Occupational Exposure to Carbon Nanotubes and Nanofibers

the DF estimate, although a larger difference (approximatelya factor of two) is due to differences inthe spherical particle model-based estimates (e.g.,MPPD 2.0 vs. 2.1) (Sections A.2.2; A.6.1.1; andA.6.1.2).The values used by NIOSH [2010] and Pauluhn[2010b] are similar for the VE and DF, i.e., for humanand rat, respectively:••VE (m3/d): 10 and 0.015 [Pauluhn 2010b],9.6 and 0.09 [NIOSH 2010]; and••DF: 0.118 and 0.057 [Pauluhn 2010b],0.086 and 0.046 [NIOSH 2010].The other two factors—retention half-time (RT)and interspecies normalization factor (NF)—candiffer largely depending on the assumed mode ofaction concerning how the deposited CNT interactswith the lung tissue over time. These factorsare discussed below.A.6.3.2.1 Interspecies dosenormalization factorThe interspecies NF adjusts for the size differencein the lung (surface area or volume) into which theCNT dose deposits. Studies of other inhaled particlesor fibers are relevant to evaluating mechanismsthat may also apply to CNT in the lungs. Possibledose metrics related to the modes of action forpulmonary inflammation and fibrosis include theCNT mass, surface area, or volume dose per alveolarepithelial cell surface area or alveolar macrophagecell volume in each species. Normalizingthe dose (e.g., NOAEL) across species to the totalaverage alveolar macrophage cell volume in rat orhuman lungs is based on the experimental observationof overloading of alveolar clearance in rats andmice exposed to respirable poorly soluble particlesor fibers [Bolton et al. 1983; Morrow 1988; Bellmannet al. 1991; Elder et al. 2005; Pauluhn 2010b].(a) Alveolar macrophage cell volumeAt a sufficiently high particle dose, pulmonaryclearance can become impaired due to overloadingof alveolar macrophage-mediated clearance. In rats,the overloading dose has been observed as particlemass (~1 mg/g lung), volume (~1 µl/g lung forunit density particles) [Morrow 1988; Muhle et al.1990], or surface area (200–300 cm2 particles perrat lung) [Tran et al. 2000]. On a volume basis, anoverloading particle dose corresponds to approximately6%–60% of total alveolar cell volume, whenoverloading begins and is complete, respectively[Morrow 1988]. The 60% value has been observedexperimentally [Oberdörster et al. 1992], althoughparticle clearance impairment may start at lowerparticle volume lung dose [Bellmann et al. 1991;Kuempel et al. 2001a]. Biological responses to overloadinginclude: accumulation of particle-filledmacrophages in the alveoli, increased permeabilityof the epithelial cell barrier, persistent inflammation,increased particle translocation to the alveolarinterstitium and lung-associated lymph nodes,as well as increasing alveolar septal thickening, lipoproteinosis,impaired lung function, and fibrosis[Muhle et al. 1990, 1991].Although the overload mode of action in the rat hasbeen well-studied, the extent to which overloadingis involved in human lung responses to inhaledparticles is not as clear due to observed differencesin both the kinetics and the pattern of particle retentionin the lungs of rats and humans. Whereasparticle clearance in rats is first-order at doses belowoverloading, studies in workers have shownthat human lung clearance of respirable particles isnot first-order even at relatively low retained particlemass lung low doses [Kuempel 2000; Kuempelet al. 2001; Tran and Buchanan 2000; Gregorattoet al. 2010, 2011]. That is, some portion of the particledose that deposits in the pulmonary region isretained for a very long time (retention half-timeof several years) [ICRP 1994; Kuempel et al. 2001;Gregaratto et al. 2010]. Humans also apparently retaina greater portion of the particles in the alveolarinterstitium, whereas rats retain more particles inthe alveolar space [Nikula et al. 1997, 2001]. Thegreater interstitial particle retention may increasethe dose to the target tissue for pulmonary fibrosisin humans relative to that for the same depositeddose in rats lungs. Given the differences in theparticle clearance kinetics and retention patternsin rats and humans, normalizing the dose acrossNIOSH CIB 65 • Carbon Nanotubes and Nanofibers133