Occupational Exposure to Carbon Nanotubes and Nanofibers

species based on the total alveolar macrophage volumemay not be the best dose metric for predictingadverse lung responses in humans.(b) Alveolar epithelial cell surface areaAnother dose metric that may be relevant to the inflammatoryand fibrotic lung responses is the particleor CNT dose per surface area of alveolar epithelialcells [US EPA 1994; Donaldson et al. 2008].It is the epithelial cell surface with which particlesinteract when they migrate through the epithelialcell layer into the interstitium, and epithelial cells arealso involved in recruitment of inflammatory and fibroticcells [Bohning and Lippmann 1992; Driscollet al. 1996; Tran et al. 2000]. For this reason, normalizingthe dose based on the total alveolar epithelialcell surface area may be more predictive of the humanlung response. However, since both the alveolarmacrophages and epithelial cells are involved in thelung responses to inhaled particles, some combinationof dose metrics may ultimately be most predictivein this dynamic biological system.In the absence of a more complete biologicallybasedmodel, an evaluation of the quantitative influenceof each assumed dosimetric mode of action(e.g., based on either the alveolar macrophage cellvolume or the epithelial cell surface area) providesinformation on the sensitivity of the risk assessmentand OEL derivation to the interspecies dosenormalization factor. Thus, replacing the alveolarmacrophage volume ratio in equation A–10 with aNF A/NF Rof 0.4m2/102m2 [Stone et al. 1992] resultsin a total AF that is 4.5 × greater. That is,Equation A–12:AF = (9.6m3/0.102m3) × (0.118/0.057) × (10/1)× (0.4m2/102m2) = 7.7Equation A–13:HEC_NOAEL = 0.1mg/m3 / 7.7 = 0.013 mg/m3The larger AF results in a corresponding smallerhuman-equivalent concentration. This illustratesthat the risk estimates for CNT—as for other inhaledparticles—is sensitive to the assumed mode of actionconcerning the interspecies normalizing factor.A.6.3.2.2Interspecies Dose Retention FactorThe retained dose to the target tissue is influencedby the clearance mechanism in the lung region inwhich the particles deposit. RT in equation 2 (asthe kinetic factor in Pauluhn [2010b]) is intendedto account for the differences in the rat and humanparticle retention half-time. This factor is also dependenton the assumptions concerning the biologicalmode of action. In the rat, evidence suggeststhat doses of poorly soluble low toxicity particlesbelow those causing overloading of lung clearance(i.e., at steady-state) would not be associated withadverse lung effects. A steady-state lung burdenmeans that the rate of particle deposition equalsthe rate of clearance such that once the steady-stateburden had been achieved, the lung burden wouldbe the same over time if exposure conditions didnot change. For example, if steady-state lung burdenwas reached after subchronic (13 week) exposureto a given exposure concentration, then thechronic (2 yr) lung burden would be the same giventhe same rates of exposure and clearance. However,the steady-state lung burden may not been entirelyreached by 13 weeks in the rat or in an equivalenttime in humans. Based on the rat overload modeof action, Pauluhn [2010b] assumed that humanswould achieve a steady-state lung burden if exposedat an equivalent total particle volume dose inthe alveolar macrophages (over a roughly equivalenthuman exposure duration of 10 years to a rat3 month exposure). A ratio of 10/1 for human/ratretention half-time rate was used [Pauluhn 2010b],based on a simple first-order clearance rate modelof particle clearance from the lungs in both rats andhumans [Snipes et al. 1989]. The volumetric doseof CNT associated with overloading in the rat wasequivalent to a relatively low mass dose comparedto other poorly soluble particles [Pauluhn 2010b.2011]. Moreover, human lung-particle retentiondata have shown that a simple first-order clearancemodel would underpredict the human long-termlung dose at similar low mass doses [ICRP 1994;Kuempel et al. 2001; Gregoratto et al. 2010]. That is,the human long-term retained lung burden wouldbe expected to exceed a steady-state lung burdenpredicted from the rat model (i.e., low-dose firstorderclearance with dose-dependent impairment,134 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers