CURRENT ISSUES IN THE MEASUREMENT OF … · CURRENT ISSUES IN THE MEASUREMENT OF [email protected] Isocyanates & Health 2013 1 ISOCYANATE SKIN EXPOSURE Dhimiter Bello, Sc.D.,

4/4/2013

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CURRENT ISSUES IN THE MEASUREMENT OF

Isocyanates & Health [email protected] 1

ISOCYANATE SKIN EXPOSURE

Dhimiter Bello, Sc.D., M.Sc.Assoc. Professor, Exposure Biology

Work Environment DepartmentCollege of Health Sciences

UMass Lowell

Visiting Professor, Harvard School of Public HealthMolecular & Integrative Physiological Sciences

Department of Environmental Health

DisclaimerDr. Bello has received funding from the International Isocyanate Institute (III) to develop a new analytical method


Isocyanate Institute (III) to develop a new analytical method for MDI based on the reagent 1,8-diaminonaphthalene. All other research is funded through the National Institute For Occupational Health & Safety (NIOSH).

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Why do we care about skin exposure to NCO?

C t t d titi

[email protected] Isocyanates & Health 2013 3

1. Contact dermatitis –* mostly irritant but also some allergic

2 Role of skin in systemic2. Role of skin in systemic sensitization & asthma

Redlich et al. Isocyanate exposure and health effects OEM 2007 4th ed., Ch 30

MDI Fabric Coating Application

Formulation:• MDI/pMDI


p

• POLYOL• Toluene/ MEK 75/25%• THF• NMP• OTHER ADDITIVES

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MDI truck bed liningFormulation:

• MDI/pMDI


• POLYOL • Et-, diEt-,Pr-Glycol• Xylene• N-Butyl acetate• Diethyltoluenediamine• Other additives

AUTOBODY SHOPS

Formulation:• pHDI/pIPDIFormulation:• pHDI/pIPDI


• POLYOLS• Toluene/Xylene• MEK• n-Butyl Acetate

• POLYOLS• Toluene/Xylene• MEK• n-Butyl Acetate

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Allergic Contact DermatitisIsocyanates & Health [email protected] 7

Slide courtesy of Prof. C. Redlich, Yale


Tissue Dosimetry

1-3% of skin cells are dendritic cells (APC)

R-NCO

?

(image, A. Wisnewski)

DOSE = (Number of) Activated Dendritic Cells, DC *** L. Nodes

Tissue Dose = Isocyanate-Carrier Protein Complex Concentration in viable epidermis;

[Albumin-NCO Complex ??]

CD1a

Exposed SA > Critical Value !

Other co-exposures DC***

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NORMAL SKIN HISTOLOGY

KeratinizedLayer (SC)

Forehead /Scalp, 13 μm

Volar

SC Thickness


Layer (SC)

Viable Epidermis

Forearm 15±2 μm

Back of Hand

25±11 μm

P l

Dermis

Slide courtesy of Adam Wisnewski

Palm50±10 μm

70-80% Protein 70/10% α-/β-keratinmostly intracellular


5-15% Lipids SphyngolipidsVarious ceramides (41%)Mostly intercellular

20% water~20% water

ALBUMIN DEPOT

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Co-Exposures & Skin Additive Skin Permeability A

Kp (x10-4 cm/h)Skin Toxicity B

Skin Sensitizer ?

THF Neat: Low (0 46) N N


THF Neat: Low (0.46)In H2O, 61 or 100x

N N

NMP Neat & aqueous: 20-100,VERY HIGH!

Y N

Toluene / Xylenes Neat 2, ModerateVapors & aqueous,

Y N

Butyl Acetate 4, Moderate Y N

Polyol/s & Glycols Variable (<10), Low - Moderate

Variable, some Y

?

Amine catalysts Variable – Low to High (20); aqueous,

Y Y, but uncommon C

Surfactants - ? ?

