preliminary study revealing a new association in patients undergoing maintenance hemodialysis: manganism symptoms and T1 hyperintense changes in the basal ganglia. Am. J. Neuroradiol. 2007;28:1474-9 Sjogren B et al. Effects on the nervous system among welders exposed to aluminum and manganese. Occup Environ Med 1996;53:32-40 .

5. Mn-Hearing Connection • Decreased acoustic startle response in Mn-exposed rats • Mn transporters and Mn accumulation shown in mouse cochlea after systemic exposure • Mn and noise can independently cause oxidative stress in cells Vezér T, et al. Behavioral effects of subchronic inorganic manganese exposure in rats. Am J Ind. Med. 2007;50:841-52. Ma C et al. 2008 Manganese accumulation in the mouse ear following systemic exposure. J Biochem Mol Toxicol 2008;22(5):305-10. Milatovic D et al. Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Tox App Pharm 2009; In press. HaMai D, Bondy S Oxidative basis of manganese neurotoxicity. Ann NY Acad Sci 1012:129-41. Henderson D et al. The role of oxidative stress in noise-induced hearing loss. Ear Hear 2006;27(1):1-19. LePrell C et al. Mechanisms of noise-induced hearing loss indicate multiple methods of prevention. Hearing Research 2007;226:22-43. .

6. Mn-Hearing Connection

7. Significance of Studying Hearing Loss in Children • NIDCD est. 950,000 children with hearing loss in 2005 • Lifetime costs of $417,000 per affected person • Poor academic performance, emotional problems • Can negatively affect education, employment, health care utilization, and life expectancy • Detecting early hearing loss is opportunity to prevent future problems and improve quality of life NIDCD Outcomes Research in Children With Hearing Loss Dec 12-13 2006 http://www.nidcd.nih.gov/funding/programs/hb/outcomes/ Gifford K et al. Hearing loss in children. Pediatrics in Review 2009;30(6):207-16 Smith RJ et al. Sensorineural hearing loss in children. Lancet. 2005;365(9462):879-98 Bush JS Practice Guidelines: Screening Recommendation to Identify Hearing Loss in Children Am Fam Physician 2003;67(11):2409-13

8. www.eh.uc.edu/CARES A Community-Based Participatory Research Study Communities Actively Researching Exposure Study EN Haynes1, CC Beidler2, KN Dietrich1, M Barnas3, T Reponen1, P Ryan1, P Succop1, AR Wittberg2,4 , A Bhattacharya1, BP Lanphear5, W Menrath1, S Roda1, RO Wright6 1University of Cincinnati Department of Environmental Health, 2Neighbors for Clean Air, 3Marietta College, 4Mid-Ohio Valley Health Department, 5Simon Frasier University, 6Boston Channing Laboratory Background Manganese (Mn) is an essential element, yet is neurotoxic in excess. Despite the fact that infants and young children may be at greater risk for Mn neurotoxicity than adults, very few studies have evaluated the effect of chronic Mn exposure on child development. Marietta, Ohio, a rural Appalachian community, has been home to the only manganese refinery in the US and Canada for over 50 years. The local concerned community group, Neighbors for Clean Air (NCA) has partnered with researchers at the University of Cincinnati (UC) to assist them in understanding their exposure and related health effects. Hypothesis Exposure to Mn during early childhood is significantly associated with neurodevelopmental deficits in high exposed children ages 7-9 years compared to an age matched low/unexposed group. Specific Aims Specific Aim 1: Assess environmental Mn exposure within a high Mn exposure community, Marietta, OH and a low Mn exposure community, Cambridge, Ohio. Specific Aim 2: Evaluate comparisons of the neurobehavioral effects in children exposed to Mn in a high Mn exposure community, Marietta, OH and a low Mn exposure community, Cambridge, Ohio. Specific Aim 3: Evaluate comparisons of the neuromotor effects in children exposed to Mn exposure community, Marietta, OH and a low Mn exposure community, Cambridge, Ohio. Study Design Funding provided by the National Institute of Environmental Health Sciences (1 R01 ES016531-01) Courtesy of Erin Haynes.

