Occupational Exposure to Carbon Nanotubes and Nanofibers

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Table A–6. Benchmark dose estimates and associated working lifetime airborne concentrations—grade 2 or higher severity oflung responses in rats after subchronic inhalation of MWCNT (dose metric: estimated deposited or retained dose in lungs)Human working lifetimeairborne concentration ‡(µg/m 3 )Rodent HumanBMD †BMDLBMDRodent study and response * (µg/lung) (µg/lung) (mg/lung)BMDL(mg/lung) BMC BMCLDeposited lung doseMa-Hock et al. [2009]Granulomatous inflammation44 29 11 7.4 1.0 0.69Pauluhn [2010a]Alveolar septal thickening235 120 60 31 6.4 3.3Retained lung doseMa-Hock et al. [2009]Granulomatous inflammation24 16 6.3 4.0 6.2 4.0Pauluhn [2010a]Alveolar septal thickening150 66 38 17 44 19* Histopathology grade 2 is slight [Ma-Hock et al. 2009] or slight/mild [Pauluhn 2010a] severity (proportion of animals with that response). Benchmark responselevel—10% excess (added) risk in exposed animals.† BMD: estimated benchmark dose (maximum likelihood estimate). BMDL: estimated 95% lower confidence limit of the BMD; multistage (polynomial degree 2) [US EPA2010]. P values for the rodent dose-response models: 0.67 for Ma-Hock et al. [2009] and 0.98 for Pauluhn et al. [2010a] (deposited dose); 0.76 for Ma-Hock et al. [2009]and 0.99 for Pauluhn [2010a] (retained dose).‡ 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.114 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
histopathology grade 2 or higher lung responses(Table A–6) compared with those estimated fromhistopathology grade 1 (minimal) or higher responses(Table A–5) because more animals developedthe grade 1 or higher response at a given dose(i.e., histopathology grade 1 or higher is a moresensitive response).A.3.2 Comparison of Shorttermand SubchronicDose-response DataTwo studies of MWCNT (Baytubes) provided anopportunity to examine the effect of dose-rate onthe same lung response measured at the same timepoint. Wistar rats were exposed by inhalation foreither one 6-hr day [Ellinger-Ziegelbauer and Pauluhn2009] or 13 weeks (6 hr/d, 5 d/wk) [Pauluhn2010a]. Lung responses were examined in bothstudies at 13 weeks after the first exposure day.Histopathology severity scores for alveolar septalthickening were available for each study. The numberof male rats with alveolar septal thickening (ofminimal or higher grade) and the respective exposureconcentrations are as follows:••Ellinger-Ziegelbauer and Pauluhn [2009]: 1,0, and 6 rats (6 total per group) at 0, 11.0, and241.3 mg/m3.••Pauluhn [2010a, extended by personal communication]:0, 0, 9, 10, 10 rats (10 total pergroup) at 0, 0.1, 0.45, 1.62, and 5.98 mg/m3.The dose metric used for this comparison was thedeposited lung dose, estimated from MPPD 2.0[CIIT and RIVM 2006] based on the particle sizedata (MMAD and GSD) and the rat exposure conditionsreported in each study.To evaluate whether these data [Pauluhn 2010a;Ellinger-Ziegelbauer and Pauluhn 2009] can bedescribed by the same dose-response relationship,a multistage (polynomial degree 2) model [USEPA 2010] was fit to the combined data (FigureA–4). This model provided adequate fit to the dataNIOSH CIB 65 • Carbon Nanotubes and Nanofibers(P = 0.37), suggesting that these data can be describedby the same dose-response model using theestimated total deposited lung dose, regardless ofthe dose rate differences (i.e., dose administered in1 day vs. during 91 days). This finding is consistentwith the impaired clearance and biopersistence ofthe deposited MWCNT in the rat lungs at thesedoses as shown in Pauluhn [2010a].A.3.3 Estimated Excess Risksof Working LifetimeExposures to Low-massConcentrations of MWCNTStandard risk assessment approaches for non-cancerendpoints have typically assumed a thresholdmodel, with extrapolation beyond the point of departurebased on uncertainty factors, e.g., US EPA[1994]. NRC [2009] and others have recommendedusing risk-based low-dose extrapolation for noncancerendpoints. NIOSH practice has also includedrisk-based low-dose extrapolation for noncancerendpoints. In the absence of information onthe shape of the dose-response relationship in thelow-dose region, assumptions can include linearand nonlinear model-based extrapolation. Linearextrapolation is the most protective (i.e., unlikelyto underestimate the risk). However, the actual riskcould be much lower, including zero.Low-dose linear extrapolation of the working lifetime-equivalent10% excess risk estimates in TableA–5 (deposited dose assumption) results in BMC(BMCL) estimates of 0.051 (0.019) µg/m3 or 0.077(0.038) µg/m3 associated with 1% excess risk (Ma-Hock et al. [2009] or Pauluhn [2010a], respectively).The corresponding BMC (BMCL) estimates associatedwith 0.1% excess risk are 0.0051 (0.0019)µg/m3 or 0.0077 (0.0038) µg/m3. Multistage modelbasedestimates are higher for the BMCs, but nearlyidentical for the BMCLs: 0.16 (0.019) µg/m3 or 0.24(0.042) µg/m3 associated with 1% excess risk; and0.050 (0.0020) µg/m3 or 0.075 (0.0042) µg/m3 associatedwith 0.1% excess risk (Ma-Hock et al. [2009]or Pauluhn [2010a], respectively).115
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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
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 and 136: Figure A-3 (continued). Benchmark d
Page 137 and 138: Table A-3. Benchmark dose estimates
Page 139: Table A-5. Benchmark dose estimates
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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