Occupational Exposure to Carbon Nanotubes and Nanofibers

these same dose groups; this effect persisted afterthe end of exposure, but resolved by the 39 th weekin the 0.4 mg/m3 group. The 0.4 mg/m3 dose groupwas considered the LOAEL for inflammatory lungeffects, while 0.1 mg/m3 was considered the NO-AEL [Pauluhn 2010a]. Concerning the focal septalthickening observed at 0.4 mg/m3, pathologists’ interpretationsmay differ as to whether these earlystageresponses would be considered adverse orto have the potential to become adverse. NIOSHinterpreted the alveolar septal thickening (and associatedeffects) in the 0.4 mg/m3 and higher dosegroups as being adverse changes of relevance to humanhealth risk assessment due to their persistenceand consistency with the early-stage changes in thedevelopment of pulmonary fibrosis. For these reasons,the alveolar septal thickening of minimal orhigher grade (i.e., proportion of rats with this response,which included rats exposed at 0.4 mg/m3and higher doses) was selected as the benchmarkresponse in the Pauluhn [2010a] study. Althoughthese data were reported as the average histopathologyscore in each dose group [Pauluhn 2010a,Table 3], NIOSH requested the response proportiondata as these were needed for the dichotomousBMD modeling. These data were provided by Dr.Pauluhn in response to this request [personal communication,J. Pauluhn and E. Kuempel, 1/27/10].Pulmonary inflammation has been associated withexposure to airborne particles and fibers, and it is ahallmark of occupational lung disease in humans. Itis also a precursor to particle-associated lung cancerin rats [IARC 2010; NIOSH 2011a]. Pulmonaryinflammation can be measured by the increase inpolymorphonuclear leukocytes (PMNs) in bronchoalveolarlavage (BAL) fluid following exposureto various particles including CNT. However, forsome CNT, the inflammation resolves, while thefibrosis continues to develop [Shvedova et al. 2005,2008; Mercer et al. 2010; Pauluhn 2010a]. This indicatesthat neutrophilic inflammation in BAL fluidmay not be a good predictor of adverse lung effectsfrom some CNT, which appear to cause fibrosisby a different mechanism than for other types ofparticles and fibers (by resembling the lung basementmembrane and serving as a framework forfibroblast cell growth, without eliciting a persistentinflammatory response) [Wang et al. 2010b]. Inother studies, the inflammatory effects of MWCNTwere associated with granuloma development [Ma-Hock et al. 2009] and with alveolar lipoproteinosis,a more severe inflammatory lung response, observedat higher doses of MWCNT [Ma-Hock etal. 2009].Minimal or higher levels of severity of these lung responseswere selected as the benchmark responses.This included minimal level (grade 1 or higher) ofpulmonary inflammation [Ma-Hock et al. 2009]or alveolar septal thickening [Pauluhn 2010a] asobserved by histopathology. The incidence data onthe minimal level of effect that is persistent providesa sensitive measure of a critical effect, which is ofinterest for health risk assessment. It is not knownwhether the human-equivalent effects to those observedin the animal studies would be associatedwith abnormal lung function or clinical disease, orif progression to more severe levels could occur ifthese effects developed as a result of chronic exposure.To evaluate sensitivity of risk estimates to theselection of a minimal level of disease, risk estimateswere also derived for the next level of response(grade 2 or higher) in the subchronic animal studies.The lung response measures in this risk assessmentare either dichotomous (proportion of animalsobserved with the response endpoint) or continuous(amount or level of response in individualanimals) (Table A–1). The dichotomous responsesinclude the incidence of lung granulomas [Lam etal. 2004]; granulomatous inflammation [Ma-Hocket al. 2009]; and histopathology grade of alveolarinterstitial (septal) thickening [Pauluhn 2010a].The continuous responses include the amount ofhydroxyproline (as mass) [Muller et al. 2005] andalveolar interstitial connective tissue thickness[Shvedova et al. 2005, 2008; Mercer et al. 2011].A.2.1.4 Summary ofDose-response DataCollectively, the data available for CNT risk assessmentinclude dose-response data from severalrodent species and strains, both males and females,NIOSH CIB 65 • Carbon Nanotubes and Nanofibers99