Manganese Toxicity: Recent Research I have nothing to ... · Manganese, 2012-2016 0 5 10 15 20 25 30 35 40 >0.1 >1 >5 Percent of Detectable 3 Samples Mn Exposure (mg/m3) N = 1,886

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Manganese Toxicity: Recent Research AdvancesRoberto Lucchini, MD

Division Occupational Medicine

Selikoff Centers for Occupational Health

New York, USA

I have nothing to disclose

UCSF_CME/ Presentation Slide / March 10, 2017

Total attendees (417)

4

155 In-person AttendeesBelgiumBrazilCanadaChinaCosta RicaFranceGermany GreeceItalyMexico MongoliaMorocco NetherlandsNorwaySouth AfricaSouth KoreaSwedenUnited KingdomUnited Sates

261 Webcast ParticipantsAustraliaBelgium

BahiaCanada

Costa Rica Ecuador

FranceGermany

GreeceIndonesia

ItalyJamaicaMorocco

MexicoNetherlands

NepalNorway

PeruPuerto Rico

RussiaSweden

Sri LankaTanzania

United KingdomUnited StatesUCSF_CME/ Presentation Slide / March 10, 2017

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Plenaries 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

Documentary Film: Le manganisme (circa 1953)Film by Jean Rodier, J. Boyer and Richard Chenay. Made possible by Centre National du Cinema, Paris

Workplace exposure and standards


1st Preventive measure for Mn-air exposure

Study in 75 Pennsylvania plants (Tanaka & Lieben, 1969)

▶ 144 workers: air Mn dust/fumes > 5 mg/m3

7 cases & 15 borderline cases of manganism▶ 48 workers: air Mn dust/fumes < 5 mg/m3

0 cases

1970: 1st Industrial hygiene measure for air-Mn

US-OSHA & ACGIH: ceiling value of 5 mg Mn/m³

Harry A. Roels, Université Catholique de Louvain, Belgium


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2nd Preventive measure for Mn-air exposure

1980s-1990s: Belgium, Canada, Italy & Sweden Independent epidemiologic investigations Mn-air exposures < 1 mg Mn/m³ Findings of sub/preclinical CNS changes:

decreased neuropsychological and psychomotor performances,

cognitive deficits, and mood disturbances

1995: 2nd Industrial hygiene measure for air-Mnto prevent sub/preclinical CNS manifestaions

ACGIH (TLV-TWA 8h, 1995) : 5 0.20 mg/m3 (total dust)

no change

US-OSHA (Ceiling, 1970) 5 mg/m³US-NIOSH (REL-TWA) 1 mg/m³


3rd Preventive measure for Mn-air exposure

Application of particle size-selective criteriafor inhalation of airborne particulate matter (PM)on industrial aerosol containing Mn particles:

- inhalable fraction : PM < 100 µm- respirable fraction: PM < 10 µm

Inhalable Respirable*EU-SCOEL (2011): 0.2 mg/m³ 0.05 mg/m³

ACGIH (2012/13): 0.2 0.1 mg/m³ 0.02 mg/m³

*Higher neurotoxic potential of fine particles (e.g., welding fume )


Results of OSHA Compliance Monitoring for Manganese, 2012-2016

0

5

10

15

20

25

30

35

40

>0.1 >1 >5

Percent of Detectable Sam

ples

Mn Exposure (mg/m3)

N = 1,886 totalN = 62 (3%) > 1 mg/m3

N = 8 (0.4%) > 5 mg/m3

William Perry, Occupational Safety and Health Administration


Majority are welders, millwrights, blasters

Commercial Industrial Machinery Repair

Transportation Equipment Manufacturers

Auto, Light Duty Vehicle Manufacture

Machinery Manufacturing

Fabricated Metal Products

Primary Metals Manufacture

Specialty Trade Contractors

Heavy and Civil Engineering Construction

Industry Sectors Where Mn Exposures Have Been Commonly Found


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Welders exposure according to Mn forms/valence


Highest Full-shift TWA Breathing Zone Exposure to Total Mn Inhalable Fractions (µg/m3)Oil Refinery Construction:

