State of knowledge on the occupational exposure to carbon nanotubes

International Journal of Hygiene and Environmental Health 225 (2020) 113472

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State of knowledge on the occupational exposure to carbon nanotube a,∗

I. Guseva Canu , K. Batsungnoen a b c

a,b

c

, A. Maynard , N.B. Hopf

T

a

Center for Primary Care and Public Health (unisanté), University of Lausanne, Switzerland Institute of Public Health, Suranaree University of Technology, Thailand School for the Future of Innovation in Society, Arizona State University, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Nanotechnology Systematic review CNT number concentration CNT mass concentration Exposure registry Health surveillance

Carbon nanotubes (CNT) trigger fascination as well as anxiety, given their unique physical and chemical properties, and continuing concerns around their possible health effects. CNT exposure assessment is an integral component of occupational and environmental epidemiology, risk assessment, and management. We conducted a systematic review to analyze the quality of CNT occupational exposure assessments in field studies and to assess the relevance of available quantitative data from occupational hygiene and epidemiological perspectives. PubMed and Scopus databases were searched for the period 2000–2018. To grade the quality of each study, we used a standardized grid of seven criteria. The first criterion addressed 12 items deemed most relevant CNT physical-chemical properties with respect to their in vitro and in vivo toxicity. We included 27 studies from 11 countries in the review and graded them high (n = 2), moderate (n = 15) and low quality (n = 10). Half of the studies measured elemental carbon mass concentration (EC) using different methods and aerosol fractions. In 85% of studies, the observed values exceed the US National Institute for Occupational Safety and Health Recommended Exposure Limit. The quantification of CNT agglomerates and/or CNT contained fibers becomes increasingly common although lacking methodological standardization. Work activities with the greatest mean CNT mass concentrations were non-enclosed and included sieving, harvesting, packaging, reactor cleaning, extrusion and pelletizing. Some of the large studies defined standardized job titles according to exposure estimates at corresponding workstations and classified them by decreasing CNT exposure level: technicians > engineers > chemists. The already initiated harmonization of CNT exposure assessment and result reporting need to continue to favor not only studies in the field, but also to identify companies and workers using CNTs to characterize their exposures as well as monitor their health. This will enable an objective and realistic evaluation of risks associated with CNT applications and an appropriate risk management.

1. Introduction Carbon nanotubes (CNT) trigger fascination as well as anxiety (Maynard et al., 2006). The uncertainty around their short, medium and long-term toxicity to human health and the environment sustains this ambivalence and underlines challenges in weighing the overall benefits and risks of expanding CNTs applications in various industries. CNTs have high electrical conductivity, thermal conductivity, tensile strength, elasticity, absorbency, aspect ratio, but low weight. Great variations in the size and other characteristics make CNTs useful in a multitude of emerging nanotechnology fields (Venkataraman et al., 2019). Some examples are semiconductors, electrostatic paints, and fuel systems in automotive and aerospace industry (Venkataraman et al., 2019). Structural composites are used for thermal management (Nguyen et al., 2016) and as flame-retardants for sporting goods

∗

(Nowack et al., 2013). Single wall CNTs (SWCNT) have precious electronic properties. Multi-walled CNTs (MWCNT) are used in mechanical and thermodynamic applications (Kingston et al., 2014). Some researchers have compared some forms of CNTs to other hazardous high aspect ratio fibers, such as asbestos (Emerce et al., 2019; Methner et al., 2012b; Poland et al., 2008). However, we are only beginning to understand possible health effects associated with CNT exposures. The Agency for Research on Cancer (IARC) classified a particular rigid MWCNT (Mitsui-7) as ‘possibly carcinogenic to humans’ (Group 2B) (Grosse et al., 2014). Other CNTs such as single, multiple, rigid, and flexible MWCNT did not have sufficient data to be classified (i.e., ‘not classifiable as to its carcinogenicity to humans’ (Group 3)) (Grosse et al., 2014). The lack of data pertained to the absence of epidemiological studies available and that most of the in vivo studies used Mitsui-7 CNTs. Mitsui-7 CNTs induce proliferative airways

Corresponding author. Unisanté Department of Occupational and Environmental Health, Route de la Corniche 2, 1066, Epalinges-Lausanne, Switzerland. E-mail address: [email protected] (I. Guseva Canu).

https://doi.org/10.1016/j.ijheh.2020.113472 Received 15 August 2019; Received in revised form 17 December 2019; Accepted 29 January 2020 1438-4639/ © 2020 Published by Elsevier GmbH.

