Occupational Exposure to Carbon Nanotubes and Nanofibers

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(single or multiwall; purified or unpurified). These early-stage, noncancerous adverse lungeffects in animals include: (1) the early onset and persistence of pulmonary fibrosis inCNT-exposed mice [Shvedova et al. 2005, 2008; Porter et al. 2010; Mercer et al. 2011], (2)an equal or greater potency of CNT compared with other inhaled particles known to behazardous (e.g., crys talline silica, asbestos) in causing pulmonary inflammation and fibrosis[Lam et al. 2004; Shvedova et al. 2005; Muller et al. 2005], and (3) reduced lung clearancein mice or rats exposed to relatively low-mass concentrations of CNT [Mercer et al. 2009;Pauluhn 2010a]. Findings of acute pulmonary inflammation and interstitial fibro sis havealso been observed in mice exposed to CNF [Murray et al. 2012]. The extent to which theseanimal data may predict clinically significant lung effects in workers is not known. However,NIOSH considers these animal study findings of pulmonary inflammation, granulomas,and fibrosis associated with exposure to CNT and CNF to be relevant to human health riskassessment because similar lung effects have been observed in workers in dusty jobs [Romand Markowitz 2006; Hubbs et al. 2011].Some studies also indicate that CNT containing certain metals (nickel, 26%) [Lam et al.2004] or higher metal content (17.7% vs. 0.2% iron) are more cytotoxic in vitro and in vivo[Shvedova et al. 2003, 2008]. However, in experimental animal studies, both unpurified andpurified (low metal content) CNT are associated with early onset and persistent pul monaryfibrosis and other adverse lung effects [Lam et al. 2004; Shvedova et al. 2005; 2008]. Otherstudies indicate that differences in physical-chemical properties, including functionalizationor bio-modification, may alter the lung retention and biological responses [Kagan et al.2010; Osmond-McLeod et al. 2011; Pauluhn 2010a; Oyabu et al. 2011]. Although a numberof different types of CNT and CNF have been evaluated, uncertainty exists on the generalizabilityof the current animal findings to new CNT and CNF.In addition to the early-stage non-cancer lung effects in animals, some studies in cells oranimals have shown genotoxic or carcinogenic effects. In vitro studies with human lungcells have shown that single-walled carbon nanotubes (SWCNT) can cause genotoxicityand abnormal chromosome number by interfering with mitosis (cell division) [Muller etal. 2008b; Sargent et al. 2009, 2011; Kisin et al. 2011]. Other in vitro studies did not showevidence of genotoxicity of some MWCNT [Wirnitzer et al. 2009; Kim et al. 2011].Studies in mice exposed to multi-walled carbon nanotubes (MWCNT) have shown themigration of MWCNT from the pulmonary alveoli to the intrapleural space [Hubbs et al.2009; Porter et al. 2010; Mercer et al. 2010]. The intra pleural space is the same site in whichmalignant mesothelioma can develop due to asbestos exposure. Intraperitoneal injection ofCNT in mice has resulted in inflammation from long MWCNT (> 5 μm in length), but notshort MWCNT (< 1 μm in length) or tangled CNT [Poland et al. 2008; Takagi et al. 2008;Muller et al. 2009; Murphy et al. 2011]. In rats administered CNT by peritoneal injection,the pleural inflammation and mesothelioma were related to the thin diameter and rigidstructure of MWCNT [Nagai et al. 2011]. In a study of rats administered MWCNT or crocidoliteby intrapulmonary spraying, exposure to either material produced inflammation inthe lungs and pleural cavity in addition to mesothelial proliferative lesions [Xu et al. 2012].Pulmonary exposure to CNT has also produced systemic responses including an increasein inflammatory mediators in the blood, as well as oxidant stress in aortic tissue and increaseplaque formation in an atherosclerotic mouse model [Li et al. 2007; Erdely et al.2009]. Pul monary exposure to MWCNT also depresses the ability of coronary arteriolesto respond to dilators [Stapleton et al. 2011]. These cardiovascular effects may be due toviiiNIOSH CIB 65 • Carbon Nanotubes and Nanofibers
neurogenic sig nals from sensory irritant receptors in the lung. Mechanisms, such as inflammatorysignals or neurogenic pathways causing these systemic responses, are underinvestigation.Additional research is needed to fully explain the mechanisms of biological responses toCNT and CNF, and the influence of physical-chemical properties. The findings of adverserespiratory effects and systemic effects reported in several animal studies indicate the needfor protective measures to limit worker exposure to CNT and CNF.CNT and CNF are currently used in many industrial and biomedical applications, includingelectronics, lithium-ion batteries, solar cells, super capacitors, thermoplastics, polymercomposites, coatings, adhesives, biosensors, enhanced electron-scanning microscopyimaging techniques, inks, and in pharmaceutical/biomedical devices. CNT and CNF canbe encountered in facilities ranging from research laboratories and production plants tooperations where CNT and CNF are processed, used, disposed, or recycled. The data onworker personal exposures to CNT and CNF are extremely limited, but reported workplaceairborne concentrations for CNT [Maynard et al. 2004; Han et al. 2008a; Bello et al. 2009,2010; Tsai et al. 2009; Lee et al. 2010; Cena and Peters 2011; Dahm et al. 2011] and CNF[Methner et al. 2007; Evans et al. 2010; Birch 2011a; Birch et al. 2011b] indicate the potentialfor worker exposures in many tasks or processes and the reduction or elimination of exposureswhen measures to control exposure are used.Assessment of the Health Risk and RecommendedExposure LimitNIOSH has determined that the best data to use for a quantitative risk assessment andas basis for a recommended exposure limit (REL) are the nonmalignant pulmonary datafrom the CNT animal studies. At present, data on cancer and cardiovascular effects are notadequate for a quantitative risk assessment of inhalation exposure. NIOSH considers thepulmonary responses of inflammation and fibrosis observed in short-term and subchronicstudies in animals to be relevant to humans, as inflammatory and fibrotic effects are alsoobserved in occupational lung diseases associated with workplace exposures to other inhaledparticles and fibers. Uncertainties include the extent to which these lung effects inanimals are associated with functional deficits and whether similar effects would be clinicallysignificant among workers. However, these fibrotic lung effects observed in some ofthe animal studies developed early (e.g., 28 days after exposure) in response to relativelylow-mass lung doses, and also persisted or progressed after the end of exposure [Shvedovaet al. 2005, 2008; Ma-Hock et al. 2009; Pauluhn 2010a; Porter et al. 2010; Mercer et al. 2011;DeLorme et al. 2012; Murray et al. 2012]. Given the relevance of these types of lung effectsto humans, the REL was derived using the published subchronic and short-term animalstudies with dose-response data of early stage fibrotic and inflammatory lung responses toCNT exposure (Section 5 and Appendix A).Critical effect levels for the noncancerous lung effects estimated from the animal doseresponsedata (e.g., BMD, benchmark dose and BMDL, the 95% lower confidence limit estimatesof the BMD) have been extrapolated to humans by accounting for the factors influencingthe lung dose in each animal species. The no observed adverse effect level (NOAEL)and lowest observed adverse effect level (LOAEL) estimates reported in the subchronicinhalation studies were also evaluated as the critical effect levels. Working-lifetime exposureNIOSH CIB 65 • Carbon Nanotubes and Nanofibersix
