Occupational Exposure to Carbon Nanotubes and Nanofibers

histopathology grade 2 or higher lung responses(Table A–6) compared with those estimated fromhistopathology grade 1 (minimal) or higher responses(Table A–5) because more animals developedthe grade 1 or higher response at a given dose(i.e., histopathology grade 1 or higher is a moresensitive response).A.3.2 Comparison of Shorttermand SubchronicDose-response DataTwo studies of MWCNT (Baytubes) provided anopportunity to examine the effect of dose-rate onthe same lung response measured at the same timepoint. Wistar rats were exposed by inhalation foreither one 6-hr day [Ellinger-Ziegelbauer and Pauluhn2009] or 13 weeks (6 hr/d, 5 d/wk) [Pauluhn2010a]. Lung responses were examined in bothstudies at 13 weeks after the first exposure day.Histopathology severity scores for alveolar septalthickening were available for each study. The numberof male rats with alveolar septal thickening (ofminimal or higher grade) and the respective exposureconcentrations are as follows:••Ellinger-Ziegelbauer and Pauluhn [2009]: 1,0, and 6 rats (6 total per group) at 0, 11.0, and241.3 mg/m3.••Pauluhn [2010a, extended by personal communication]:0, 0, 9, 10, 10 rats (10 total pergroup) at 0, 0.1, 0.45, 1.62, and 5.98 mg/m3.The dose metric used for this comparison was thedeposited lung dose, estimated from MPPD 2.0[CIIT and RIVM 2006] based on the particle sizedata (MMAD and GSD) and the rat exposure conditionsreported in each study.To evaluate whether these data [Pauluhn 2010a;Ellinger-Ziegelbauer and Pauluhn 2009] can bedescribed by the same dose-response relationship,a multistage (polynomial degree 2) model [USEPA 2010] was fit to the combined data (FigureA–4). This model provided adequate fit to the dataNIOSH CIB 65 • Carbon Nanotubes and Nanofibers(P = 0.37), suggesting that these data can be describedby the same dose-response model using theestimated total deposited lung dose, regardless ofthe dose rate differences (i.e., dose administered in1 day vs. during 91 days). This finding is consistentwith the impaired clearance and biopersistence ofthe deposited MWCNT in the rat lungs at thesedoses as shown in Pauluhn [2010a].A.3.3 Estimated Excess Risksof Working LifetimeExposures to Low-massConcentrations of MWCNTStandard risk assessment approaches for non-cancerendpoints have typically assumed a thresholdmodel, with extrapolation beyond the point of departurebased on uncertainty factors, e.g., US EPA[1994]. NRC [2009] and others have recommendedusing risk-based low-dose extrapolation for noncancerendpoints. NIOSH practice has also includedrisk-based low-dose extrapolation for noncancerendpoints. In the absence of information onthe shape of the dose-response relationship in thelow-dose region, assumptions can include linearand nonlinear model-based extrapolation. Linearextrapolation is the most protective (i.e., unlikelyto underestimate the risk). However, the actual riskcould be much lower, including zero.Low-dose linear extrapolation of the working lifetime-equivalent10% excess risk estimates in TableA–5 (deposited dose assumption) results in BMC(BMCL) estimates of 0.051 (0.019) µg/m3 or 0.077(0.038) µg/m3 associated with 1% excess risk (Ma-Hock et al. [2009] or Pauluhn [2010a], respectively).The corresponding BMC (BMCL) estimates associatedwith 0.1% excess risk are 0.0051 (0.0019)µg/m3 or 0.0077 (0.0038) µg/m3. Multistage modelbasedestimates are higher for the BMCs, but nearlyidentical for the BMCLs: 0.16 (0.019) µg/m3 or 0.24(0.042) µg/m3 associated with 1% excess risk; and0.050 (0.0020) µg/m3 or 0.075 (0.0042) µg/m3 associatedwith 0.1% excess risk (Ma-Hock et al. [2009]or Pauluhn [2010a], respectively).115