Occupational Exposure to Carbon Nanotubes and Nanofibers

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Ma-Hock et al. [2009] subchronic rat inhalationstudy of MWCNT. Aschberger et al. [2010] proposedOELs of 1 µg/m 3 for MWCNT studied byMa-Hock et al. [2009] and 2 µg/m 3 for MWCNTfrom Pauluhn [2010a], by adjusting 0.1 mg/m 3 (theLOAEL in Ma-Hock et al. [2009] and the NOAELin Pauluhn [2010a]) for rat-to-human daily exposureand respiratory volume, and applying an overallassessment factor of 50 and 25, respectively.Pauluhn [2010b] derived an OEL using subchronicdata in rats inhaling MWCNTs (Baytubes®) [Pauluhn2010a]. This approach was based on the biologicalmechanism of volumetric overloading of alveolarmacrophage-mediated clearance of particlesfrom the lungs of rats [Morrow 1988]. Increasedparticle retention half-time (an indication of lungclearance overload) was reported in rats exposedby subchronic inhalation to MWCNT (Baytubes®)at 0.1, 0.4, 2.5, or 6 mg/m 3 The overloading of ratlung clearance was observed at lower-mass doses ofMWCNT (Baytubes®) compared with other poorlysoluble particles; and the particle volume dose wasbetter correlated with retention half-time amongpoorly soluble particles including CNT [Pauluhn2010a, b]. Pauluhn [2010b] reported benchmarkconcentration (BMC) estimates of 0.16 to 0.78 mg/m 3 for rat lung responses of pulmonary inflammationand increased collagen, but selected the lowerNOAEL of 0.1 mg/m 3 to derive a human-equivalentconcentration. The NOAEL was adjusted for humanand rat differences in factors affecting theestimated particle lung dose (i.e., ventilation rate,alveolar deposition fraction, retention kinetics, andtotal alveolar macrophage cell volume in each species).The product of these ratios resulted in a finalfactor of 2, by which the rat NOAEL was divided,to arrive at a human-equivalent concentration of0.05 mg/m 3 (8-hr TWA) as the OEL for MWCNT(Baytubes®). No uncertainty factors were used inderiving that estimate.The Japanese National Institute of Advance IndustrialScience and Technology (AIST) derived anOEL for CNT of 30 µg/m 3 [Nakanishi 2011a,b],based on studies supported by the New Energy andIndustrial Technology Development Organization(NEDO) of Japan. Rat NOAELs for pulmonaryinflammation were identified in 4-week inhalationstudies of SWCNT and MWCNT [Morimotoet al. 2011a,b]. Human-equivalent NOAELs wereestimated by accounting for rat and human differencesin exposure duration, ventilation rate, particledeposition fraction, and body weight [Nakanishi2011b]. The rat NOAELs of 0.13 and 0.37 mg/m 3 forSWCNT and MWCNT, respectively, were estimatedto be equivalent to 0.03 and 0.08 mg/m 3 in humansincluding adjustment by an uncertainty factorof 6. This total uncertainty factor included a factorof 2 for uncertainty in subchronic-to-chronicextrapolation and a factor of 3 for uncertainty inrat to human toxicokinetic differences (factors of 1were assumed for toxicodynamic differences in ratsand humans and for worker inter-individual variability).A relationship was reported between theBET specific surface area of various types of CNTand pulmonary inflammation (percent neutrophilsin bronchoalveolar lavage fluid) (Figure V.2 in Nakanishi[2011b]). Thus, the OEL of 0.03 mg/m 3 wasproposed for all types of CNT, based on the data forthe SWCNT with the relatively high specific surfacearea of ~1,000 m 2 /g (which was noted wouldbe more protective for other CNTs with lower specificsurface area). A period-limited (15-yr) OELwas proposed due to uncertainty in chronic effectsand based on the premise that the results will be reviewedagain within that timeframe with furtherdata [Nakanishi 2011a].In summary, these currently proposed OELs forCNT range from 1 to 50 µg/m 3 (8-hr TWA concentration)[Aschberger et al. 2010; Nanocyl 2009;Pauluhn 2010b; Nakanishi (ed) 2009a], includingthe NIOSH REL of 1 µg/m 3 . Despite the differencesin risk assessment methods and assumptions, all ofthe derived OELs for CNT are low airborne massconcentrations relative to OELs for larger respirablecarbon-based particles. For example, the currentU.S. OELs for graphite or carbon black are approximately2.5 to 5 mg/m 3 . Each of these CNT riskassessments supports the need to control exposuresto CNT in the workplace to low airborne mass concentrations(µg/m 3 ) to protect workers’ health.44 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
