Occupational Exposure to Carbon Nanotubes and Nanofibers

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Tables A–7 and A–8 provide working lifetime excessrisk estimates of early stage-lung effects (minimalor higher histopathology grade of granulomatousinflammation or alveolar septal thickening)associated with 1, 2, or 7 µg/m3 as an 8-hr TWAconcentration. These concentrations were selected aspossible limits of quantification (LOQs) that wereunder evaluation for the analytical method to measureairborne CNT in the workplace (NIOSH method5040). These estimates are based on lung doseestimates assuming either total deposited lung dose(no clearance) or retained dose (normal, sphericalparticle-based clearance). Risk estimates are higherfor the no clearance assumption than those assumingnormal clearance, within either the minimal(grade 1) (Table A–7) or slight/mild (grade 2) (TableA–8) lung responses. These excess (exposureattributable)risk estimates were derived from themultistage (degree 2) model fit to the rat subchronicdose-response data, or by linear extrapolationbelow the 10% BMC(L) estimates shown in TablesA–5 and A–6.A.4 DiscussionNIOSH conducted a quantitative risk assessment ofCNTs by evaluating dose-response data of early-stageadverse lung effects in rats and mice exposed to severaltypes of SWCNT or MWCNT (with different metalcontaminants), by several routes of exposure (inhalation,PA, or IT), and duration of exposure (singleday or subchronic) and post-exposure period (up to26 weeks). Because of the different study designs andresponse endpoints used in the rodent studies, limitedinformation was available to evaluate the extentto which the differences in the risk estimates acrossstudies are due to differences in the CNT material orare attributable to other study differences. Some evidenceindicates that CNT with certain metals (nickel,26%) [Lam et al. 2004] or with higher metal content(18% vs. 0.2% Fe) [Shvedova et al. 2008] are moretoxic and fibrogenic. However, some studies haveshown that both unpurified and purified (low metalcontent) CNT were associated with early-onset andpersistent pulmonary fibrosis at relatively low-massdoses [Shvedova et al. 2005, 2008]. The LOAELs forMWCNT (containing either 9.6% Al2O2 or 0.5% Co)were 0.1 mg/m3 [Ma-Hock et al. 2009] and 0.4 mg/m3 [Pauluhn 2010a], which are more than an orderof magnitude lower than the LOAEL of 7 mg/m3 forultrafine carbon black [Elder et al. 2005] in the sameanimal species and study design (13-week inhalationstudies in rats, although with different strains, Wistar(male and female) [Pauluhn 2010a] and F-344(female) [Elder et al. 2005]).Because no chronic animal studies or epidemiologicalstudies of workers producing or using CNThave been published to date, the best available datafor risk assessment were the subchronic inhalationstudies of MWCNT in rats [Ma-Hock et al. 2009;Pauluhn 2010a]. For SWCNT, no subchronic studieswere available, and several short-term studies(IT, PA, or inhalation exposure) in rats or miceprovide the only available dose-response data foreither SWCNT [Lam et al. 2004; Shvedova et al.2005, 2008] or for other types of MWCNT (withdifferent metal content) [Muller et al. 2005; Merceret al. 2011] (Table A–1).All of these studies reported inflammatory, granulomatous,and/or fibrotic lung effects of relevanceto human health risk assessment. These lung effectsin the animal studies were relatively early-stageand were not reversible after exposure ended (up toapproximately 6 months post-exposure [Pauluhn2010a]). In the studies with multiple post-exposurefollow-up times, the amount of pulmonary fibrosispersisted or progressed with longer follow-up [Shvedovaet al. 2005, 2008; Mercer et al. 2008; Porteret al. 2010; Pauluhn 2010a]. One of the measuresof pulmonary fibrosis used in the short-term studies[Shvedova et al. 2005, 2008; Mercer et al. 2008,2011]—alveolar epithelial cell thickness (due to increasedcollagen deposition associated with CNTmass lung dose)—was also used to develop theEPA ozone standard. This response endpoint wasselected by EPA as the adverse lung response forcross-species dose-response extrapolation, becauseit indicates “fundamental structural remodeling”[US EPA 1996; Stockstill et al. 1995].The excess risk estimates based on the subchronicand short-term studies of MWCNT and SWCNTsuggest that workers are at >10% excess risk of118 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
developing early-stage adverse lung effects (pulmonaryinflammation, granulomas, alveolar septalthickening, and/or fibrosis) if exposed for a workinglifetime at the estimated upper LOQ of 7 µg/m3based on NIOSH Method 5040 for measuring theairborne concentration of CNT [NIOSH 2010a](Appendix C; Tables A–3 through A–8). Workinglifetime airborne concentration (8-hr TWA) estimatesof 0.51–4.2 µg/m3 MLE and 0.19–1.9 µg/m395% LCL were associated with a 10% excess riskof early-stage lung effects (histopathology grade 1minimal or higher) based on the subchronic inhalationstudies (Table A–5). For histopathologygrade 2 (slight [Ma-Hock et al. 2009] or slight/mild[Pauluhn 2010a]), the working lifetime 8-hr TWAconcentrations associated with an estimated 10%excess risk are 1.0 to 44 µg/m3 MLE and 0.69 to 19µg/m3 95% LCL (Table A–6).As discussed in Section A.2.3, the 10% BMDL estimatesare a typical POD for extrapolation to lowerrisk. NIOSH does not consider 10% or greater excessrisk levels of these early-stage lung effects tobe acceptable if equivalent effects were to occur inworkers as a result of working lifetime exposuresto CNT. Linear extrapolation by application of uncertaintyfactors (e.g., Table A–14) would resultin lower 8-hr TWA concentrations. However, thelowest LOQ of NIOSH Method 5040 (1 µg/m3) isthe best that can be achieved at this time in mostworkplaces and is similar to or greater than the8-hr TWA concentrations estimated to be associatedwith 10% excess risk of minimal (grade 1)effects (Table A–7). Some of the risk estimates areless than 10% at the