A. Johanson & Rauma 2008; B. NIOSH pocket Guide 2005, Irritation &/or Toxicity; C, 3-dimethylaminopropylamine

Reacting Systems Active Hydrogen Compound Structure Relative Reaction Rate *

(Uncatalyzed @ 25C)

Primary Aliphatic Amine RNH2 100,000


y p 2 ,Secondary Aliphatic Amine R2NH 20,000-50,000Primary Aromatic Amine ArNH2 200-300

Primary Hydroxyl ROH 100

Water H2O 100

Carboxylic Acid RCOOH 40

Secondary Hydroxyl R2CHOH 30Secondary Hydroxyl R2CHOH 30

Urea RNHCONHR 15

Tertiary Hydroxyl R3COH 0.5

Urethane RNHCOOR 0.3

Amide RCONH2 0.1

Herrington & Hock Flexible Polyurethane Foams 2nd ed. 1998 The Dow Chemical Co.

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NCO Losses to Reactions with the Tape Strip

1.2 ug tNCO pMDI


pHDI+pIPDI, DCX-612 ug tNCO

ATR-FTIR, 10x1cm ZnSe crystal

40.0

60.0

80.0

100.0

tive

Inte

nsity

%

NCO Decay40.0

60.0

80.0

100.0

tive

Inte

nsity

%

NCO Decay

NCO + Tape strip

0.0

20.0

Ref

ere… 0 1 2 3 4 5 6 7 8 9 10

Rel

at

Minutes

NCO + Tape Strip

0.0

20.0

Ref

eren

… 1 2 3 4 5 6 7 8 9 10

Rel

a

Minutes

strip

Losses to Reactions with Sampling [email protected] Isocyanates & Health 2013 14

100

Spike of 1.2ug tNCO of DCX-61 (pHDI+pIPDI) onto tape strip -

% Recovery Tape Trip after 1 minute*After 1 min reaction

50

75

100

over

y (%

), LC

ana

lysi

s

Tape Trip after 1 minute

% Recovery Tape Trip after 5 minutes*After 5 min reaction

0

25

HDI Dione Biuret Isocyanurate pHDI pIPDI Total NCO

Rec

o

Isocyanate species

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Residence Time of NCOs on Skin

MDI GP Skin210 ng/cm2

pHDI on GP Skin

pHDI GP Skin, 310 ng/cm2

nC8-NCO,

Residence time of NCOs on Skin

MDI 62 5nmol NCO/cm2

pHDI on GP SkinpIDPI -similar

nC8 NCO,1.84 ug/cm2


0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80

Time (min)

Rel

ativ

e Si

gnal

Inte

nsity

MDI_62.5nmol NCO/cm2pHDI_62.5

Forearm of a human volunteer

Mean of triplicates

How do We Measure NCO Skin Exposure? [email protected] Isocyanates & Health 2013 16

Sampling for quantitative isocyanate skin exposure has relied heavily on REMOVAL techniques especially WIPES and TAPEtechniques, especially WIPES and TAPE STRIPS. INTERCEPTION techniques (such as gloves, reagent impregnated patches/gloves) are slowly been phased in. Inherent in these approaches, especially removal techniques, is the potential for significant underestimation of p gskin exposure. For aromatic systems in particular, such underestimation may be orders of magnitude.

Heederik et al 2012Eur Resp Rev 21: 124

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300.00 total NCO (ug/m3)= Sum(Impinger+Filter)

How Much Loss? Insights from Air Sampling of MDI Spray Foam Insulation


y = 0.83x - 50.16R² = 0.50

100.00

150.00

200.00

250.00

A_M

AP

UV2

54

= Sum(Impinger+Filter)

-50.00

0.00

50.00

0.00 50.00 100.00 150.00 200.00 250.00Met

hod

A

Method B_ Perimidone MS/MS

Exposure Marker vs. Total NCO (e.g. MDI vs. Total Respirable NCO species)


20.0ug NCO/m3

120.0

MS)

y = 0.043xR² = 0.449

5.0

10.0

15.0

4,4'

