Occupational Exposure to Carbon Nanotubes and Nanofibers

or overloading, of particle clearance after reachinga critical lung dose).An alternative approach evaluated was to use theMPPD 2.0 [CIIT and RIVM 2006] human lungdosimetry model to estimate directly the retainedlung burden in humans over a working lifetime.This approach assumes a mode of action in whichthe cumulative retained particle dose is related tothe adverse lung responses, regardless of the doserate (i.e., the time required to reach that dose). Thecumulative exposure concept (concentration ×time), known as “Haber’s Law,” is a typical defaultassumption in risk assessment for long-term exposuresin the absence of other data [US EPA 1994].Some studies in workers (coal miners) have shownthat the working lifetime cumulative exposure andthe retained lung dose are better predictors of pulmonaryfibrosis than the average exposure concentrationwithout consideration of duration [NIOSH2011b]. Yet, there remains uncertainty about howwell a cumulative dose received over a short durationmay predict the response to the same cumulativedose received over a longer duration (i.e., at alower dose rate). The direction of error could goeither way, depending on the biological mechanismsof response. For example, a lower dose ratemay allow the lung defense mechanisms to adaptto the exposure (e.g., by increasing clearance or repairmechanisms), which could reduce the adverseresponse at a later time point. On the other hand, alonger time in which a substance is in contact withthe tissue may exacerbate the response, resultingin a more severe effect at the later time point. Theactual lung response may be some combination ofthese effects.To evaluate the assumptions used to estimate thehuman and rat retention kinetics, estimates werecompared from the MPPD2.0 lung dosimetrymodel [CIIT and RIVM 2006] to the ratio of 10/1for RT H/RT Aused by Pauluhn [2010a]. The rat andhuman lung dosimetry models take into accountthe ventilation rates, the deposition fraction by respiratorytract region (predicted from particle sizeand breathing rate and pattern, nasal vs. oronasal),and the normal average clearance rates. Usingthe particle size and breathing rate values for thePauluhn 2010a study (Table A–2), the rat retainedlung burden at the end of the 13 week exposureto 0.1 mg/m3 was estimated to be ~12 µg (TableA–10). This is similar to the 8.7 µg lung burden estimatedfrom the cobalt-tracer based measurement(Table A–10).Assuming that the rat has achieved steady-statelung burden after 13 wk exposure to 0.1 mg/m3, thechronic lung burden should also be approximately12 µg. § Extrapolating the rat lung dose of 0.012 mgto the human-equivalent lung burden would resultin either:••13.5 mg—estimated by dividing the rat lungdose by an interspecies NF for the average totalalveolar macrophage cell volume (i.e., 3.03× 10 10 µm3/3.49 × 10 13 µm3) (rat/human); or••3.0 mg based on the average total alveolarepithelial cell surface area (0.4 m2/102 m2)(rat/human).The associated 8-hr TWA concentration for 45-yrswould result in human-equivalent lung burdens (estimatedfrom MPPD 2.0 human model [CIIT andRIVM 2006]) of 16 µg/m3 and 3.5 µg/m3, respectively,for the normalized lung burdens based onthe alveolar macrophage cell volume or the alveolarepithelial cell surface area (Table A–13). The value of16 µg/m3 is approximately 3-fold lower than the ~50µg/m3 as the human equivalent concentration to therat NOAEL reported in Pauluhn [2010b] (or 3.5 ×lower than the 58 µg/m3 HEC_LOAEL by applyingan AF of 1.7 without rounding to 2). This differenceis due to the approximately 3x higher retained lungdose estimates after a 45-year working lifetime (TableA–14) to that estimated as a 10-year steady-statelung burden [Pauluhn 2010a]. This suggests that theRT of 10 may underestimate the rat to human lungretention kinetics, and that a factor of 35 (i.e., 10 ×3.5) may be more realistic. Since the MPPD modelalready takes into account the ventilation rate anddeposition fraction, the difference in the humanretained lung dose estimates is due to greater§At 2 years, the MPPD model predicted a lung burdenof 13 µg and a lung burden plus lung-associatedlymph node burden of 23 µg.NIOSH CIB 65 • Carbon Nanotubes and Nanofibers135