Occupational Exposure to Carbon Nanotubes and Nanofibers

the deposited (no clearance) and the retained (normalclearance) doses predicted from the sphericalparticlebased models [MPPD, CIIT and RIVM2007, ARA 2011]. This is because the CNT depositedin the lungs may undergo some clearance, althoughevidence from animal studies suggests theclearance rate may be slower than for other poorlysoluble particles at relatively low-mass doses in therats and mice [Deng et al. 2007; Mercer et al. 2009;Pauluhn 2010a; 2011; Elgrabli et al. 2008b].A.2.3 Animal Dose-responseModeling and BMDEstimationThe dose-response data in rats and mice exposedto SWCNT or MWCNT were modeled usingbenchmark dose methods [Crump 1984; US EPA2010]. A benchmark dose has been defined as “. . .a statistical lower confidence limit for the dosecorresponding to a specified increase in level of[adverse] health effect over the background level”[Crump 1984]. The increased level of adverse effect(called a benchmark response, or BMR) associatedwith a BMD is typically in the low region of thedose-response data (e.g., a 10% excess risk). In thisdocument, the term BMD is used to describe thepoint estimate based on maximum likelihood estimation,and the term BMDL is used to describe thelower 95% confidence limit (i.e., as originally definedby Crump [1984]). A 10% excess risk, basedon dichotomous or quantal data, is used becauseit is at or near the limit of sensitivity in the animalbioassay [US EPA 2012; Crump 2002]. The BMDLassociated with a 10% BMR is used as a point ofdeparture (POD) for low-dose extrapolation usinglinear or nonlinear methods (depending onthe mode of action evidence) [US EPA 2012]. Thelow-dose extrapolation may include estimation ofthe probability of effects at low doses or below a referencevalue (not risk-based) by accounting for uncertaintiesin the dose estimation (e.g., extrapolationfrom animal to human, inter-individual variability,limitations in the animal data [US EPA 2012].A.2.3.1 Dichotomous Response DataFor dichotomous data (yes/no response), a BMDis defined as the dose associated with a specifiedincrease in the probability of a given response, eitheras an excess risk (i.e., additional probabilityabove background) or as a relative risk (i.e., relativeto the background probability of having a normalresponse) [Crump 2002].In this analysis, the BMD (using dichotomous data) isthe dose d corresponding to a specified excess (added)risk (e.g., 10%) in the proportion of animals witha given adverse lung response (BMR), as follows:Equation A–2:BMR = P(d) – P(0)where P(d) is the probability of an adverse responseat the BMD, and P(0) is the probability ofthat adverse response in an unexposed population[Crump 2002; US EPA 2010].The dichotomous BMR lung responses include thepresence or absence of granulomatous inflammation[Ma-Hock et al. 2009] or alveolar septal thickening[Pauluhn 2010a] (Table A–1). The proportionof animals responding with the minimal orhigher severity was selected as the benchmark response.The BMD(L) estimates are expressed as themass dose of SWCNT or MWCNT in rodent lungsassociated with the specified BMR. These animalbasedBMD(L)s are extrapolated to humans basedon species-specific differences in the estimated depositionand retention of CNTs in the lungs (SectionA.2.4).A.2.3.2 Continuous Response DataBMD estimation using continuous data requiresspecifying a BMR level along the continuum of responses.Continuous response data provide informationon the amount or degree of a biologicalresponse. Continuous response measures may includenonzero levels that are associated with thenormal structure or function (e.g., a certain numberimmune cells or amount of protein in healthylungs). These levels can become elevated in responseNIOSH CIB 65 • Carbon Nanotubes and Nanofibers103