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Epidemiologic studies of U.S. workers handling carbon nanotubes: the interface between
exposure and health
Mary K Schubauer-Berigan*, Matthew M Dahm*, Aaron Erdely§
National Institute for Occupational Safety and Health *Division of Surveillance, Hazard Evaluations, and Field Studies, Cincinnati,
OH §Health Effects Laboratory Division, Morgantown, WV
Presented at Quantifying Exposure to Engineered Nanomaterials Workshop, July 2015
The findings and conclusions in this presentation have not been formally disseminated by the National Institute for Occupational Safety and Health and should not be construed to represent any agency determination or policy.
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Health concerns about nanomaterials • Special properties of nanomaterials
may enhance toxic potential – Small size – Large surface area per unit mass – High aspect ratio – Different surface charge
• Long, thin shape may confer asbestos-like properties – Some CNT & carbon nanofibers (CNF) – Metal nanowires or nanocellulose
Silver-Oxide Coating on Surface of Silicon Wafer, image courtesy of Samuel Peppernick
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Health concerns about nanomaterials Toxicological & environmental studies of nanoparticles suggest possible: --Pulmonary effects (CNT & CNF)
Pulmonary fibrosis Penetration of pleura Mitotic disruption (mutagenesis) Lung tumor promotion
--Cardiovascular effects (air pollution epidemiology) Decreased heart rate variability Arterial vasoconstriction Increased blood pressure Higher plasma viscosity
--Initiation of inflammatory cascade
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Multi-walled CNT Reaching Pleural Surface
Image courtesy of Robert Mercer, NIOSH
7 days post-exposure; 40 μg aspiration in mice; *indicates site of persistent fibrosis; [Porter et al. Toxicology 269 (2010) 136–147]
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Challenges in studying engineered nanomaterial workers
Small workforce sizes Findings in U.S. workforce handling engineered carbonaceous
nanomaterials (ECN) (Schubauer-Berigan et al. 2011; 2013): N = ~650 in 2009 Growing at 15% annually 75% of workforce handling CNT & CNF, which is growing at 22% annually
Industry characterized by a high degree of automation, even for large-scale production
Challenging materials Typical CNT diameters: 1-50 nm, lengths of 1-100 µm Typical daily quantities handled in grams Air concentrations associated with significant health effect (e.g., 1 µg/m3)
for CNT as elemental carbon (EC)
Short latency: materials only recently commercialized
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How do we prioritize engineered nanomaterials for occupational epidemiologic study?
1. Degree of potential hazard – Results of toxicological studies, including mechanistic
information – Analogy from other materials (air pollution, asbestos)
2. Potential for exposure – Number of workers – Quantity of materials used – Results of exposure assessments
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NIOSH approach: Phased industrywide studies
Phase I: Collected information to determine feasibility of industrywide studies of engineered carbonaceous nanomaterial (ECN) workforce • Estimated U.S. workforce size and growth for different types
of ECN in companies larger than R&D Phase II: Conducted industrywide exposure assessment for CNT & CNF, the most widely used ECN • Optimized methods to measure CNT & CNF exposure in
workplaces Phase III: Conduct epidemiologic studies • Evaluating markers of early biological effects in relation to
metrics of exposure and develop prospective cohort
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Phase II: Industrywide exposure assessment study
• Conducted 2010-2012 (Dahm et al. 2012, 2013, 2015) • Objectives:
– Develop methods to measure exposures to CNTs and CNFs at biologically relevant levels using key exposure metrics.