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exposures (Boccuni et al., 2017). Scientific articles in this field are published at an astonishing rate. We aimed at updating the review originally conducted by (Guseva Canu et al., 2016a) by targeting the update to occupational exposures to CNTs. Our objectives were to analyze the quality of CNT exposure assessments in occupational studies available, and to assess the relevance of available quantitative data from the occupational hygiene and epidemiological perspectives.

diseases (Bishop et al., 2017), mesothelioma, lung adenocarcinoma, hyperplasia and fibrosis (Kuempel et al., 2017) in experimental studies. Toxicological findings of CNTs in general have shown to delete cyclin dependent kinase inhibitor 2 A/2B (CDKN2A/2B) tumor suppressor genes (Nagai et al., 2011), accumulate oxidative stress and inflammatory cytokines (Kuempel et al., 2017; Yamashita et al., 2010), and cause DNA damage (Emerce et al., 2019; Jackson et al., 2015; Lindberg et al., 2013; Moller and Jacobsen, 2017). In humans, exposure to CNTs has been associated with development of respiratory allergies, self-reported by study participants (Schubauer-Berigan et al., 2018). The association with spirometry-based metrics of pulmonary function was missing in all (Lee et al., 2015b; Schubauer-Berigan et al., 2018; Vlaanderen et al., 2017), but one study by Liao et al. (2014). They observed significant changes in peak expiratory flow rate and forced expiratory flow at 25% between the NTC exposed workers and controls (Liao et al., 2014). Some cardiovascular and hematological effects have been also reported. Schubauer-Berigan et al. (2018) found that resting heart rate and hematocrit levels were positively associated with several exposure estimates in CNT exposed workers. Lee et al. (2015b) reported some slight abnormalities in hematology and blood biochemistry, namely in the aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, low-density lipoprotein cholesterol, and monocyte number, although none of the workers showed simultaneous increases of these markers. Vlaanderen et al. (2017) also reported significant differences in monocyte number between MWCNTexposed workers and controls, along with differences in number of white blood cells and neutrophils, mean platelet volume, immature reticulocytes and platelet fractions. Other biological effects reported in literature are: lung inflammation (reduced FENO concentrations (Vlaanderen et al., 2017), increased levels of oxidative stress markers (malonaldehyde (MDA), 4-hydroxy-2-hexanal (4-HH) and 4-hydroxynonenal) in exhaled breath condensate (Lee et al., 2015b); increased profibrotic and inflammatory markers in sputum (KL-6, IL-5, IL-8, IL1β, IL-4, and TNF-α levels) and in blood (IL-1β, IL-4, TNF-α (Fatkhutdinova et al., 2016)), increased levels of endothelial damage markers (CRP, ICAM-1 and VCAM-1) in blood (Beard et al., 2018; Kuijpers et al., 2018) and significant variation in 16 immunological marker concentration between MWCNT-exposed workers and controls (Vlaanderen et al., 2017). Gene expression profiling studies in blood showed MWCNT's potential to exert pulmonary and cardiovascular adverse effects. Moreover, these studies suggest that MWCNTs carcinogenic potential in humans operates via the epigenetic machinery, DNA repair, cell cycle control, and oncogenic activity (Ghosh et al., 2017; Shvedova et al., 2016). Although the adverse effects identified in humans are similar to the toxicological endpoints identified in in vivo animal studies, there is yet no evidence of causal inference between these effects and CNT exposures (Schulte et al., 2019). Establishment of such evidence requires relevant exposure data that can be correlated to toxicological and epidemiological endpoints, and enable dose-response relationship investigation in unbiased epidemiological studies. Exposure assessment of CNT is thus paramount when relating toxicological endpoints to exposures as well as identifying adverse effects based on the most consistent dose-response relationships. It also constitutes an integral component of occupational and environmental epidemiology, risk assessment and management as well as regulatory actions (Guseva Canu et al., 2018, 2019). In 2016, Guseva Canu et al. reviewed the completeness and reliability of available exposure data for use in epidemiology and risk assessment of carbon-based fibrous nanomaterials (Guseva Canu et al., 2016a). They called for a coordinated effort in producing surveys and exposure inventories based on a harmonized strategy of CNT characterization, exposure measurements and reporting results (Guseva Canu et al., 2016a). Several attempts have been made since to understand what exposures to engineered nanomaterials exist (Debia et al., 2016), and which measurement techniques are used to measure CNT