-MD

I (M

S/M

S)

y = 0.1817xR² = 0.353

20.0

40.0

60.0

80.0

100.0

DI

(ug

NC

O /m

3 , M

S/M

0.00.00 50.00 100.00 150.00 200.00

Perimidone MS/MS

0.00.00 50.00 100.00 150.00 200.00 250.00

MD

tNCO (ug/m3) from Perimidone MS/MS

15 min sampling time

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MAP-Impregnated gloves vs. tape strips

0.100

1.000

10.000

100.000

4,4'

-MD

I ng

/cm

2)

Left hand Skin dosimeterTape stripping


Analysis of spatial distribution of exposure

23

0.001

0.010

Thumb finger

Index finger

Middle finger

Ring finger

Little finger

Palm

4 (n

Hand location

10.000

100.000

Right hand Skin dosimeter

Tape stripping

1

2345

67

89 0.010

0.100

1.000

10.000

Thumb finger

Index finger

Middle finger

Ring finger

Little finger

Palm

4,4'

-MD

I (n

g/cm

2)

Hand location

Aliphatic Polyisocyanates – HDI Unsuitable as an Exposure Marker


LU

800

1000 1200

FLD1 A, Ex=370, Em=418 (IOMSSA 1\000121\IOM245X2 D)

HDI, 0.01-1% of tNCO

min 10 15 20 25 30 350

200 400 600 800

LU

400 600 800

1000 1200 1400

FLD1 A, Ex=370, Em=418 (IOMSSA 1\000309\IOM0290 D)

min 10 15 20 25 30 350

200

min 10 15 20 25 30 35

LU

0 200 400 600 800

1000 1200 1400

FLD1 A, Ex=370, Em=418 (IOMSSA 1\000309\IOM0314 D)

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LC-MS/MS: Necessary, but likely [email protected] Isocyanates & Health 2013 21

MRM_MDI

MRM_3-Ring MDI

UV

UV spectrum – No NCO

Research Needs & Future DirectionsNext generation interception dosimeters!Removal techniques that rely on bound


q yspecies and proteomic markers rather than free residual NCO!LC-UV-MS/MS analytical finish & DAN-like

complementary techniques Co-exposures & skin uptake/disease, p p ,

especially solvents, amine catalysts or byproducts and low MW glycols!Route-specific biomarkers

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Questions?

X 2012 23

[email protected]

18000

17800

16950

75600

171600

Middle

Ring

Little

Palm

Total

Fing

er

M1- End of Shift - Cleaning


24550

18700

18000

0 20000 40000 60000 80000 100000 120000 140000 160000 180000 200000

Thumb

Index

ng 4,4'-MDI

16770Palm

Total

M1 Back - 8am-2:30pm

2450

1770

1820

1550

1590

7590

0 2000 4000 6000 8000 10000 12000 14000 16000 18000

Thumb

Index

Middle

Ring

Little

Palm

ng 4,4'-MDI

Fing

er

Left hand Right hand

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The B sideThe B-side (in spray foam insulations):

Polyether Polyol; CAS # Trade Secret; 20-30%


Polyether Polyol; CAS # Trade Secret; 20 30%Agriculture based Polyol; CAS # Trade Secret; 15-30%Tris-iso-chloropropyl phosphate; CAS # 13674-84-5; 15-40%Surfactant 1; CAS # Trade Secret; 5-20%Surfactant 2; CAS # Trade Secret; 0-1%Tertiary Amine Catalyst; CAS # Trade Secret; 1-5%Water; CAS # 7732-18-5; 1-20%

Icynene open cell foam

26

Extravascular albuminTotal HSA: IV = 32.8%; Skin =27.6%; Muscle = 26.9%; Others =12.7%

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27

Urinary HDI Metabolites-what for?

40

60

80

100

120

HD

A u

g/g

crea

tinin

e

0

20

-5 0 5 10 15 20

Time (hours)

Urin

ary

H

Documents

CURRENT ISSUES IN THE MEASUREMENT OF … · CURRENT ISSUES IN THE MEASUREMENT OF [email protected] Isocyanates & Health 2013 1 ISOCYANATE SKIN EXPOSURE Dhimiter Bello, Sc.D.,