Job Process Sol. 0, 2+ 3+, 4+ Sum

Tank Stick, CS 28 74 250 380

Piping Stick, CS 3.3 38 18 57

Vessels Stick, CS 26 210 52 320

John HowardDirector, NIOSH

TLV= 100 µg/m3

Asphalt Tank, Respirable Mn (µg/m3)Five Welders

050

100150200250300350400

Sol Mn Mn (0,+2) Mn (+3,+4) Mn (sum)

12345TLV

20 ug/m3

Welders exposure warrant effective exposure controlVentilation improvementsMay require respiratory protection – high efficiency filtering face-piece (?); PAPR welding helmets



Nail Clippings Surrogate: Biomonitoring Welding-Mn Exposure

Man

gan

ese

(per

cen

t co

ntr

ol)

Experimental rats were exposed (2mg/rat; 1/week x 28 weeks) to different welding fumes or manganesechloride 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.




Nail Clips for Biomonitoring ofWelding-related Mn Exposure

Experimental rats were exposed (2mg/rat; 1/week x 28 weeks) to different welding fumes or manganesechloride by intra-tracheal instillation (to overcome superficial contamination of nails that could occur bywhole-body inhalation). Brain regions (striatum and midbrain) and nail clippings were collected andsubjected to analysis of manganese content.


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Updating the NIOSH REL!

NIOSH quantitative risk assessment:- 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/


Brain Imaging in welders


0.000

0.002

0.004

0.006

0.008

0.010

0.012

0.014

ControlMn-Exposed WorkersMn-Exposed Welders

Caudate Anterior Putamen

Posterior Putamen

Av

era

ge

Ki V

alu

e, A

dju

ste

d f

or

Ag

e

*

FDOPA PET including Symptomatic Welders and Mn-Exposed Workers

Criswell SR, Perlmutter JS, Videen TO. Neurology. 2011;76:1296-301.

Average FDOPA PET Ki by region for controls, welders, and workers. * = different from controls, p < 0.01

Criswell et. al, in submission

Susan R. Criswell Washington U

Saint Louis


Increase in UPDRS3 Score Due to Welding Fume Exposure by Years as a Welder

Brad A. RacetteWashington U Saint Louis


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Cumulative Mn exposure to welding fume at estimated Mn concentrations (0.14 mg Mn/m3) near some regulatory thresholds appeared to increase progression of parkinsonism in a dose-dependent manner.

Workers performing Flux-cored arc welding (FCAW) may be at particularly greater risk of developing progressive parkinsonism.

More stringent workplace monitoring of Mn exposures, greater use of personal protective equipment and ventilation, and systematic worker assessment may be indicated to reduce morbidity.

What do we call this syndrome?

Racette et al.Dose-dependent progression of parkinsonism in manganese-

exposed welders. Neurology. 2016 Dec 28.


Indiana cohort(Lafayette, IN, US)

NumberMean airborne Mn

[mg/m3]Mean years of exposure Mean age

Controls 22 0.007 ± 0.001 0 35 ± 11

Welders (low exp) 17 0.09 ± 0.03 12 ± 7 39 ± 10

Welders (high exp) 15 0.23 ± 0.19 15 ± 9 43 ± 11

A: Recruitment of welders and controls:• From same local truck trailer manufacturer, male only• Welders: more than 3 years of welding history Controls: no exposure history

PD cohort Number Males / femalesRange of disease onset

(years)Mean age

(years)

PD patients 19 9 F 0.75- 11 63.7 ± 9.1

controls 18 7 F N/A 59.7 ± 10.2

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

psych. history

Ulrike Dydak, Purdue University


Mn Toe Nail Levels

*P = 0.0018

Eric Ward, Frank Rosenthal Purdue University


Exposure versus Toe Nail Mn


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

Past year exposure Cumulative exposure

p = 0.002 p = 0.006

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Neurological Exam: UPDRS-III

Uniform Parkinson Disease Rating Scale – Part III (motor assessment)

Note: a UPDRS score < 15 is not considered pathological!