• Filter based: EC & size-specific fiber concentrations • Direct reading instruments (DRI): particle number, active surface area
– Characterize full-shift and task-specific exposures in a representative sample of primary and secondary manufacturers
• Findings: both inhalable and respirable EC mass and TEM structure count concentrations should be used in epidemiologic study
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Variation in elemental carbon exposure by task (Dahm et al. 2012)
**CNT Waste collection, General office work, Milling CNT composite, Sieving and Spray Coating
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Correlation of EC vs. TEM filter-based
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0 1 2 3 4 5 6 7 8 9
CN
T St
ruct
ure
Cou
nts
by T
EM (s
truc
ture
s/cm
3 )
Inhalable elemental carbon (µg/m3)
ρ = 0.44, p=0.01
NIOSH REL 1 µg/m3 Respirable, background-corrected
OSHA asbestos PEL 0.1 fiber/cm3
Adapted from Dahm et al. (2012)
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Correlation of background-corrected DRI with filter-based samples (Dahm et al. 2013)
r= 0.19 p-value= 0.49
-20000
-10000
0
10000
20000
30000
40000
0 1 2 3 4 5
Part
icle
Con
cent
ratio
n (p
/cm
3 )
Mass Concentration of EC (µg/m3)
r= 0.13 p-value= 0.64
-20000
-10000
0
10000
20000
30000
40000
0 0.1 0.2 0.3 0.4
Part
icle
Con
cent
ratio
n (p
/cm
3 )
CNT Structure Counts by TEM (structures/cm3)
r= 0.23 p-value= 0.41
0
5
10
15
20
25
30
35
0 0.2 0.4 0.6 0.8 1 1.2
Activ
e Su
rfac
e Ar
ea (µ
m2 /
cm3 )
Mass Concentration of EC (µg/m3)
r= -0.45 p-value= 0.32
0
5
10
15
20
25
30
35
0 0.1 0.2 0.3 0.4
Activ
e Su
rfac
e Ar
ea (µ
m2 /
cm3 )
CNT Structure Counts by TEM (structures/cm3)
r= -0.05 p-value= 0.91
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Exposure Assessment Challenges Do these two structures
have the same potential for toxicity?
Images courtesy of Joe Fernback, NIOSH
Images from personal breathing zone samples from CNT manufacturing (Dahm et al. 2012)
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Examples of CNT Structures by Size
0
5
10
15
20
25
30
35
40
45
50
Single CNT <1μm 1-2μm 2-5μm 5-10μm >10μm
Aver
age
CNT
Stru
ctur
es C
ount
ed p
er S
ampl
e
Size Bin
N
M
L
J
I
G
(Dahm et al. 2015)
Site
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Possible exposure determinants • Synthesis method, for primary manufacturers • Type and toxicity of raw materials • Nominal aspect ratio of CNT or CNF • Form of CNT and CNF used—dry powder, liquid • Coatings • Type of processes and tasks performed by worker • Use & adequacy of personal protective equipment • Length of shift
– Time spent working directly with CNT or CNF – Time spent potentially indirectly exposed to CNT or
CNF • High-concern activities: Harvesting, dry powder
handling, cleaning operations and waste disposal
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Epidemiology
Cross-sectional study Exposure registry
Potency testing
In vitro screening
Elemental carbon analysis
PBZ sampling
Electron microscopy
Toxicology Assessment
Exposure Assessment
In vivo exposure Detection of CNT in
sputum
Biomarkers
Prospective cohort study?
NIOSH carbon nanotube
collaborative studies Biologically
relevant dose
Dermal sampling
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Phase III: Epidemiologic studies
– Carbon nanotube and nanofiber-exposed workers
– Measures of early health effects – Measures of best exposure metrics:
• Elemental carbon • TEM-based, size-specific structure counts
– Include workers with varying ranges of exposure
A. Cross-sectional study (in progress)
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Epidemiologic studies A. Cross-sectional study • Medical exams:
– Basic physical examination – Spirometry and cardiovascular
function • Biological sample collection (blood,
sputum) • Collection of information on other
influential factors • Simultaneous measurement of
exposure to CNT and CNF, modified by exposure factors
• Exposure-response analyses
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Biomarkers measured in cross-sectional study
Biomarker type Biomarker* Rationale
Pulmonary fibrosis KL-6 glycoprotein MMP1, 7 & 9
KL-6 is early marker of pulmonary fibrosis in workers exposed to some metals; MMPs are involved in degradation of extracellular matrix
Oxidative stress Myeloperoxidase, SOD, 8-OHdG TNF-α, 8-isoprostane
Mouse analogs elevated with CNT exposure
Distinguish local vs. systemic inflammation (with serum markers)
Inflammation Interleukins (e.g., IL-6 & IL-8), CRP, TNF-α, etc.
