Transcript Chronic Environmental Manganese Exposure and Audiometric

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
Outline
Manganese
 Hearing Loss
 Significance to
Occupational/Environmental Health
 Field Investigation
 Discussion
 Future Directions

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.
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
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.
Mn-Hearing Connection
Mn and noise
cause oxidative
stress-common
mechanism?
Mn accumulates
in mouse
cochlea with
systemic
exposure
Mn exposure
and noise
associated with
hearing loss
Mn
ototoxic?
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
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
of Cincinnati Department of Environmental Health, 2Neighbors for Clean Air, 3Marietta College, 4Mid-Ohio Valley Health Department, 5Simon Frasier University, 6Boston Channing Laboratory
Study Design
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 Cohort
7-8 year old children
N = 400
Exposure Assessment
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
Biomarker
Background
Health Assessment
1University
Marietta, OH
Cambridge, OH
7-8 year old children
N = 200
7-8 year old children
N = 200
Home Environmental Sampling
Home Environmental Sampling
- Interior Dust
- Exterior Dust
- Water
- Interior Dust
- Exterior Dust
- Water
Ambient Air Sampling
Ambient Air Sampling
-PM2.5 6 days/week
-4 weeks/season
-PM2.5 6 days/week
-1 week/season
Personal Air Sampling
N = 40
Biological Measures
Biological Measures
Blood: Pb, Mn, Hg, Cd
Hair: Mn
Teeth: Pb, Mn
Urine: Cr, As, Mn, Cd
Blood: Pb, Mn, Hg, Cd
Hair: Mn
Teeth: Pb, Mn
Urine: Cr, As, Mn, Cd
Neuropsychological Assessment
Neuropsychological Assessment
-Child IQ
-BASC-2
-CVLT-C
-BRIEF
-School Achievement Test
-Child IQ
-BASC-2
-CVLT-C
-BRIEF
-School Achievement Test
Neuromotor Assessment
-Grooved Pegboard
Neuromotor Assessment
-Grooved Pegboard
-Fingertapping
-BOT-2
-Sway (n = 40)
-Fingertapping
-BOT-2
-Sway (n = 40)
Funding provided by the National Institute of Environmental Health Sciences (1 R01 ES016531-01)
Courtesy of Erin Haynes.
Study Cohort
7-9 year old children
N=400
Exposure
Assessment
Study Design
Sensory
Assessment
Health
Assessment
Biomarkers
Marietta OH
N=200
Home Environmental Sampling
Ambient Air Sampling
Cambridge OH
N=200
Home Environmental Sampling
Ambient Air Sampling
Personal Air Sampling
Blood, Hair, Urine, Tooth
Blood, Hair, Urine, Tooth
Neuropsychological
Assessment
Neuropsychological
Assessment
Neuromotor Assessment
Neuromotor Assessment
Postural Sway
Auditory Assessment
Olfactory Assessment
Postural Sway
Auditory 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.
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.
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 .
Study Objective: To determine if chronic
environmental manganese exposure causes
hearing loss in children.
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.
Specific Aims
1.
2.
3.
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.
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
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
Ambient Mn Levels
Marietta Cambridge
(ng/m3) (ng/m3)
Mean
13.585 3.144
Min
Max
N
0.044 0.395
72.892 10.885
83 10
Sample 10/20/08- 11/12/08 –
dates
6/9/09 5/13/09
Courtesy of Matt Terrell CIH
Biomarkers – Not Back Yet!
Blood
 Urine
 Hair
 Tooth

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.
Audiometry Results
Average age 8 years
25 male 27 female
Marietta
(N=29)
Mean Threshold
(dB)
Cambridge
(N=23)
Mean Threshold
(dB)
Frequency (Hz)/Side
1000 L
4.48
4.13
500L
8.28
8.48
1000L
4.31
3.91
2000L
6.56
7.61
4000L
5.69
7.17
8000L
11.38
10.00
12,500L
1.90
0.87
14,000L
-10.34
1000R
2.41
1.96
500R
7.07
4.57
1000R
2.76
2.17
2000R
6.38
6.30
4000R
4.48
4.78
8000R
10.17
9.35
12,500R
-0.17
4.78
14,000
-9.83
-7.17
-9.78
(p < 0.036)
Preliminary Results

No significant difference between groups
except at 12,500 Hz/Right, where
Marietta’s hearing was better than
Cambridge’s
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
Limitations

Small number of subjects makes it difficult
to measure small differences between
groups

Difficult to accurately determine noise
exposure
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

Occupational Implications –
What is the effect of Mn on hearing in
exposed workers?
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
Thank You
UC/PRP
Marietta
NIOSH
Erin Haynes
Christi Themann
Mary Beth Genter
Shawn Standridge
Cyndy Cox
Paul Succop
Amit Bhattacharya
Matt Terrell
Sue Ross
Mary Barnas
Dawn Wittberg
Richard Wittberg
Philip LeMasters
Alison Paytosh
John Barnas
Bruce Bernard
Donnie Booher
Kevin Dunn
Karl Feldmann
Scott Brueck
(and especially Erin and Jude)
Questions?