0

5

10

15

20

25

30

35

40

Sc

ore

Parkinson Study

PD Controls PD Patients

*p < 0.001

18190

5

10

15

20

25

30

35

40

UP

DR

S S

core

UPDRSLocal Welders

Control Welder

22 31

p = 0.07

Ulrike Dydak, Purdue University


Significant elevation of UPDRS scores in high exposure group!

0

2

4

6

8

10

12

14

16

18

UP

DR

S S

core

Control Low Exp.Welder High Exp. Welder

*p=0.03

**p<0.01

N=22 N=14N=17

0

2

4

6

8

10

12

14

16

18

UP

DR

S S

core

Control Welder

N=22 N=31

p=0.07

Uniform Parkinson Disease Rating Scale – Part III (motor assessment)

By Plant


R1 (~Brain Mn) Comparison

No significance was found

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

GP left GP right SN left SN right FWMleft

FWMright

R1

rela

xati

on ti

me

(1/s

))

Comparison of R1 at different brain regions PD

Control

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

GP left GP right SN left SN right FWM left FWM right

R1

rela

xati

on ti

me

(1/s

)

R1 in different brain regions welders

w control

p=0.0048p=0.0022

p<0.0001 p=0.0003

WelderControl PD Patient

PD patients - CtrlWelders - CtrlUCSF_CME/ Presentation Slide / March 10, 2017

Correlation of MRI R1 versus past 3 months exposure

Frontal Cortex

R-square 0.5 P-value <0.01

Correlation of Brain Manganese vs Exposure

Relation of R1 relaxation rate

correlated significantly with

occupational exposure

Correlations were found between

the R1 relaxation rate and Mn

exposure over the past 3 months in

the regions responsible for

behavioral and motor deficits:

o Inferior Frontal Cortex (R=0.5, p<0.01)

o Motor Cortex (R=0.4, p=0.02)

No correlation is found between R1 and exposure 7-12 months ago

No correlation in the Globus Pallidus!

Chien-Lin Yeh, Purdue University


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Neurobehavioralassessment in community exposure


Demographic & Biological Measures by Cohort

Marietta & Cambridge, OH

N=410

East Liverpool, OH

N=106

Female 46% 61%

Caucasian 94% 83%

Biological measures GM ± GSD GM ± GSD

Hair Mn (ng/g) 416.51 ± 2.44 360.22 ± 2.17

Blood Mn (µg/L) 9.67 ± 1.27 10.06 ± 1.30

Blood Pb (µg/dL) 0.82 ± 1.58 1.13 ± 1.96

Serum Cotinine (µg/L) 0.08 ± 7.84 0.76 ± 6.12

Marietta and Cambridge biomarkers: n=310-370East Liverpool biomarkers: n=67-98

Erin Haynes, U Cincinnati


Penalized splines for hair and blood Mn levels in association with WISC-IV outcome measures. All models include both hair Mn and blood Mn, plus ln serum creatinine, blood Pb, and community residence. (A) Full Scale IQ (n = 295), also adjusted for sex, parent’s IQ, parent education, parent confidence t-score.

The solid line represents the estimate with the 95% confidence interval indicated by dotted lines. The distributions of Mn levels are indicated by vertical lines on the x-axis.


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(B) Perceptual Reasoning (n = 298) also adjusted for parent’s IQ; and

(C) Processing Speed (n = 272), also adjusted for sex, ln serum ferritin, parent confidence t-score, birth weight.

The solid line represents the estimate with the 95% confidence interval indicated by dotted lines. The distributions of Mn levels are indicated by vertical lines on the x-axis.


Residents: “We are very concerned”

In Chicago, nearly 20,000 people live within a 1-mile radius of SH Bell’s South Avenue O Terminal, which, according to the company’s website, is its second largest warehousing facility. Nearly two-thirds of those people are living below the poverty level, and almost 90 percent are minorities, according to EPA. Of those living within 1 mile of the facility, more than 6,000 are children.

“That stretch where the company is, there are homes right across the street from [S.H. Bell]. “said Annmarie Garza, an East Side resident and mother who has been spreading the word about manganese to other parents in the neighborhood. There are some poor people who live there because nobody else wants to live in front of that. And I worry about their kids, knowing that this company has this stuff coming out.”