LOQ of 1 µg/m 3 (8-hr TWA),in particular those based on the slight/mild (grade2) rat lung effects and assumed normal clearance(Table A–8).Although uncertainties and limitations exist inthese animal studies, the evidence supports thehealth-based need to reduce exposures below 1 µg/m3. These risk estimates indicate the need for researchto develop more sensitive measurementmethods for airborne CNT in the workplace, todemonstrate effective exposure control, and toevaluate the need for additional risk managementmeasures such as the use of respirators and otherpersonal protective equipment and medical screening(Section 6, Appendix B). Chronic bioassay dataare also needed to reduce the uncertainty concerningthe potential for chronic adverse health effectsfrom long-term exposure to CNT. Evaluation of thefactors that influence the risk estimates and the areasof uncertainty are discussed below.A.4.1 The Use of Short-termData to Predict LongertermResponseSeveral factors suggest that in the absence ofchronic data these short-term and subchronic animaldata may be reasonable for obtaining initial estimatesof the risk of human noncancer lung effectsfrom exposure to CNT. First, some fraction of CNTthat deposit in the lungs are likely to be biopersistentbased on studies in animals [Muller et al. 2005;Deng et al. 2007; Elgrabli et al. 2008b; Mercer et al.2009; Pauluhn 2010a, b] and studies of other poorlysoluble particles in human lungs [ICRP 1994;Kuempel et al. 2001; Gregoratto et al. 2010]. Second,the pulmonary fibrosis developed earlier andwas of equal or greater severity than that observedfrom exposure to the same mass dose of other inhaledparticles or fibers (silica, carbon black, asbestos)examined in the same study [Shvedova et al.2005; Muller et al. 2005]. Third, the adverse lungresponses persisted or progressed after the end ofexposure up to 90 days after a single- or multipledayexposure to SWCNT or MWCNT [Lam et al.2004; Muller et al. 2005; Shvedova et al. 2005, 2008;Ellinger-Ziegelbauer and Pauluhn 2009; Porter etal. 2010] or 26 weeks after a 13-week inhalation exposureto MWCNTs (Baytubes) [Pauluhn 2010a].There is uncertainty in estimating working-lifetimehealth risk from either subchronic or short-termanimal studies, and perhaps from the shorter-termstudies. The strength of the subchronic inhalationstudies is that they provide exposure conditionsthat are more similar to those that maybe encountered by workers exposed to airborneCNT. However, there is some uncertainty aboutthe deposited and retained dose in the rat lungsNIOSH CIB 65 • Carbon Nanotubes and Nanofibers119
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CURRENT INTELLIGENCE BULLETIN 65Occ
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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
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ContentsForeword ..................
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A.3.2 Comparison of Short-term and
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ESPFeFMPSFPSSgGMGSDHCLHECHEPAhrISOI
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AcknowledgementsThis Current Intell
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1 IntroductionMany nanomaterial-bas
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2 Potential for ExposureThe novel a
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CNMs, with MWCNT agglomerates obser
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composite materials with local exha
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information on air contaminants. Sa
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3 Evidence for Potential Adverse He
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decreasing agglomerate size increas
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examined up to 60 days post-exposur
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3.3 SWCNT and MWCNTIntraperitoneal
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The same potency sequence was obser
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Table 3-3. Findings from published
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Table 3-7 (Continued). Findings fro
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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
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 ..........
Page 121 and 122: A.1 IntroductionThe increasing prod
Page 123 and 124: provide an informal check on the es
Page 125 and 126: these same dose groups; this effect
Page 127 and 128: Table A-1. Rodent study information
Page 129 and 130: the deposited (no clearance) and th
Page 131 and 132: The other BMDS models failed to con
Page 133 and 134: Figure A-2. Benchmark dose model (m
Page 135 and 136: Figure A-3 (continued). Benchmark d
Page 137 and 138: Table A-3. Benchmark dose estimates
Page 139 and 140: Table A-5. Benchmark dose estimates
Page 141 and 142: histopathology grade 2 or higher lu
Page 143: Table A-8. Working lifetime percent
Page 147 and 148: Figure A-4. Dose-response relations
Page 149 and 150: cell surface area). However, the wo
Page 151 and 152: purified or unpurified (with differ
Page 153 and 154: Table A-9. Comparison of rat or hum
Page 155 and 156: A.6.1.3 Pulmonary Ventilation RateT
Page 157 and 158: used as the effect levels in evalua
Page 159 and 160: the DF estimate, although a larger
Page 161 and 162: or overloading, of particle clearan
Page 163 and 164: Table A-13. Human-equivalent retain
Page 165 and 166: A.7.1 Particle CharacteristicsBoth
Page 167 and 168: and density. The following MMAD and
Page 169: Table A-15. CNT lung dose normalize
Page 172 and 173: B.1 Key Terms Related toMedical Sur
Page 175 and 176: APPENDIX CNIOSH Method 5040
Page 177 and 178: filter. In the method evaluation, d
Page 179 and 180: Most of the studies on sampling art
Page 181 and 182: e analyzed to determine the onset o
Page 184: Delivering on the Nation’s promis
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