Occupational Exposure to Carbon Nanotubes and Nanofibers

More documents

Recommendations

Info

Table A–12. Effect level estimates in rats after subchronic (13-wk) inhalation exposure tomultiwall carbon nanotubes (MWCNT)Effect level in ratsStudyLOAEL(mg/m 3 )NOAEL(mg/m 3 )BMC(mg/m 3 )BMCL(mg/m 3 )BMRMa-Hock et al. [2009] 0.1 nd 0.060 0.023 Granulomatousinflammation(≥ minimum, severitygrade 1+)0.5 0.1 0.12 0.082 Granulomatousinflammation(≥ mild, severitygrade 2+) *Pauluhn et al. [2010] 0.45 0.1 0.10 0.051 Alveolar septalthickening(≥ minimal, severitygrade 1+)1.5 0.45 0.87 0.45 Alveolar septalthickening (≥ mild,severity grade 2+)Abbreviations: NOAEL: No observed adverse effect level; LOAEL: Lowest observed adverse effect level; BMC: Benchmark concentration(maximum likelihood estimate) associated with 10% excess risk of specified BMR. BMCL: 95% lower confidence limit ofthe BMC; based on a multistage model, polynomial degree 2, P = 0.88); BMR: Benchmark response; nd: not determined*Same response proportion per dose, and therefore the same BMD(L) estimates, for alveolar lipoproteinosis.critical effect selected is the proportion of ratswith minimal (grade 1) or higher severity of pulmonaryinflammation or alveolar septal thickening(as reported by Ma-Hock et al. [2009] and Pauluhn[2010a]). In addition, grade 2 (slight/mild)or greater effects (as reported in the same studies)were also evaluated as a response endpoint sincethe interpretation of the histopathology, for a slightor mild response, may be less variable than that fora minimal response, and may also be more relevantto a potential adverse health effect in humans.The critical effect levels in the main analysis are theBMD(L) estimates from the dose-response modelingof the rat estimated deposited or retainedlung dose and to the human-equivalent lung doseestimates. The working lifetime exposure concentrationthat would result in that equivalent lungdose was then calculated, assuming either particlesizespecific lung deposition only (assuming noclearance) or the estimated retained lung dose (assumingnormal spherical particle clearance).In the main risk analysis, BMD methods were selectedover NOAELs or LOAELs because of severalstatistical advantages (Section A.2). However,BMD(L) estimates may also be uncertain, for example,when the dose spacing is not optimal, asoccurred in the CNT subchronic studies (FiguresA–1 and A–4). In this sensitivity analysis, NOAELsand LOAELs reported in the subchronic inhalationstudies [Ma-Hock et al. 2009; Pauluhn 2010a] are130 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers
used as the effect levels in evaluations of alternativemethods to derive OEL estimates. A quantitativecomparison of possible critical effect levelsis shown in Table A–12. The BMDL estimates aregenerally similar to the NOAEL estimates (within afactor of approximately 1 to 4), which suggests thatthe BMDL estimates may be reasonable despite thesparse data in the low dose region of the subchronicinhalation studies (Figure A–1).A statistical analysis was performed to compare theNOAEL and BMD estimates (in this example, theBMD is an exposure concentration, or BMC). Themaximum likelihood estimate of the excess risk (ofa minimal or higher grade of alveolar septal thickening)at 0.1 mg/m3 is 0.10 (i.e., 10%), based on theBMD model fitted to the dose-response data in thePauluhn [2010a] study (Table A–12). Yet, 0.1 mg/m3was identified as a NOAEL based on zero adverseresponse being observed [Pauluhn 2010a]. In orderto assess the precision of the estimate of the excessrisk associated with this NOAEL, the likelihood ofthe data in the NOAEL and control groups was reparameterizedin terms of the respective sum anddifference of the expected response proportions;and an upper confidence limit for the differencewas assessed by inverting its likelihood ratio teststatistic. When a nominal confidence coefficient of95% for a two-sided interval was applied, a valueof 0.17 (i.e., 17%) was obtained for the UCL of thedifference. Hence, the results supporting the use of0.1 mg/m3 as a NOAEL are also statistically consistentwith the results from the BMD model sincethe MLE of excess risk based on the model is lessthan the UCL.In a standard risk assessment approach, BMDLestimates may be considered equivalent to a NO-AEL for use as a POD in risk assessment [US EPA1994]. Once an effect level is selected in a given animalstudy, it is extrapolated to a human-equivalenteffect level (e.g., as 8-hr TWA concentration),or human-equivalent concentration (HEC). ThisHEC_POD (human-equivalent point-of-departure)is the POD for either extrapolating to a lower (acceptable)risk level or applying uncertainty factors inthe derivation of an OEL. These steps are discussedfurther in Section A.6.3.A.6.3 Alternative OELEstimation MethodsAs mentioned in the previous section, a standardrisk assessment method using animal data typicallyinvolves first identifying a critical effect levelin animals (e.g., NOAEL or BMDL), which is thePOD animal. A HEC_POD is estimated by extrapolatingthe animal dose to humans by accounting for thebiological and physical factors that influence thelung dose across species † . Lung dosimetry modelscan account for these interspecies differencesand provide equivalent dose estimates in animalsand humans given the exposure concentration andduration, the breathing rates and patterns, andthe physical properties of the aerosol. A simplifiedstandard approach in lieu of a lung dosimetrymodel to apply a total dosimetric adjustment factorto the animal effect level (Section A.6.3.1). It isuseful to evaluate both approaches given that thelung dosimetry models have not been specificallyvalidated for respirable CNT.A.6.3.1 Illustration of Human-Equivalent ConcentrationEstimationThe human equivalent concentration HEC) to aPOD animal(e.g., NOAEL) in an animal study can becalculated as:Equation A–8:HEC_POD = POD animal/ DAFwhere DAF is the dosimetric adjustment factor,andEquation A–9:DAF = (VE H/VE R) × (DF H/DF A) × (RT H/RT A) × (NF A/NF H)where VE is the ventilation rate (e.g., as total volumeof air inhaled per exposure day, m3/d) in†HEC_POD is then divided by appropriate uncertaintyfactors (UFs) to account for variability and uncertaintyin its estimation (Section A.6.3.3).NIOSH CIB 65 • Carbon Nanotubes and Nanofibers131
Page 1 and 2:
CURRENT INTELLIGENCE BULLETIN 65Occ
Page 3 and 4:
Current Intelligence Bulletin 65Occ
Page 5 and 6:
ForewordThe Occupational Safety and
Page 7 and 8:
Executive SummaryOverviewCarbon nan
Page 9 and 10:
2009; Pauluhn 2010a; Porter et al.
Page 11 and 12:
neurogenic sig nals from sensory ir
Page 13 and 14:
possible. Until the results from an
Page 15 and 16:
••Follow exposure and hazard as
Page 17 and 18:
Periodic Evaluations••Evaluatio
Page 19 and 20:
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 51 and 52:
Page 53 and 54:
Page 55 and 56:
Table 3-7 (Continued). Findings fro
Page 57:
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 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 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 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: A.6.1.3 Pulmonary Ventilation RateT
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
show all

Occupational Exposure to Carbon Nanotubes and Nanofibers

Create successful ePaper yourself

Delete template?

Save as template?