Table 5–5. Recommended occupational exposure limits for CNTReference Occupational exposure limit (OEL) CommentsPauluhn [2010b]0.05 mg/m 3 (8-hr TWA) for MWCNT(Baytubes®)Based on rat subchronic (13-wk) inhalationstudy of MWCNT (Baytubes®) andprevention of lung clearance overload andassociated pulmonary effects. Rat NOAELof 0.1 mg/m 3 adjusted by a factor of 2 forworker exposure day, air intake, deposition,and clearance kinetics. No uncertaintyfactors were applied.Nakanishi (ed) [2011a,b] 30 µg/m 3 (8-hr TWA) for CNT Based on 4-wk inhalation studies ofSWCNT and MWCNT in rats. LowestNOAEL of 0.13 mg/m 3 (for high surfacearea SWCNT) used as basis for CNTOEL). Adjusted for worker exposure day,air intake, deposition fraction, and bodyweight; uncertainty factor of 6. OEL isperiod-limited (15-yr).Nanocyl [2009] 2.5 µg/m 3 (8-hr TWA) for MWCNT Adjusted rat LOAEL of 0.1 mg/m 3(subchronic inhalation) [Ma-Hock et al.2009] to workers and applied assessmentfactor of 40.Aschberger et al. [2010]BSI [2007]2 µg/m 3 (8-hr TWA) for MWCNT1 µg/m 3 (8-hr TWA) for SWCNT0.01 fibers/ml for fibrous nanomaterialswith high aspect ratios (> 3:1 and length> 5000 nm)Adjusted rat NOAEL of 0.1 mg/m 3(subchronic inhalation) [Pauluhn 2010a]for worker exposure day and air intake;assessment factor of 25.Adjusted rat LOAEL of 0.1 mg/m 3(subchronic inhalation) [Ma-Hock et al.2009] for worker exposure day and airintake; assessment factor of 50.Benchmark exposure level (BEL) based onone tenth of the asbestos exposure limitNIOSH CIB 65 • Carbon Nanotubes and Nanofibers45
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CURRENT INTELLIGENCE BULLETIN 65Occ
Page 3 and 4:
Current Intelligence Bulletin 65Occ
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ForewordThe Occupational Safety and
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Executive SummaryOverviewCarbon nan
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2009; Pauluhn 2010a; Porter et al.
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neurogenic sig nals from sensory ir
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possible. Until the results from an
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••Follow exposure and hazard as
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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
Page 60 and 61: length, respectively) [Muller et al
Page 63 and 64: 5 CNT Risk Assessment and Recommend
Page 65 and 66: A-6). Risk estimates derived from o
Page 67 and 68: Table 5-4. Factors, assumptions, an
Page 69: and analytical methods. NIOSH is re
Page 73 and 74: deficits in animals or clinically s
Page 75: (3) Rat lung dose estimationIn the
Page 78 and 79: tasks where worker exposures exceed
Page 80 and 81: As part of the evaluation of worker
Page 82 and 83: Table 6-1. EC LODs and LOQs for 25-
Page 84 and 85: 6.2 Engineering ControlsOne of the
Page 86 and 87: Table 6-6 (Continued). Examples of
Page 88 and 89: Table 6-7 (Continued). Engineering
Page 90 and 91: exposure estimates for SWCNT on ind
Page 92 and 93: Table 6-8. Respiratory protection f
Page 94 and 95: ••Workers in areas or in jobs w
Page 97 and 98: 7 Research NeedsAdditional data and
Page 99 and 100: ReferencesACGIH [1984]. Particle si
Page 101 and 102: Bolton RE, Vincent HJ, Jones AD, Ad
Page 103 and 104: eport issued on July 22, 2011. NEDO
Page 105 and 106: Kobayashi N, Naya M, Mizuno K, Yama
Page 107 and 108: Methner M, Hodson L, Geraci C [2010
Page 109 and 110: Human Services, Centers for Disease
Page 111 and 112: Piegorsch WW, Bailer AF [2005]. Qua
Page 113 and 114: AD, Baron PA [2003]. Exposure to ca
Page 115: Varga C, Szendi K [2010]. Carbon na
Page 119 and 120: 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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