2. Material and methods 2.1. Literature search and study selection As initial corpus of literature, we considered studies included in the previous review by (Guseva Canu et al., 2016a), which covered a 14year span from the 2000/01/01 through 2014/08/01. This corpus of literature was built through a systematic literature search conducted in the frame of IARC Monograph on CNT (Grosse et al., 2014) and was checked and confirmed as being exhaustive by the IARC documentarists. For the purpose of this review, we reassessed the eligibility of the studies included in this initial corpus. This eligibility analysis resulted in exclusion of studies on carbon nanofibers (CNFs) and studies conducted in experimental settings or in silico (exposure modelling studies). Furthermore, we updated this initial corpus with studies published over the last four years (from 2014/08/01 through 2018/03/ 28). To identify the new literature, we performed a systematic literature search in PubMed and Scopus databases. The systematic search strings can be found in Supplementary material File 1. To be eligible, the studies had to meet the following criteria: 1-being conducted in an occupational setting where nanomaterials were produced, handled and processed or where workers used nano-enabled products, 2-reporting quantitative results on CNT exposure measured at workplaces, 3-written in English language. Conference proceedings, editorials and review articles were not considered eligible. Two independent reviewers (IGC and KB) performed a first screening, by examining titles and abstracts of all identified publications to pre-select potentially eligible ones. A second screening consisted of studying the full texts of all pre-selected publications, and retaining those meeting all inclusion criteria. In case of discrepancies between the two independent reviewers, the opinion of the third reviewer (NBH) was asked to reach consensus. When several publications reported the results from the same epidemiological or exposure assessment study, only the most complete and the most informative publication was included. 2.2. Data extraction We used the standardized data extraction form, developed and used by (Guseva Canu et al., 2016a). This form, completed using an MS Excel sheet by two independent reviewers (NBH and IGC), enabled systematic extraction of data as follows: country and calendar period of study conduction; type of the workplace and type of activity performed; short description on CNT type, size and quantities produced; detailed description of the tasks performed; the process or technology used; the presence and type of engineering exposure control measures; the use of personal protective equipment and their type; the type of samples collected (personal, personal breath zone, or air samples); the measured total dust mass concentration (in μg/m3), the exposure metric used as proxy of CNT gravimetric concentration (e.g., catalyze metal concentration, elemental carbon mass concentration) and the measurement results; the evidence of CNT on TEM/SEM (yes/no); the number of CNT-structures per cm3; and the study reference. All above-mentioned data were extracted per task, and according to the specific exposure regimen or exposure control conditions, in order to generate the summary exposure estimates per workplace and task. In addition to extracting the previously described exposure determinants, we extracted exposure measurement techniques and devices used. 2

