Occupational Exposure to Carbon Nanotubes and Nanofibers

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and reference worker conditions, including 9.6 m3of air inhaled per 8-hr day (corresponding to 17.5breaths/min and tidal volume of 1143 ml), andwork for 8 hr/d, 5 d/wk, 50 wk/yr, for 45 years.In the two subchronic inhalation studies for MW-CNT, excess risk estimates were derived based oneither the estimated deposited lung dose or the estimatedretained lung dose [Ma-Hock et al. 2009;Pauluhn 2010a].A.3 ResultsA.3.1 Benchmark Dose andWorking LifetimeExposure EstimatesThe estimates of the rodent BMD(L)s, the humanequivalentBMD(L)s, and the associated workinglifetime 8-hr TWA exposure concentrations (MLEand 95% LCL)—called the benchmark concentration(BMC) and the BMCL (95% LCL of theBMC)—are shown in Tables A–3 through A–5.All dose-response models used in this risk assessmentprovided adequate fit (P > 0.05) to the rodentdata for BMD(L) estimation (P values for thePearson X2 goodness of fit test shown in TablesA–3 through A–5).In Table A–3, the BMD(L) and BMC(L) * estimatesare based on the IT, PA, or short-term inhalationexposure studies of SWCNT or MWCNT withcontinuous response measures. Lung responses inrodents were evaluated at 32 to 60 days after firstexposure. Rodent dose is the administered (IT orPA) or estimated deposited dose (inhalation). TheBMR is the specified adverse lung response at 1.1standard deviations above the estimated rodentcontrol mean response (i.e., alveolar connectivetissue thickness or amount of hydroxyproline) (asexplained in Section A.2.3.2). Considerably higher8-hr TWA concentrations are estimated basedon the endpoint of lung hydroyxproline amount[Muller et al. 2005] compared with those based on*Abbreviation for both BMC and BMCL estimates.the alveolar connective tissue thickness endpoint,which is a more sensitive (earlier) indicator of fibrosis[Mercer et al. 2008].In Table A–4, the BMD(L) and BMC(L) estimatesare based on the IT exposure study of SWCNT withdichotomous response measures. Lung responseswere evaluated 90 days after the first exposure. TheBMR is the 10% excess risk of the specified adverselung response (proportion of rats with lung granulomas).Although Lam et al. [2005] report doseresponsedata for three different preparations ofSWCNT (containing either 2% Fe, 27% Fe, or 26%Ni), the BMD(L) and BMC(L) estimates are providedonly for the SWCNT with 2% Fe, which wasthe only dataset of the three reported by Lam et al.[2005] that was adequately fit by the BMD model(Table A–4).Table A–5 provides the BMD(L) and BMC(L) estimatesbased on the two subchronic inhalation studiesof MWCNTs, which also report dichotomousresponse measures. Lung responses were evaluatedat the end of the 13-week (91 d) exposure period.Rodent dose is either the total deposited lung doseor the retained lung dose at the end of exposure.The BMR is estimated as the 10% excess risk of thespecified adverse lung response (granulomatousinflammation or alveolar septal thickening of histopathologygrade 1 or higher). As expected, the estimatesbased on deposited lung dose are lower thanthose based on the retained lung dose, because theassumption of no clearance in the deposited lungdose results in a lower estimated 8-hr TWA concentrationto attain the human-equivalent BMD(L)lung burdens. The estimates for MWCNT (with9.6% Al 2O 3) based on the rat granulomatous inflammationresponse are lower than those for MW-CNT (Baytubes) (with 0.53% Co) based on the ratalveolar septal thickening response.Table A–6 shows the animal and human BMD(L)estimates and equivalent working lifetime 8-hrTWA concentration estimates, BMC(L), associatedwith grade 2 (slight/mild) or higher lung responsesin the subchronic inhalation studies, based on theestimated deposited lung dose. As expected, higherBMD(L)s and BMC(L)s are estimated from the110 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
Table A–3. Benchmark dose estimates * and associated human working lifetime airborne concentrations—continuous responsedata in rats or mice exposed to SWCNT or MWCNT by IT, PA, † or short-term inhalation (dose metric: administered or estimateddeposited lung dose)Rodent HumanHuman workinglifetime airborneconcentration ‡(µg/m 3 )Rodent study, CNT type, and responseBMD §, (µg/lung)BMDL(µg/lung)BMD(mg/lung)BMDL(mg/lung) BMC BMCLIT or PAMuller et al. [2005]—MWCNT (2% Al)Hydroxyproline amount (at 60 d) in rats760 486 194 124 18 12Shvedova et al. [2005]—SWCNT (0.2% Fe)Alveolar connective tissue thickness (at 60 d) in mice7.8 6.5 14 12 1.8 1.5Mercer et al. [2011]—MWCNT (0.3% Fe)Alveolar connective tissue thickness (at 60 d) in mice27.1 14.1 50 27 4.7 2.5Inhalation (5 hr/d, 4 d)Shvedova et al. [2008]—SWCNT (18% Fe)Alveolar connective tissue thickness (at 32 d) in mice0.48 0.33 0.89 0.62 0.11 0.075* Benchmark response level: 1.1 standard deviations above estimated control mean response [Crump 1995; US EPA [2010]; associated with a 10% increase in abnormalresponse (assumed greater than the 99 th percentile of the distribution of control responses).† IT—intratracheal instillation [Muller et al. 2005]; PA—pharyngeal aspiration [Shvedova et al. 2005] and [Mercer et al. 2011].‡ 8-hr time weighted average (TWA) concentration associated with the human-equivalent BMD(L)s; BMC: maximum likelihood estimate of the benchmark concentration.BMCL: 95% lower confidence limit of the BMC.§ BMD: estimated benchmark dose (maximum likelihood estimate). BMDL: estimated 95% lower confidence limit of the BMD; polynomial (degree 2) model [US EPA 2010]. P values for the rodent dose response models: 0.67 for Muller et al. [2005], 0.23 for Shvedova et al. [2005], 0.41 for Mercer et al. [2011], and not applicable (linear) for Shvedovaet al. [2008].NIOSH CIB 65 • Carbon Nanotubes and Nanofibers111
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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
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 ..........
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: Figure A-3 (continued). Benchmark d
Page 139 and 140: Table A-5. Benchmark dose estimates
Page 141 and 142: histopathology grade 2 or higher lu
Page 143 and 144: Table A-8. Working lifetime percent
Page 145 and 146: developing early-stage adverse lung
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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