4 Conclusions—Hazard and Exposure Assessment
5.2 Other Derived Occupational Exposure Limits for CNT
Occupational Exposure Limits for CNT
One of the earliest OELs for CNT was proposed by the British Standards Institute [BSI 2007]—the benchmark exposure limit (BEL) of 0.01 fiber/cm3, or one-tenth of their asbestos exposure limit (Table 5–5). Nanocyl [2009] derived an estimated OEL of 2.5 µg/m3 for an 8-hr TWA exposure based on applying an overall assessment (a.k.a. uncertainty) factor of 40 to the LOAEL of 0.1 mg/m3 in the
Ma-Hock et al. [2009] subchronic rat inhalation study of MWCNT. Aschberger et al. [2010] pro-posed OELs of 1 µg/m3 for MWCNT studied by Ma-Hock et al. [2009] and 2 µg/m3 for MWCNT from Pauluhn [2010a], by adjusting 0.1 mg/m3 (the LOAEL in Ma-Hock et al. [2009] and the NOAEL in Pauluhn [2010a]) for rat-to-human daily expo-sure and respiratory volume, and applying an over-all assessment factor of 50 and 25, respectively.
Pauluhn [2010b] derived an OEL using subchronic data in rats inhaling MWCNTs (Baytubes®) [Pau-luhn 2010a]. This approach was based on the bio-logical mechanism of volumetric overloading of al-veolar macrophage-mediated clearance of particles from the lungs of rats [Morrow 1988]. Increased particle retention half-time (an indication of lung clearance overload) was reported in rats exposed by subchronic inhalation to MWCNT (Baytubes®) at 0.1, 0.4, 2.5, or 6 mg/m3 The overloading of rat lung clearance was observed at lower-mass doses of MWCNT (Baytubes®) compared with other poorly soluble particles; and the particle volume dose was better correlated with retention half-time among poorly soluble particles including CNT [Pauluhn 2010a, b]. Pauluhn [2010b] reported benchmark concentration (BMC) estimates of 0.16 to 0.78 mg/
m3 for rat lung responses of pulmonary inflamma-tion and increased collagen, but selected the lower NOAEL of 0.1 mg/m3 to derive a human-equivalent concentration. The NOAEL was adjusted for hu-man and rat differences in factors affecting the estimated particle lung dose (i.e., ventilation rate, alveolar deposition fraction, retention kinetics, and total alveolar macrophage cell volume in each spe-cies). The product of these ratios resulted in a final factor of 2, by which the rat NOAEL was divided, to arrive at a human-equivalent concentration of 0.05 mg/m3 (8-hr TWA) as the OEL for MWCNT (Baytubes®). No uncertainty factors were used in deriving that estimate.
The Japanese National Institute of Advance Indus-trial Science and Technology (AIST) derived an OEL for CNT of 30 µg/m3 [Nakanishi 2011a,b], based on studies supported by the New Energy and Industrial Technology Development Organization
(NEDO) of Japan. Rat NOAELs for pulmonary inflammation were identified in 4-week inhala-tion studies of SWCNT and MWCNT [Morimoto et al. 2011a,b]. Human-equivalent NOAELs were estimated by accounting for rat and human differ-ences in exposure duration, ventilation rate, particle deposition fraction, and body weight [Nakanishi 2011b]. The rat NOAELs of 0.13 and 0.37 mg/m3 for SWCNT and MWCNT, respectively, were estimated to be equivalent to 0.03 and 0.08 mg/m3 in humans including adjustment by an uncertainty factor of 6. This total uncertainty factor included a fac-tor of 2 for uncertainty in subchronic-to-chronic extrapolation and a factor of 3 for uncertainty in rat to human toxicokinetic differences (factors of 1 were assumed for toxicodynamic differences in rats and humans and for worker inter-individual vari-ability). A relationship was reported between the BET specific surface area of various types of CNT and pulmonary inflammation (percent neutrophils in bronchoalveolar lavage fluid) (Figure V.2 in Na-kanishi [2011b]). Thus, the OEL of 0.03 mg/m3 was proposed for all types of CNT, based on the data for the SWCNT with the relatively high specific sur-face area of ~1,000 m2/g (which was noted would be more protective for other CNTs with lower spe-cific surface area). A period-limited (15-yr) OEL was proposed due to uncertainty in chronic effects and based on the premise that the results will be re-viewed again within that timeframe with further data [Nakanishi 2011a].
In summary, these currently proposed OELs for CNT range from 1 to 50 µg/m3 (8-hr TWA con-centration) [Aschberger et al. 2010; Nanocyl 2009;
Pauluhn 2010b; Nakanishi (ed) 2009a], including the NIOSH REL of 1 µg/m3. Despite the differences in risk assessment methods and assumptions, all of the derived OELs for CNT are low airborne mass concentrations relative to OELs for larger respira-ble carbon-based particles. For example, the cur-rent U.S. OELs for graphite or carbon black are ap-proximately 2.5 to 5 mg/m3. Each of these CNT risk assessments supports the need to control exposures to CNT in the workplace to low airborne mass con-centrations (µg/m3) to protect workers’ health.
Table 5–5. Recommended occupational exposure limits for CNT
Reference Occupational exposure limit (OEL) Comments Pauluhn [2010b] 0.05 mg/m3 (8-hr TWA) for MWCNT
(Baytubes®) Based on rat subchronic (13-wk) inhalation
study of MWCNT (Baytubes®) and prevention of lung clearance overload and associated pulmonary effects. Rat NOAEL of 0.1 mg/m3 adjusted by a factor of 2 for worker exposure day, air intake, deposition, and clearance kinetics. No uncertainty factors were applied.
Nakanishi (ed) [2011a,b] 30 µg/m3 (8-hr TWA) for CNT Based on 4-wk inhalation studies of SWCNT and MWCNT in rats. Lowest NOAEL of 0.13 mg/m3 (for high surface area SWCNT) used as basis for CNT OEL). Adjusted for worker exposure day, air intake, deposition fraction, and body weight; uncertainty factor of 6. OEL is period-limited (15-yr).
Nanocyl [2009] 2.5 µg/m3 (8-hr TWA) for MWCNT Adjusted rat LOAEL of 0.1 mg/m3 (subchronic inhalation) [Ma-Hock et al.
2009] to workers and applied assessment factor of 40.
Aschberger et al. [2010] 2 µg/m3 (8-hr TWA) for MWCNT
1 µg/m3 (8-hr TWA) for SWCNT
Adjusted rat NOAEL of 0.1 mg/m3 (subchronic inhalation) [Pauluhn 2010a]
for worker exposure day and air intake;
assessment factor of 25.
Adjusted rat LOAEL of 0.1 mg/m3 (subchronic inhalation) [Ma-Hock et al.
2009] for worker exposure day and air intake; assessment factor of 50.
BSI [2007] 0.01 fibers/ml for fibrous nanomaterials with high aspect ratios (> 3:1 and length
> 5000 nm)
Benchmark exposure level (BEL) based on one tenth of the asbestos exposure limit