Birgit Clauss Henn, U Boston


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The PHIME CohortPublic Health Impact of Metal Exposure(PI: Roberto Lucchini, Donald Smith, Robert Wright)

• Cross‐sectional study of 720 children ages 11‐14 yrs

• Mn measured in environmental & biological samples

• Neuropsychological & behavioral assessment

SMR Parkinsonism vs. Mn in dust p=0.005



Saliva Mn negatively associated with verbal learning & memory

Linear regression models adjusted for age, sex, SES, ln‐blood Pb; Ln‐transformed saliva Mn.*p<0.10, **p<0.05

Associations between Saliva Mn & California Verbal Learning Test

Adjusted Beta (95% CI)

Total words recalled -1.22 (-1.85 to -0.58)**

Words recalled after trial 5 -0.30 (-0.46 to -0.14)**

Words recalled with short recall -0.30 (-0.48 to -0.13)**

Words recalled with long recall -0.32 (-0.49 to -0.15)**

Errors: perseverations -0.29 (-0.80 to 0.22)

Errors: intrusions 0.24 (-0.05 to 0.54)

• No consistent associations with other biomarkers

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Mathilda Chiu, Mount Sinai

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New Bedford Cohort Study (NBC)

• 788 newborns enrolled at birth 1993-1998

• Maternal residence in towns next to PCB-contaminated New BedfordHarbor

• Assess relation early life exposure to PCBs, OC pesticides and metalswith child neurodevelopment andgrowth

49

Susan Korrick, Harvard School PH


Prenatal Mn and Behavior at Age 8 in the New Bedford Cohort

Prenatal Mn exposures associated with: Increased risk of ADHD-associated behavior on Conners

Behavioral Rating Scale – Teachers only among girls Suggestive decrements on WISC FD (attention/working

memory) only among girls Suggestive evidence that postnatal (not prenatal) Pb

exposure may enhance Mn’s CRS-T and WISC FD associations in girls

No association with Continuous Performance Test measures of attention or impulse control


Penalized Splines of Cord Blood Manganese & ADHD symptoms at 8 yrs

We do not know very much about the effects of women’s occupational exposure to Mn

• Women compose 37% of the Guangxi manganese-exposedworkers healthy cohort (Lv et al, 2014) and 35% of the highexposure category (Wang et al, 2015)

• In 2010, women made up 21% of workers in manganese mines in India (Labour Bureau, Government of India, 2012)

• A Canadian study reported elevated urinary Mn concentrations in 132 women apprentice welders (Arrandale et al, 2014)

We know little about women’s possible Mn exposures in other occupations.

SEX DIFFERENCES Donna Mergler, Université du Québec à Montréal


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PROGRESS Birth CohortProgramming Research in Obesity, Growth, Environment and Social Stressors(Pis Robert Wright, Rosalind Wright, Andrea Baccarelli, Martha M. Téllez‐Rojo)

Marcela Tamayo y Ortiz, National Inst Public Health, Mexico

Prenatal Depression and Neurodevelopment

• Has been linked to lower IQ, negative emotionality, and Bayley IIMental Development Index scores.

• Prevalence of depression in pregnant women in the MexicanSocial Security Institute was 23.3% 2

• National Institute of Perinatology 21.7% of pregnant women havea probable depressive episode 3

• 10% of pregnant women suffer from depression (weeks 6 to 10and in the third trimester of pregnancy) 4

1 Makrides etal2010,Nulman etal2012,Nulman etal.2015,Greenata.2016,Bhang etal20162Ortega,Lartigue andFigueroa2001 3QuiñonesDelgadoandLopez‐Trejo20154Dossettetal.2008,Ceballos‐Martínez,etal.2010),Olhaberry,etal.2013.



Co‐Exposure to Manganese and Depression and Neurodevelopment

• Could be acting on the same dopamine pathway.• No previous studies on their prenatal co‐exposure and child

neurodevelopment.