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findings on SWCNT exposure, measured primarily at R&D facilities (n = 3). Four other studies measured MWCNT (n = 3) and SWCNT exposure (n = 1) during composite production at secondary manufacturing facilities, while five studies did not specify CNT type (Bekker et al., 2015; Heitbrink et al., 2015; Lee et al., 2013; Sirven et al., 2017; Yeganeh et al., 2008). The quality scoring of some studies included in the previous review were downgraded because of the added CNT physical-chemical properties quality rating (Tables 1 and S2). Most studies evaluated using our approach were of moderate (n = 15, 55%) or low quality (N = 10, 37%), and only two studies obtained high quality grade (Fonseca et al., 2015; Thompson et al., 2015). The major drawbacks consisted of inaccurate assessment and/or reporting of CNTs characteristics, in particular six of the 12 items were missing such as method of purification and remaining impurities, surface coating and functionalization treatment, surface charge, and bulk density (Table S2). Only one third of studies reported CNT dimensions (i.e., length and diameter distribution). While 81% of studies (n = 22) took into account the use of collective and personal protective equipment when assessing CNT exposure, only 33% (n = 9) provided sufficiently detailed task and time schedule description. Thirteen studies reported the number of workers involved in the CNT exposure assessment, although it was unclear whether the reported numbers corresponded to all workers potentially exposed to CNTs or only some of them, and how representative they were in the latter case. In 41% of studies (n = 11), the amount of CNT production was declared (Table S2). Inaccurate assessment and/or reporting of background exposure to carbonaceous nanoparticles was another common drawback. Detailed statistical analysis of background data were performed in only 37% of studies (n = 10). Methner et al. performed the most complete background exposure assessment compared to the other studies included in the review. Their background assessment including temporal and spatial comparisons of particle number and mass concentrations, as well as morphological and chemical analysis of particles collected on filters (Methner et al., 2012a). Procedures for measuring background CNT concentrations were as described by Methner et al. (2012a) until 2016, when Eastlake and colleagues requested that background concentrations should be data logged continuously with the direct reading instrument in an area deemed background during the time workplace exposures were recorded (Eastlake et al., 2016). In other studies with a rather complete background exposure assessment, the missing assessment was most often the chemical analysis of background air samples (n = 7), followed by lack of morphological analysis (n = 2), or both (n = 1). Sixteen studies (59%) assessed at least three different exposure metrics, including mass concentration, particle number concentration, particle size distribution, and elemental carbon mass concentration (EC), in addition to perform chemical and morphological analysis of particles. Data processing was deemed satisfactory in only 44% of studies (Bekker et al., 2015; Hedmer et al., 2014a; Hedmer et al., 2014b; Kouassi et al., 2017; Kuijpers et al., 2016; Methner et al., 2012a; Shvedova et al., 2016; Thompson et al., 2015), and clearly insufficient in seven studies. The absence or inadequate reporting of statistically

2.3. Assessment of biases and evidence quality rating To evaluated the quality of included papers we adapted the quality assessment grid initially created by Boccuni et al. (2017). They developed it based on the GRADE methodology (Balshem et al., 2011) regardless nanomaterial type, and included seven major criteria with an assigned sub-score value between −2 and +2 depending on the quality of their assessment and reporting in original studies. Several steps were needed to adapt this assessment specifically for CNTs. We redefined the first criterion i.e., CNT information by characterizing the most relevant physical-chemical properties with respect to their in vitro and in vivo toxicity (12-items). The relevant properties were selected from the Technical standards (TS) established by the International standard organization (ISO) for CNT, namely the ISO/TS 10798 for SWCNT (ISO/ TS, 2011) or ISO/TS 11888 for MWCNT (ISO/TS, 2017). The relevant properties for CNT include: technical name, number of walls (e.g., SWCNT, DWCNT, or MWCNT), purification method (e.g., oxidation), type and amount of impurities, surface coating and/or specialty treatment, physical form (e.g., powder, paste, suspension), distribution of CNT diameter (inner and outer) and length, bulk density, CNT surface area, agglomeration state, and surface charge. All other grid criteria were unchanged (Supplementary material, Table S1). We gave all items identified for a given criterion equal weight which resulted in a maximum possible sub-score value of two. For example, each item of the 1st criterion was given a weight of 0.166, while the three last items of the second criterion were each weighted at 0.333. The final quality was ranked High (14–8), Moderate (7–1), Low (0 to −7), or Very low (−8 to−14) based on the total score, calculated as sum of the seven subscores. Two reviewers (NBH and IGC) rated each study independently. The results were then compared and all discrepancies were discussed and solved by consensus. 3. Results and discussion 3.1. Description of included studies and their quality In total, this review included 27 publications (Bekker et al., 2015; Dahm et al., 2012; Dahm et al., 2018; Dahm et al., 2015; Fonseca et al., 2015; Han et al., 2008; Hedmer et al., 2014b; Heitbrink et al., 2015; Kato et al., 2017; Kim et al., 2016; Kouassi et al., 2017; Kuijpers et al., 2016; Lee et al., 2015a; Lee et al., 2010; Lee et al., 2013; Lee et al., 2015b; Maynard et al., 2004; Methner et al., 2012a; Methner et al., 2010; Ogura et al., 2013; Ogura et al., 2011; Ono-Ogasawara et al., 2015; Shvedova et al., 2016; Sirven et al., 2017; Takaya et al., 2012; Thompson et al., 2015; Yeganeh et al., 2008). Sixteen were carried forward from the initial review and eleven were selected in the new systematic literature search (Fig. 1). Overall, these publications reported findings from eleven different countries across three geographical regions: Europe, Northern America, and Asia (Table 1). Studies mainly focused on MWCNTs (n = 9, 37%), or both MWCNT and SWCNT manufacturing (n = 5, 20%). Four studies (Kouassi et al., 2017; Maynard et al., 2004; Ogura et al., 2013; Ogura et al., 2011) reported

