Occupational Exposure to Carbon Nanotubes and Nanofibers

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5.3 Evaluation of Uncertaintiesin CNT Risk Assessmentand RELAnimal data have been used to evaluate the healthhazard and risk of occupational exposure to CNTand CNF. Limited human exposure data are available,and NIOSH is not aware of any studies or reportsat this time of any adverse health effects inworkers producing or using CNT or CNF. The bestavailable scientific information to develop recommendedexposure limits is from the subchronic(13-wk) animal inhalation studies of two types ofMWCNT and the shorter-term animal studies ofSWCNT and other types of MWCNT.The analysis of animal data in this risk assessmentincludes: (1) identifying the adverse health effectsthat are associated with exposure to CNT or CNFin laboratory animals; (2) evaluating the severity ofthe response and the relevance to humans; and (3)estimating the human-equivalent dose and likelihood(risk) of adverse effects in workers. Ideally,sufficient evidence is desired to derive exposurelimits that are estimated to be associated with essentiallya zero risk of an adverse health effect evenif exposed 8 hr/d, 40 hr/wk. over a 45-yr workinglifetime. However, limitations in the scientific dataresult in uncertainties about those hazards and riskestimates. Characterizing the degree of that uncertainty,and the extent to which use of those data areuseful for occupational health risk managementdecision-making, is an important step in risk assessment.Alternative models and methods contributeto the differences in the risk estimates, andthere is uncertainty about which biological endpoints,animal models, and interspecies and doserate extrapolation methods may be most predictiveof possible human health outcomes.5.3.1 Strength of Evidence forEstimating a Health-Based RELfor CNT and CNFNIOSH and others have used the published animaldose-response data to develop OELs for varioustypes of CNT (see Section 5.2). The methods andassumptions differ across these studies and haveresulted in mass-based OELs ranging from 1 µg/m 3to 50 µg/m 3 . A proposed benchmark exposure limit(BEL) of 0.01 fiber/cm 3 for CNT has also been proposed[BSI 2007].In the NIOSH risk assessment (Appendix A), theanimal effect level estimates (and also the equivalentworking lifetime estimates) for early-stagenoncancer lung effects (granulomatous inflammation,interstitial thickening, or fibrosis) differ byapproximately two orders of magnitude dependingon the animal study, CNT type, and lung dose estimationmethods (Tables A–3 through A–6; TableA–13). However, these estimated human-equivalent45-yr working lifetime exposure concentrations(8-hr TWA) are all relatively low airbornemass concentrations (approximately 0.1–19 µg/m 3before adjusting for uncertainty in these estimates).The major areas of uncertainty in the CNT riskassessment include: (1) the critical effect or lungresponse measure including level of severity; (2)dose rate and retention assumptions for extrapolationfrom subchronic or short-term animal studiesto chronic exposure in humans; and (3) low doseextrapolation using the benchmark dose models toestimate risks below the 10% benchmark dose. Therelatively minor areas of uncertainty include: (1)benchmark dose estimation; (2) impact of route ofexposure; and (3) rat lung dose estimation.These uncertainties can result in either under-estimationor over-estimation of the true health risk toworkers at a given exposure scenario. Each of theseareas is discussed further below.5.3.2 Major Areas of Uncertainty(1) Lung response and severity levelThe REL is based on estimates of excess risk of earlystagenoncancer lung effects, which NIOSH has determinedare relevant to human health risk assessment(Section A.2.1.3). The extent to which theselung responses would be associated with functional46 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
deficits in animals or clinically significant effects inhumans is uncertain. However, these lung responsesinclude early onset fibrosis which persisted or progressedafter the end of exposure [Shvedova et al.2005. 2008; Porter et al. 2010; Mercer et al. 2011].Limited evidence in animals suggests that theseeffects may be associated with some lung functiondecrement (reduced breathing rate in mice) [Shvedovaet al. 2008]. A quantitative measure of pulmonaryfibrosis—alveolar interstitial (septal, orconnective tissue) thickening [Shvedova et al. 2005,2008; Mercer et al. 2011]—was previously used indeveloping the health basis for the U.S. air contaminantstandards for another lung toxicant, ozone [USEPA 1994]. EPA selected this health endpoint asthe critical lung effect in animals and extrapolatedto humans the lung dose associated with this effect[US EPA 1996; Stockstill et al. 1995]. Additionalmeasures of early stage lung effects in rats and micethat were used in this CNT risk assessment includeminimal or greater alveolar septal thickening, granulomas,or granulomatous inflammation [Pauluhn2010a; Ma-Hock et al. 2009; Lam et al. 2004].The choice of health endpoint and severity levelfrom the subchronic studies resulted in differentREL estimates by factors of several-fold to an orderof magnitude (Table A–5 and A–6). In addition toquantitative differences in risk estimates for noncancereffects, there is also qualitative uncertaintyabout the risk of other disease endpoints, includingcancer. Possible cancer risk (e.g., associatedwith fiber-like structures) is an area of considerableuncertainty for CNT and CNF which warrants targetedresearch and a high level of exposure controluntil the risk is understood [Schulte et al. 2012].(2) Dose rate and retentionAppendix A–6 provides some analyses to show thequantitative influence of dose rate and lung retentionassumptions on the risk estimates and RELderivation (Tables A–5 and A–6; Section A.6.3.2.2).The lung effects were assumed to be associated withthe total lung dose, regardless of the dose rate. Ifthe average daily deposited lung dose is assumed(i.e., no difference in rat or human clearance rates),then the human-equivalent concentration wouldbe ~30 times higher than that based on the ICRP[1994] clearance model, and ~10 times higher thanthat assuming simple first-order kinetics [Snipes etal. 1989; Pauluhn 2010b]. The human-equivalentworking lifetime (8-hr TWA) estimates based ondeposited lung dose (assuming no clearance) arelower by a factor of ~5–7 than those estimatesbased on retained lung burden (assuming normalclearance) (Tables A–5 and A–6).(3) Inter-species dose normalizationAlternative assumptions about the biologicallyrelevantmeasure of equivalent dose can result inconsiderable differences in the human-equivalentdose. NIOSH normalized the inter-species lung dosebased on the ratio of the human-to-animal averagealveolar surface area. Alternatively, Pauluhn [2010b]normalized the dose from rat to humans based onthe average total alveolar macrophage cell volume.This difference resulted in a factor of ~4 in the humanequivalentlung burdens and working lifetime 8-hrTWA concentration estimates (Table A–13).(4) Low dose extrapolationAll of these animal data and methods result in lowequivalent working lifetime exposure estimates.The animal NOAEL, LOAEL, and BMD(L) * estimates,and the equivalent human working lifetimeexposure estimates, indicate low mass concentrations(8-hr TWA) over a 45-year working lifetime(
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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 ..................
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 and 64: 5 CNT Risk Assessment and Recommend
Page 65 and 66: A-6). Risk estimates derived from o
Page 67 and 68: Table 5-4. Factors, assumptions, an
Page 69 and 70: and analytical methods. NIOSH is re
Page 71: Table 5-5. Recommended occupational
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 and 120: ContentsA.1 Introduction ..........
Page 121 and 122: 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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