9. Study Cohort 7-9 year old children N=400 Marietta OH N=200 Cambridge OH N=200 Study Design Home Environmental Sampling Home Environmental Sampling Exposure Assessment Ambient Air Sampling Ambient Air Sampling Personal Air Sampling Biomarkers Blood, Hair, Urine, Tooth Blood, Hair, Urine, Tooth Neuropsychological Assessment Neuropsychological Assessment Health Assessment Neuromotor Assessment Neuromotor Assessment Postural Sway Postural Sway Sensory Assessment Auditory Assessment Auditory Assessment Olfactory Assessment Olfactory Assessment Marietta Community Actively Researching Exposure Study (CARES) NIEHS 1R01ES016531-01 http://www.eh.uc.edu/CARES/index.html Courtesy of Erin Haynes.

10. Eramet Marietta, Inc. is the leading producer of Mn emissions in US - operating 50 years USEPA Toxic Release Inventory http://www.epa.gov/tri/ Marietta Community Actively Researching Exposure Study (CARES) NIEHS 1R01ES016531-01 http://www.eh.uc.edu/CARES/index.html Courtesy of Erin Haynes.

11. ATSDR Health Consultation- Washington County Air Quality Marietta Air Emissions http://www.atsdr.cdc.gov/hac/pha/marietta/wca_p1.html Courtesy of Erin Haynes .

12. Study Objective: To determine if chronic environmental manganese exposure causes hearing loss in children.

13. Study Design Hypothesis: Children aged 7-9 years residing in a community with high air Mn levels will have significantly decreased hearing function compared to age-matched children residing in a community with low air Mn levels.

14. Specific Aims Develop a questionnaire to assess potential confounders in children undergoing audiometry testing to control for confounders. Perform audiometry testing in children residing in a community with high air Mn levels and children residing in a community with low air Mn levels. Evaluate comparisons of audiometric effects in children residing in a community with high air Mn levels and children residing in a community with low air Mn levels.

15. Methods • Cross-sectional analysis • Independent Variable: • Mn exposure as measured by ambient Mn levels and blood, hair, urine, tooth Mn levels • Dependent Variable: • Hearing loss as measured by extended high frequency (EHF) audiometry

16. Subjects selected from Marietta CARES • Inclusion Criteria: • Age 7-9 years • Mother has resided in Marietta since 16th week of pregnancy • Born in Marietta • Family does not plan to move from area in next year • Exclusion Criteria: • History of congenital hearing loss • Ear infection within one month of testing

17. Ambient Mn Levels Courtesy of Matt Terrell CIH

18. Biomarkers – Not Back Yet! • Blood • Urine • Hair • Tooth

19. EHF Audiometry testing Pure Tone 500 – 14,000 Hz Reuter W et al. Extended high frequency audiometry in pre-school children. Audiology 1998;37(5):285-94. Knight K et al. Early changes in auditory function as a result of platinum chemotherapy: use of extended high frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncology 2007;25(10):1190-95. Sakamoto M et al. Average thresholds in the 8 to 20 Khz range as a function of age. Scand Audio 1998;27(3):189-92.

20. Audiometry Results

21. Preliminary Results • No significant difference between groups except at 12,500 Hz/Right, where Marietta’s hearing was better than Cambridge’s

22. Discussion – Next Steps • Test more subjects(?) • Analyze relationship of blood, hair, urine Mn levels with audiometric function • Estimate exposure with air Mn modeling and correlate with audiometric function • Further analyze data regarding confounders such as noise exposure and antioxidant consumption • Look at age, gender effects

23. Limitations • Small number of subjects makes it difficult to measure small differences between groups • Difficult to accurately determine noise exposure

24. Strengths • Study part of Marietta CARES with expertise of research group • Unique setting to study effects of Mn exposure • Engagement with and participation of community • Occupational applications

25. Occupational Implications –What is the effect of Mn on hearing in exposed workers?

26. This research study was partially supported by:The National Institute for Occupational Safety and Health Pilot Research Project Training Program University of Cincinnati Education and Research Center Grant #T42/OH008432-04 This study was approved by the UC IRB #08-3-6-IEE

27. Thank You UC/PRPMariettaNIOSH Erin Haynes Mary Barnas Bruce Bernard Christi Themann Dawn Wittberg Donnie Booher Mary Beth Genter Richard Wittberg Kevin Dunn Shawn Standridge Philip LeMasters Karl Feldmann Cyndy Cox Alison Paytosh Scott Brueck Paul Succop John Barnas Amit Bhattacharya Matt Terrell Sue Ross (and especially Erin and Jude)

28. Questions?