Page 1 and 2: CURRENT INTELLIGENCE BULLETIN 65Occ
Page 3 and 4: Current Intelligence Bulletin 65Occ
Page 5 and 6: ForewordThe Occupational Safety and
Page 7 and 8: Executive SummaryOverviewCarbon nan
Page 9: 2009; Pauluhn 2010a; Porter et al.
Page 13 and 14: possible. Until the results from an
Page 15 and 16: ••Follow exposure and hazard as
Page 17 and 18: Periodic Evaluations••Evaluatio
Page 19 and 20: ContentsForeword ..................
Page 21 and 22: A.3.2 Comparison of Short-term and
Page 23 and 24: ESPFeFMPSFPSSgGMGSDHCLHECHEPAhrISOI
Page 25 and 26: AcknowledgementsThis Current Intell
Page 27 and 28: 1 IntroductionMany nanomaterial-bas
Page 29: 2 Potential for ExposureThe novel a
Page 32 and 33: CNMs, with MWCNT agglomerates obser
Page 34 and 35: composite materials with local exha
Page 36 and 37: information on air contaminants. Sa
Page 39 and 40: 3 Evidence for Potential Adverse He
Page 41 and 42: decreasing agglomerate size increas
Page 43 and 44: examined up to 60 days post-exposur
Page 45 and 46: 3.3 SWCNT and MWCNTIntraperitoneal
Page 47 and 48: The same potency sequence was obser
Page 49 and 50: Table 3-3. Findings from published
Page 55 and 56: Table 3-7 (Continued). Findings fro
Page 57: Table 3-8. Findings from published
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length, respectively) [Muller et al
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5 CNT Risk Assessment and Recommend
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A-6). Risk estimates derived from o
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Table 5-4. Factors, assumptions, an
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and analytical methods. NIOSH is re
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Table 5-5. Recommended occupational
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deficits in animals or clinically s
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(3) Rat lung dose estimationIn the
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tasks where worker exposures exceed
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As part of the evaluation of worker
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Table 6-1. EC LODs and LOQs for 25-
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6.2 Engineering ControlsOne of the
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Table 6-6 (Continued). Examples of
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Table 6-7 (Continued). Engineering
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exposure estimates for SWCNT on ind
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Table 6-8. Respiratory protection f
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••Workers in areas or in jobs w
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7 Research NeedsAdditional data and
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ReferencesACGIH [1984]. Particle si
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Bolton RE, Vincent HJ, Jones AD, Ad
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eport issued on July 22, 2011. NEDO
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Kobayashi N, Naya M, Mizuno K, Yama
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Methner M, Hodson L, Geraci C [2010
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Human Services, Centers for Disease
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Piegorsch WW, Bailer AF [2005]. Qua
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AD, Baron PA [2003]. Exposure to ca
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Varga C, Szendi K [2010]. Carbon na
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ContentsA.1 Introduction ..........
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A.1 IntroductionThe increasing prod
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provide an informal check on the es
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these same dose groups; this effect
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Table A-1. Rodent study information
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the deposited (no clearance) and th
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The other BMDS models failed to con
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Figure A-2. Benchmark dose model (m
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Figure A-3 (continued). Benchmark d
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Table A-3. Benchmark dose estimates
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Table A-5. Benchmark dose estimates
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histopathology grade 2 or higher lu
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Table A-8. Working lifetime percent
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developing early-stage adverse lung
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Figure A-4. Dose-response relations
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cell surface area). However, the wo
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purified or unpurified (with differ
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Table A-9. Comparison of rat or hum
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A.6.1.3 Pulmonary Ventilation RateT
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used as the effect levels in evalua
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the DF estimate, although a larger
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or overloading, of particle clearan
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Table A-13. Human-equivalent retain
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A.7.1 Particle CharacteristicsBoth
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and density. The following MMAD and
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Table A-15. CNT lung dose normalize
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B.1 Key Terms Related toMedical Sur
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APPENDIX CNIOSH Method 5040
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filter. In the method evaluation, d
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Most of the studies on sampling art
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e analyzed to determine the onset o
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Delivering on the Nation’s promis
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