Occupational Exposure to Carbon Nanotubes and Nanofibers

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A.7 Evaluation of Carbon Nanofiber Studies in Mice and Rats ................... 139A.7.1 Particle Characteristics ............................................ 139A.7.2 Experimental Design and Animals .................................. 139A.7.3 Lung Responses .................................................. 139A.7.4 Effects in Other Tissues ........................................... 140A.7.5 Equivalent Lung Dose Estimation Methods .......................... 140A.7.6 Equivalent Lung Dose Estimation Results ............................ 14294 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
A.1 IntroductionThe increasing production and use of CNT and thepreliminary significant toxicology findings necessitatean assessment of the potential adverse healtheffects in workers who produce or use these materials.Risk assessment is a process that uses standardizedtools and procedures to characterize thehealth risk of exposure to a hazardous substance, aswell as the uncertainties associated with those riskestimates. Research studies in toxicology, epidemiology,exposure measurement, and other areasprovide the data needed to perform the risk assessment.The standard risk assessment paradigm inthe United States includes four basic steps: hazardassessment, exposure assessment, dose-responseanalysis, and risk characterization [NRC 1983,2009]. Risk assessment also involves the initialsteps in problem formulation and evaluation of thevarious risk management options [NRC 2009]. Themost recent guidance [NRC 2009] recommendsasking these questions: ”What are the options availableto reduce the hazards or exposures that havebeen identified, and how can risk assessment beused to evaluate the merits of the various options?”Risk assessment is intended to provide informationneeded to determine risk management options.Risk assessment practice seeks to use the best availabledata and scientific methods as the basis forpublic and occupational health decision-making[NRC 2009]. When sufficient dose-response dataare available (e.g., from animal studies), quantitativerisk assessment can be performed. Quantitativerisk assessment provides estimates of the severityand likelihood of an adverse response associatedwith exposure to a hazardous agent [Piegorsch andBailer 2005; NRC 2009]. Risk assessments are usedin developing occupational exposure limits and inselecting and evaluating the effectiveness of exposurecontrols and other risk management strategiesto protect workers’ health.The best data available for risk assessment, in theabsence of epidemiological studies of workers producingor using CNT, are from animal studieswith CNT. These studies include two subchronicinhalation studies of MWCNT in rats and severalNIOSH CIB 65 • Carbon Nanotubes and Nanofibersshort-term studies of SWCNT, MWCNT, or CNFin rats or mice. These studies provide the data andinformation on the dose-response relationshipsand the biological mechanisms of early-stage inflammatoryand fibrotic lung effects from exposureto CNT. No chronic animal studies of CNTwere available for this risk assessment.The biological mode of action for CNT and CNF, asfor inhaled particles and fibers, generally relates totheir physical and chemical properties. These propertiesinclude: (1) nano-structure which increasesthe surface area and associated inflammogenic andfibrogenic response; (2) fiber shape which maydecrease clearance of long structures, resulting intranslocation to the interstitial and pleural tissuesof the lungs; and (3) the graphitic structure of CNTand CNF which influences their durability andbiopersistence [Donaldson et al. 2006; Shvedova etal. 2009; Castranova 2011]. CNT and CNF are heterogeneousstructures, and differences can includesize (length and diameter), metal contaminants(type and amount), surface chemistry, and tendencyto aggregate/agglomerate. CNT and CNF typicallyform agglomerates in air but may also exist asindividual structures Johnson et al. 2010, Methneret al. 2010, Dahm et al. 2011]. Evidence from shorttermand subchronic studies in animals indicatesthat CNT may be biopersistent in the lungs [Mulleret al. 2005; Deng et al. 2007; Elgrabli et al. 2008b;Mercer et al. 2009; Pauluhn 2010a,b] However,some evidence suggests that functionalization mayincrease biodegradation of CNT [Kagan et al. 2010;Osmond-McLeod et al. 2011].Dose metrics that have been associated with lungresponses to CNT or CNF in animal studies includemass, volume, number, and surface area. The CNTvolume dose was associated with the overloading ofCNT clearance from rat lungs and to the lung responses[Pauluhn 2010a]. The specific surface area(m2/g) dose of various types of CNTs was associatedwith the pulmonary inflammation response inrats [Nakanishi 2011a]. Mercer et al. [2011] showedthat on a mass basis, SWCNT is more fibrogenicthan MWCNT, but this difference disappeared afteraccounting for the greater specific surface area ofthe SWCNT than MWCNT. Murray et al. [2012]95
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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
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
Page 115: Varga C, Szendi K [2010]. Carbon na
Page 119: ContentsA.1 Introduction ..........
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 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
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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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