Occupational Exposure to Carbon Nanotubes and Nanofibers

provide an informal check on the estimated and observedresponses in the low-dose region of the data;and sensitivity analyses of the methods and assumptionsin these analyses provides information on thequalitative and quantitative uncertainty in these riskestimates and derived OELs (Section A.6).A.2.1 Rodent Dose-responseDataA.2.1.1 Data SelectionThe published rodent studies on pulmonary responsesto CNT (Section 3, Tables 1–3c) were examinedfor possible inclusion in this risk assessment.Pulmonary effects were examined because oftheir relevance to workers who may be exposed toCNT in workplace air. The studies with adequatequantitative dose-response data to estimate BMDswere included in these analyses. These studies reportedon the size and characterization of the CNT(Table A–1) as well as the route of exposure, doses,duration of exposure or post-exposure, number ofanimals per group, and lung responses. In general,the CNT animal studies have limited data, withfew (4–20) animals per dose group and sparse dosegroup spacing, especially in the low range of thedose-response curve. Some of these studies justmeet the minimum data criteria for BMD estimation,that is, a significant dose-related trend in theselected endpoint [US EPA 2012]. It is preferable tohave data with one or more doses near the benchmarkresponse (e.g., 10%) [US EPA 2012]; however,in some studies the response proportions werequite high at each dose (e.g., 30–100%) [Lam et al.2004; Ma-Hock et al. 2009; Pauluhn 2010a]. In addition,one study [Shvedova et al. 2008] had onlyone dose group in addition to the control, but thestudy was included because it is the only animal inhalationstudy for SWCNT currently available and itprovides a useful comparison by route of exposure.No other deficiencies were noted in the selectedstudies that would have resulted in their omission.Either the individual animal dose-response dataor the mean and standard deviation of the groupresponse are required for BMD model fitting. Thedose was either the intratracheal instillation (IT)or pharyngeal aspiration (PA) administered massdose (mg/lung) or the inhaled mass concentration(mg/m3). Datasets with treatment-related mortalityof animals were not used. Data on special preparationsof CNT (e.g., ground CNT) or studies usingsensitive animal models (e.g., vitamin E deficient)were not included (although these data may be ofinterest for subsequent analyses using animal modelsto investigate biological mechanisms, includingin sensitive human populations, or to evaluate theeffect of specific alterations in CNT properties onhazard potential).Study details of the data selected for this risk assessmentare provided in Table A–1. These studiesinclude the two recently published subchronicinhalation studies of MWCNT in rats [Ma-Hocket al. 2009; Pauluhn 2010a] and several IT, PA, orshort-term inhalation studies in rats or mice exposedto SWCNT [Lam et al. 2004; Shvedova et al.2005, 2008] or MWCNT [Muller et al. 2005; Merceret al. 2011] with post-exposure durations andexamination from 4 to 26 weeks after exposure. Inthe subchronic inhalation studies, rats were headnoseexposed [Ma-Hock et al. 2009] or nose-onlyexposed [Pauluhn 2010a] to three or four differentairborne mass concentrations (6 hr/d, 5 d/week)for 13 weeks. Lung responses were examined at theend of the 13-week exposure in both studies; postexposurefollow-up was extended to 6 months inthe Pauluhn [2010a] study.The IT, PA, and short-term inhalation studies provideadditional dose-response data for comparisonto other MWCNT or SWCNT with different typesand amounts of metal contaminants. Althoughboth IT and PA routes bypass the head region anddeliver the CNT material directly to the trachea andlung airways, PA is to be considered more similarto inhalation than IT because PA provides greaterdispersion of deposited material in the lungs [Shvedovaet al. 2005, 2008]. Following the administereddose (on day 1), the lung responses were evaluatedafter a post-exposure period (e.g., 1, 7, 28, 60, and/or 90 days). For studies with more than one postexposureduration, the longest post-exposure durationdata are used in these risk analyses. SomeNIOSH CIB 65 • Carbon Nanotubes and Nanofibers97