Occupational Exposure to Carbon Nanotubes and Nanofibers

to a toxicant, and at some point, they may resultin irreversible, functional impairment of the lungs[NIOSH 1986]. If data are available, the BMRs canbe based on a biologically significant response thatis associated with, or expected to result in, a materialimpairment of health. However, there may beinsufficient data to determine a specific level thatis associated with a measurable adverse response.In that case, a statistical criterion may be used as aBMR for continuous data [Crump 1995].A statistical method (originally referred to as a“hybrid” method) is described by Crump [1995] toprovide BMD(L) estimates from continuous datathat are equivalent to a 10% excess risk based ondichotomous data, assuming that an abnormal orbiologically significant response is defined as theupper 99 th percentile of the unexposed (control)distribution. According to this method, “for a normaldistribution with constant variance, settingBMR = 0.1 and P O= 0.01 is equivalent to choosingthe BMD to be the dose that results in an increasein the mean equal to 1.1 times the standarddeviation,” assuming a normal distribution withconstant variance [Crump 1995]. That is, if one assumesthat the probability of the specified adverseresponse in the unexposed population is the upper1% of a normal distribution of responses, then selectinga BMR of 1.1 standard deviations above thecontrol mean response is equivalent to a 10% BMDas estimated in dichotomous data.In evaluating possible BMRs for the continuousdata of CNT in mice, earlier studies of chronicozone exposure in rats were examined to determineif a biologically-based BMR could be identifiedfor pulmonary fibrosis (measured as alveolarconnective tissue thickening) associated with abnormalpulmonary function [Chang et al. 1992;Costa et al. 1995; Stockstill et al. 1995]. However,those rat findings did not appear to extrapolate wellto the mice in Shvedova et al. [2005, 2008]. Thatis, the observed abnormal response in rats (associatedwith a persistent lung function deficit) was a36% increase in the control mean alveolar connectivetissue thickness [Chang et al. 1992; Costa et al.1995]; however, this amount of response occurredin up to 30% of the control (unexposed) mice inShvedova et al. [2005, 2008] (vs. 2.5% of controlsin Chang et al. [1992], in part due to the greatervariability in the alveolar tissue thickness in theunexposed mice. In addition, no data were foundof a biologically relevant BMR for the amount ofhydroxyproline in the lungs of rats or mice. In theabsence of an identified biological basis for a BMRfor the continuous response measures of alveolarconnective tissue thickening or the amount of hydroxyproline,NIOSH used the statistical criteriondescribed by Crump [1995], in which a BMR of1.1 standard deviations above the control meanresponse is equivalent to a 10% excess risk in thedichotomous data, assuming the 99 th percentile ofthe distribution of control responses is abnormal orbiologically significant.That is, the BMR for the continuous data (alveolarconnective tissue thickness and hydroxyprolineamount) is defined as follows:Equation A–3:BMR = µ(d) – µ(0)where µ(d) is the mean response at the BMD (d);µ(0) is the control mean response; and BMR is thespecified number of standard deviations (SDs) (i.e.,1.1 in these analyses). Thus, the continuous databasedBMD is the dose associated with a 10% increasein the proportion of animals exposed at dosed with response greater than the 99 th percentile ofthe control mean response. The estimates of µ(d)and µ(0) are derived from the fitted dose-responsemodels (polynomial) (Section A.2.3.3).A.2.3.3 BMD Model FittingThe animal dose-response data were fit using thebenchmark modeling software (BMDS 2.1.2) [USEPA 2010]. The dichotomous data were fit with amultistage (polynomial degree 2) model. This is theonly model that provided an adequate fit to the subchronicinhalation data, each of which [Ma-Hock etal. 2009; Pauluhn 2010] had only one dose betweenzero and 100% response for the endpoints evaluated(granulomatous inflammation or alveolar septalthickening, histopathology grade 1 or higher).104 NIOSH CIB 65 • Carbon Nanotubes and Nanofibers