Occupational Exposure to Carbon Nanotubes and Nanofibers

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spherical particle-based models and CNT airbornesize data, assuming either deposited or retainedlung dose in animals or humans.The findings from this analysis indicate that workersare potentially at risk of developing adverse lungeffects if exposed to airborne CNT during a 45-yearworking lifetime. Table 5–1 provides a summaryof the estimated exposure concentrations (8-hourTWA) associated with 10% excess risk based on theanimal data. Table 5–2 provides a summary of therisk estimates at the REL of 1 µg/m 3 (8-hour TWA).Working lifetime exposures to 0.2–2 µg/m 3 (8-hourTWA concentration) were estimated to be associatedwith 10% excess risk of early stage lung effects(minimal granulomatous inflammation or alveolarseptal thickening, grade 1 or higher) (95% lowerconfidence limit, LCL estimates) based on resultsfrom the subchronic animal inhalation studies withMWCNT [Ma-Hock et al. 2009; Pauluhn 2010a](Tables 5–1 and A–5). For slight/mild (grade 2 orhigher) lung effects, the working lifetime exposureestimates are 0.7–19 µg/m 3 (8-hour TWA concentration;95% LCL estimates) (Tables 5–1 andTable 5–1. Estimated exposure concentration associated with a 10% risk of adverse lung effectsabove background. *Lung disease indicator † Maximum likelihood estimatelimit estimateEstimated working lifetime exposure concentration (8-hr TWA) ‡95% Lower confidenceMinimal lung effects (grade 1 or higher) 0.5 to 4 µg/m 3 0.2 to 2 µg/m 3Slight or mild lung effects (grade 2or higher)1 to 44 µg/m 3 0.7 to 19 µg/m 3Abbreviation: TWA=Time-weighted average.*Excess (exposure-attributable) risk during a 45-year working lifetime.†Histopathology findings of granulomatous inflammation [Ma-Hock et al. 2009] or alveolar septal thickening [Pauluhn 2010] inrat subchronic inhalation studies of multiwall carbon nanotubes.‡Estimates vary by rat study and lung burden estimation method (Appendix A, Tables A–7 and A–8).Table 5–2. Estimated risk of adverse lung effects at recommended exposure limit of 1 µg/m 3(8-hour TWA) during a 45-year working lifetime.Excess risk †95% Upper confidenceLung disease indicator * Maximum likelihood estimatelimit estimateMinimal lung effects (grade 1 or higher) 2.4% to 33% 5.3% to 54%Slight or mild lung effects (grade 2or higher)0.23% to 10% 0.53% to 16%Abbreviation: TWA=Time-weighted average.*Histopathology findings of granulomatous inflammation [Ma-Hock et al. 2009] or alveolar septal thickening [Pauluhn 2010] inrat subchronic inhalation studies of multiwall carbon nanotubes.†Exposure-attributable risk (added risk above background). Estimates vary by rat study and lung burden estimation method(Appendix A, Tables A–7 and A–8).38 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
A–6). Risk estimates derived from other animalstudies (e.g., single dose with up to 90-day followup)using SWCNT and other types of MWCNT(Tables A–3 and A–4) are consistent with theseestimates, i.e., 0.08–12 µg/m 3 (8-hour TWA) (95%LCL estimates). These working lifetime exposureconcentration estimates vary by approximately twoorders of magnitude (across the different types ofCNT, study design, animal species/strain and gender,route of exposure, and response endpoints);yet all of these estimates are relatively low airbornemass concentrations, most within ~1–10 µg/m 3(8-hour TWA). NIOSH does not consider a 10%estimated excess risk over a working lifetime to beacceptable for these early-stage lung effects, andthe REL is set at the optimal limit of quantification(LOQ) of the analytical method carbon (NIOSHmethod 5040) (Appendix C).Additional estimates were derived from the no observedadverse effect level (NOAEL) or lowest observedadverse effect level (LOAEL) in the rat subchronicinhalation studies of MWCNT [Pauluhn2010a; Ma-Hock et al. 2009] (Section A.6.2 andA.6.3). The human-equivalent working lifetimeconcentrations of ~4-18 µg/m 3 (8-hour TWA) wereestimated to be equivalent to the rat subchronicNOAEL or LOAEL of 0.1 mg/m 3 (Table A–13). Applyingdata-appropriate uncertainty factors (e.g.,Table A–14) to estimate safe working lifetime exposure(essentially zero risk assuming a thresholdmodel) results in concentrations of less than 1 µg/m 3(8-hour TWA) over a 45-yr working lifetime.A more detailed summary of the working lifetimeexposure estimates—shown by animal study, lung response,and effect level estimate—is provided in Table5–3. Table 5–4 summarizes the factors, assumptions,and options involved in the CNT risk assessment(see Appendix A for complete information). Evaluationsof the variability and uncertainty in these riskestimates are provided in Sections 5.3, A.4, and A.6.Among the uncertainties in this risk assessmentusing animal data, there is uncertainty in extrapolatingthe respiratory effects observed in shorttermor subchronic animal studies to estimatethe probability of chronic respiratory effects inhumans. In the absence of chronic data, these animalstudies provide the best available informationto derive initial estimates of health risk for use inREL development. Subchronic (13 wk.) exposurestudies are a standard toxicity assay used in humanhealth risk assessment, although the studies withshorter exposure and post-exposure durations alsoprovide useful information about the relationshipbetween CNT lung dose and response. To the extentthat the precursor effects to chronic disease areobserved in these shorter-term studies, the hazardand risk estimates would be expected to provideuseful information for chronic disease predictionand prevention. Although there is uncertainty inthe benchmark dose estimates from the subchronicstudies because of the dose-spacing and high responseproportions, these estimates are similar tothe NOAEL and LOAEL values reported in thesestudies [Ma-Hock et al. 2009; Pauluhn 2010a](Table A–12).One of the measures of pulmonary fibrosis usedin the shorter-term studies [Shvedova et al. 2005,2008; Mercer et al. 2008, 2011]—alveolar epithelialcell thickness (due to collagen deposition)—waspreviously used in the U.S. EPA ozone standard.This biological response was selected by EPA asthe adverse lung response for cross-species doseresponseextrapolation because it indicates “fundamentalstructural remodeling” [US EPA 1996;Stockstill et al. 1995].Some of these studies provide data comparing thepotency of CNT with that of other particles or fibersfor which animal and human data are available onthe long-term adverse health effects. These studiesshow that on a mass basis, CNT had equal or greaterpotency (pulmonary inflammation or fibrosis responseat a given mass dose) to that of ultrafine carbonblack, crystalline silica, or chrysotile asbestos[Lam et al. 2004; Muller et al. 2005; Shvedova et al.2005]. These comparative toxicity findings betweenCNT and other well-studied particles or fibers helpto reduce the uncertainty about whether the lungeffects in these short-term studies are relevant toevaluating the chronic respiratory hazard of CNT.NIOSH CIB 65 • Carbon Nanotubes and Nanofibers39
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CURRENT INTELLIGENCE BULLETIN 65Occ
Page 3 and 4:
Current Intelligence Bulletin 65Occ
Page 5 and 6:
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
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
Page 60 and 61: length, respectively) [Muller et al
Page 63: 5 CNT Risk Assessment and Recommend
Page 67 and 68: Table 5-4. Factors, assumptions, an
Page 69 and 70: and analytical methods. NIOSH is re
Page 71 and 72: Table 5-5. Recommended occupational
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
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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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