Associated with lung cancer, pulmonary fibrosis, and systemic effects in human and animal models.
Coagulant cardiovascular markers
Circulating PAI-1 & fibrinogen, ICAM-1, VCAM-1, PAI-1
Elevated in mice exposed to MWCNT. Also may relate to pulmonary effects.
Neutrophils Complete blood count with differentials
Increased neutrophils in blood following exposure found in welders
*Markers in sputum, serum, or whole blood
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Epidemiologic studies Cross-sectional Study Status • Visited 12 primary and secondary
CNT and CNF manufacturers and users
• Enrolled 108 participants • Serum and sputum biomarkers
analyzed • TEM analyses remaining for some
sites • CNT detection in sputum using
dark-field microscopy
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Planned epidemiologic studies B: Exposure registry of CNT & CNF workers • Identify CNT and CNF
manufacturers, users and distributors
• Demographic, work history, and exposure information will be requested for employees working with CNT or CNF
• Information will be updated on an ongoing basis
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Planned epidemiologic studies C: Prospective cohort study of CNT & CNF workers • Use registry to identify cohort members • Evaluate health outcomes, including
pulmonary disease, CVD, cancer • Methods
– Periodic questionnaires administered to cohort
– Linkage of the cohort with disease and mortality registries
– Development of job-exposure matrix to cover all facilities, workers and time periods
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Exposure assessment challenges in epidemiology • Most-relevant metrics are uncertain
– Count, mass, surface area, aspect-ratio-specific counts – What is implication of inhalable vs. respirable size fraction?
• Signal-to-noise problem: Exposure to ENM is low compared to background ultrafine particulates – Non-specific measurement metrics (gravimetric, counts)
may give misleading results – Emphasis on DRI may detract from adoption of metrics
more specific for ENM – DRI are useful for indicating exposure to ambient (often,
process-derived) ultrafine particulates • Some filter-based metrics (e.g., electron microscopy)
can be expensive – Development of representative, task-specific JEMs
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Study Collaborators & Support Field studies Measurement methods Toxicology Matt Dahm Eileen Birch Aaron Erdely Marie de Perio Douglas Evans Linda Sargent Jim Deddens Joseph Fernback Robert Mercer Ken Sparks Melodie Fickenscher Dale Porter Donald Booher Tracy Hulderman Chrissy Toennis Suzan Bilgesu Debbie Sammons John Clark
Funding Support: • NIOSH-Nanotechnology
Research Center • National Toxicology
Program
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Epidemiology and Exposure Study References
Birch ME, et al. Exposure and emissions monitoring during carbon nanofiber production—Part I: elemental carbon and iron-soot aerosols. Ann Occup Hyg 55:1016-36, 2011.
Dahm MM, et al. Exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers. Ann Occup Hyg 56:542-556, 2012.
Dahm MM, et al. Occupational exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers: mobile direct-reading sampling. Ann Occup Hyg 57:328-344, 2013.
Dahm MM, et al. Carbon nanotube and nanofiber exposure assessments: an analysis of 14 site visits. Ann Occup Hyg 2015, 1-19, doi:10.1093/annhyg/mev020
Schubauer-Berigan MK, et al. Engineered carbonaceous nanomaterials manufacturers in the United States: Workforce size, characteristics, and feasibility of epidemiologic studies. J Occup Environ Med 53:S62-S67, 2011.
Schubauer-Berigan MK, et al. Industrywide Exposure Assessment and Cross-Sectional Epidemiologic Studies of Workers at Facilities Manufacturing, Distributing, or Using Carbon Nanotubes or Carbon Nanofibers in the United States. Protocol. National Institute for Occupational Safety and Health; Division of Surveillance, Hazard Evaluations and Field Studies. 2013. 129 pp.