CURRENT ISSUES IN THE MEASUREMENT OF ISOCYANATE SKIN EXPOSURE

Transcription

1 1 CURRENT ISSUES IN THE MEASUREMENT OF ISOCYANATE SKIN EXPOSURE Dhimiter Bello, Sc.D., M.Sc. Assoc. Professor, Exposure Biology Work Environment Department College of Health Sciences UMass Lowell Visiting Professor, Harvard School of Public Health Molecular & Integrative Physiological Sciences Department of Environmental Health Dhimiter_Bello@uml.edu 2 Disclaimer Dr. Bello has received funding from the International 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). 1

2 3 Why do we care about skin exposure to NCO? 1. Contact t dermatitis * mostly irritant but also some allergic 2. Role of skin in systemic sensitization & asthma Redlich et al. Isocyanate exposure and health effects OEM th ed., Ch 30 Dhimiter_Bello@uml.edu 4 MDI Fabric Coating Application Formulation: MDI/pMDI POLYOL Toluene/ MEK 75/25% THF NMP OTHER ADDITIVES 2

3 5 MDI truck bed lining Formulation: MDI/pMDI POLYOL Et-, diet-,pr-glycol Xylene N-Butyl acetate Diethyltoluenediamine Other additives Dhimiter_Bello@uml.edu 6 AUTOBODY SHOPS Formulation: phdi/pipdi POLYOLS Toluene/Xylene MEK n-butyl Acetate 3

4 7 Allergic Contact Dermatitis Slide courtesy of Prof. C. Redlich, Yale Dhimiter_Bello@uml.edu 8 (image, A. Wisnewski) Tissue Dosimetry 1-3% of skin cells are dendritic cells (APC) R-NCO? DOSE = (Number of) Activated Dendritic Cells, DC *** L. Nodes Tissue Dose = Isocyanate-Carrier Protein Complex Concentration in viable epidermis; [Albumin-NCO Complex??] Exposed SA > Critical Value! Other co-exposures DC*** CD1a 4

5 9 NORMAL SKIN HISTOLOGY Keratinized Layer (SC) SC Thickness Forehead /Scalp, 13 μm Volar Forearm 15±2 μm Viable Epidermis Back of Hand 25±11 μm Palm 50±10 μm Dermis Slide courtesy of Adam Wisnewski Dhimiter_Bello@uml.edu % Protein 70/10% α-/β-keratin mostly intracellular 5-15% Lipids Sphyngolipids Various ceramides (41%) Mostly intercellular ~20% water ALBUMIN DEPOT 5

6 11 Co-Exposures & Skin Additive Skin Permeability A Kp (x10-4 cm/h) THF Neat: Low (0.46) In H 2 O, 61 or 100x NMP Neat & aqueous: , VERY HIGH! Toluene / Xylenes Neat 2, Moderate Vapors & aqueous, Skin Toxicity B Skin Sensitizer? N THF Neat: Low (0 46) N N Butyl Acetate 4, Moderate Y N Polyol/s & Glycols Variable (<10), Low - Moderate Amine catalysts Variable Low to High (20); aqueous, Y Y Variable, some Y Y N N? Y, but uncommon C Surfactants -?? A. Johanson & Rauma 2008; B. NIOSH pocket Guide 2005, Irritation &/or Toxicity; C, 3-dimethylaminopropylamine Dhimiter_Bello@uml.edu 12 Reacting Systems Active Hydrogen Compound Structure Relative Reaction Rate * 25C) Primary Aliphatic Amine RNH 2 100,000 Secondary Aliphatic Amine R 2 NH 20,000-50,000 Primary Aromatic Amine ArNH Primary Hydroxyl ROH 100 Water H 2 O 100 Carboxylic Acid RCOOH 40 Secondary Hydroxyl R 2 CHOH 30 Urea RNHCONHR 15 Tertiary Hydroxyl R 3 COH 0.5 Urethane RNHCOOR 0.3 Amide RCONH Herrington & Hock Flexible Polyurethane Foams 2 nd ed The Dow Chemical Co. 6