By NIDA,Quasihuman ‐ Derivative work ofFile:DopaminePathways.png,Public Domain,https://commons.wikimedia.org/w/index.php?curid=19925266


No Yes p

Cognitive 93.2 ± 1.1 88.8 ± 2.3 0.000*

Language 91.3 ± 1.2 86.1 ± 2.5 0.000*

Motor 94.6 ± 1.2 90.2 ± 2.8 0.002*

6080

100

120

NO YES

Cog

nitiv

e

608

01

0012

0

NO YES

Leng

uage

6080

100

120

NO YES

Mot

orBayley III Scores by Depression

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80

85

90

95

100

10 20 30 40 50 10 20 30 40 50

NO YES

Cognitive Language Motor

Ba

yle

y III

sco

res

3rd trimester manganese ug/L

3T Mn and neurodevelopment stratified by depression


75

80

85

90

95

100

1 3 5 7 9 11 1 3 5 7 9 11

NO YES

Cognitive Language Motor

Ba

yle

y III

Cord blood Manganese (ug/L)

CORD blood Mn and neurodevelopment stratified by depression

Genetic influence


Does genetics matter for Mn kinetics and toxicity?

Despite under homeostatic control, blood Mn levels in the general population varies considerably (2‐5 times) between individuals.

This variation may be due to genetic variations in the SLC30A10 gene, which was recently shown to code for an important cell‐surface localized Mn efflux transporter

(Quadri et al. Am J Hum Genet. 2012; Leyva‐Illades et al. J Neurosci. 2014)

Karin Broberg, Karolinska Inst, Sweden

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3 adult cohorts - Bangladesh , Andes , Italy N=836

Blood Mn measured in populations world‐wide

PI: Marie Vahter PI: K Broberg/M. Vahter Roberto LucchiniPregnant women 26 years Men & women 34 years Men & women 69 years


3 adult cohorts - Bangladesh , Andes , Italy

SLC30A10 genotypes modify blood Mn up to 18%

AA CCCTTT

rs2275707 rs12064812

p=0.012

p=0.027 p=0.023

CC/AC

% B

loo

dM

nco

nc

rela

tive

re

fere

nce

gen

oty

pe

% B

loo

dM

nco

nc

rela

tive

re

fere

nce

gen

oty

pe


SLC30A10 and SLC39A8modify blood Mn up to 60%

Wahlberg et al. in preparation

N=717, adj for age, sex, ferritin, Mn in soil

rs227507 rs12064812 rs13107325Combined genotypes

GG GA AAAA CA CCn=415 n=225 n=32 n=324 n=299 n=57

TT TC CC CC CT/TTn=561 n=116

Low Medium Highn=86 n=548 n=29

% d

iffe

ren

ce

p<0.001 p<0.001 p=0.002 p<0.001

Blood Mn

SLC30A10 SLC39A8


SLC30A10 variation influences finger tapping and sway in Italian elderly

rs2275707 AC/CC open eyes 10% more sway p=0.065closed eyes 15% more sway p=0.033

rs12064812 CT/CC better speed finger tappingnon‐dominant hand 8.7% p=0.084dominant hand 10.8% p=0.025

SLC30A10 seems to modify Mn toxicity

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SLC30A10 allele associated with increasedMn in blood ‐reduced scoring in IQ subtests.

SLC30A10 allele associated with reducedMn in blood ‐increasing scoring in IQ subtests.

No gene‐environmentinteractions

SLC30A10 variation influences cognitive functions in Italian adolescents

1. What is a good surrogate for biomonitoringmanganese exposure in welders?


1. Blood

2. Urine

3. Hair

4. Nail

5. Saliva

2. What is the current TVL for manganese in respirable fraction?


1. 5 mg/m3

2. 1 mg/m3

3. 200 µg/m3

4. 100 µg/m3

5. 20 µg/m3

3. What gene can influence the variation of bloodmanganese and neurobehavioral performance?


1. Alfa-synuclein

2. Parkin

3. SLC30A10

4. Dopamine Receptor D4

5. ATP13A2

Documents

Manganese Toxicity: Recent Research I have nothing to ... · Manganese, 2012-2016 0 5 10 15 20 25 30 35 40 >0.1 >1 >5 Percent of Detectable 3 Samples Mn Exposure (mg/m3) N = 1,886