7 13 NCO Losses to Reactions with the Tape Strip ATR-FTIR, 10x1cm ZnSe crystal 1.2 ug tnco pmdi phdi+pipdi, DCX-61 2 ug tnco tive Intensity % Relat NCO Decay NCO + Tape Strip tive Intensity % Rela NCO Decay NCO + Tape strip 0.0 Refere Minutes Referen Minutes Dhimiter_Bello@uml.edu 14 Losses to Reactions with Sampling Media Reco overy (%), LC analysis Spike of 1.2ug tnco of DCX-61 (phdi+pipdi) onto tape strip - % After Recovery 1 min reaction Tape Trip after 1 minute* % After Recovery 5 min reaction Tape Trip after 5 minutes* 0 HDI Dione Biuret Isocyanurate phdi pipdi Total NCO Isocyanate species 7

8 Residence Time of NCOs on Skin MDI GP Skin 210 ng/cm 2 phdi GP Skin, 310 ng/cm 2 phdi nc8-nco, on GP Skin pidpi similar ug/cm 2 Relative Signal Intensity Residence time of NCOs on Skin MDI_62.5nmol NCO/cm2 phdi_ Dhimiter_Bello@uml.edu 15 Time (min) Forearm of a human volunteer Mean of triplicates Dhimiter_Bello@uml.edu 16 How do We Measure NCO Skin Exposure? Sampling for quantitative isocyanate skin exposure has relied heavily on REMOVAL techniques, 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 skin exposure. For aromatic systems in particular, such underestimation may be orders of magnitude. Heederik et al 2012 Eur Resp Rev 21: 124 8

9 17 How Much Loss? Insights from Air Sampling of MDI Spray Foam Insulation Method A_MAP UV total NCO (ug/m3) = Sum(Impinger+Filter) y = 0.83x R² = Method B_ Perimidone MS/MS Dhimiter_Bello@uml.edu 18 Exposure Marker vs. Total NCO (e.g. MDI vs. Total Respirable NCO species) MD DI (ug NCO /m 3, MS/M MS) y = x R² = ,4'-MDI (MS/MS) ug NCO/m3 y = 0.043x R² = tnco (ug/m 3 ) from Perimidone 0.00 MS/MS min sampling time Perimidone MS/MS 9

10 19 MAP-Impregnated gloves vs. tape strips Left hand Skin dosimeter Tape stripping 4,4'-MDI ng/cm2) 4 (n Thumb Index Middle Ring Little Palm Hand location Analysis of spatial distribution of exposure Right hand Skin dosimeter Tape stripping ,4'-MDI (ng/cm2) Thumb Index Middle Ring Little Palm Hand location Dhimiter_Bello@uml.edu 20 Aliphatic Polyisocyanates HDI Unsuitable as an Exposure Marker FLD1 A, Ex=370, Em=418 (IOMSSA 1\000121\IOM245X2 D) LU HDI, % of tnco FLD1 A, Ex=370, Em=418 (IOMSSA 1\000309\IOM0290 D) LU FLD1 A, Ex=370, Em=418 (IOMSSA 1\000309\IOM0314 D) LU min min min 10

11 21 LC-MS/MS: Necessary, but likely insufficient MRM_MDI MRM_3-Ring MDI UV UV spectrum No NCO 22 Research Needs & Future Directions Next generation interception dosimeters! Removal techniques that rely on bound species and proteomic markers rather than free residual NCO! LC-UV-MS/MS analytical finish & DAN-like complementary techniques Co-exposures & skin uptake/disease, especially solvents, amine catalysts or byproducts and low MW glycols! Route-specific biomarkers 11

12 X Questions? 24 M1- End of Shift - Cleaning Finger Total Palm Little Ring Middle Index Thumb ng 4,4'-MDI M1 Back - 8am-2:30pm Finger Total Palm 7590 Little 1590 Ring 1550 Middle 1820 Index 1770 Thumb ng 4,4'-MDI Left hand Right hand 12

13 25 The B side The B-side (in spray foam insulations): Polyether Polyol; CAS # Trade Secret; 20-30% Agriculture based Polyol; CAS # Trade Secret; 15-30% Tris-iso-chloropropyl phosphate; CAS # ; 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 # ; 1-20% Icynene open cell foam Extravascular albumin 26 Total HSA: IV = 32.8%; Skin =27.6%; Muscle = 26.9%; Others =12.7% 13

14 Urinary HDI Metabolites-what for? 27 Urinary HDA ug/g creatinine Time (hours) 14