Fig. 1. Flow of information throughout the different phases of the systematic review. 3

Country

USA USA USA USA USA USA USA USA Canada Japan Japan Japan Japan Japan South Korea South Korea South Korea South Korea South Korea South Korea NR (China) Russia Sweden Finland Netherland Belgium France

Reference

Maynard et al., 2004 Yeganeh et al., 2008 Methner et al., 2010 Methner 2012 Dahm et al., 2012 Dahm et al., 2015 Heitbrink et al., 2015 Dahm et al., 2018 Kouassi et al. (2017) Ogura et al., 2011 Ogura et al., 2013 Takaya et al., 2012 Ono-Ogasawara et al., 2015 Kato et al. (2017) Han et al., 2008 Lee et al., 2010 Lee et al., 2013 Lee et al., 2015a Lee et al., 2015b Kim et al., 2016 Thompson et al., 2015 Shvedova et al., 2016 Hedmer 2014 Fonseca et al., 2015 Bekker et al., 2015 Kuijpers et al., 2016 Sirven et al., 2017

4 R&D Primary manufacturer 2 R&D 2 primary manufactures 2 primary, 3 econdary, 1 hybrid manufactures 4 primary, 8 secondary, 2 hybrid manufacturers 1 primary, 1 secondary manufacturer 4 primary, 5 secondary, 3 hybrid manufacturers Primary manufacturer R&D Pilot-scale manufacturer Secondary manufacturer 1 primary, 4 secondary manufacturers Secondary pilot manufacturer 2 R&D labs 2 R&D, 2 primary manufacturers 2 user facilities Primary manufacturer 1 pilot, 1 primary manufacturer 1 R&D, 1 pilot, 2 primary manufacturers Secondary manufacturer Primary manufacturer Primary manufacturer Secondary manufacturer 5 R&D labs Primary manufacturer Hybrid manufacturer

Type of facility

Table 1 Summary of the included studies, their quality and main results.

SWCNT CNT, fulerenes MWCNT SWCNT SWCNT, MWCNT SWCNT, MWCNT, composites CNT 12 MWCNT, 4 SWCNT SWCNT SWCNT SWCNT MWCNT MWCNT MWCNT compos. MWCNT MWCNT CNT MWCNT SWCNT, MWCNT 3 MWCNT, 1 SWCNT MWCNT compos. MWCNT MWCNT SWCNT compos. CNT MWCNT CNT

Material Personal Area Area Area, PBZ Area, PBZ Area, PBZ Area Area, PBZ, surface Area, PBZ, surface Area Area Personal Area, PBZ Area Area, pesronal Area, pesronal PBZ Area, PBZ Area, PBZ Area Area, PBZ Area, PBZ Area, PBZ Area Area, PBZ Area, PBZ, surface Area, PBZ

Sampling NR NR NR NR 69 (69) 68 (68) NR 108 (108) NR NR NR NR NR NR NR NR NR 13 (9) 11 (11) NR 8 (2) 15 -22 (8–10) 3 (3) 20 (20) NR 68 (63) NR

Nb of workers

Not measured Not measured Not measured No; < LOD Yes (8 taks) Yes (2 plants) Not measured Yes, 7% resp, 29% inhal Yes (2 tasks) Not measured Yes Yes Yes (all) Not measured Not measured Not measured Not measured Yes (all) Not measured Not measured No; < LOD Yes Yes (2 tasks) Yes* (in 2 of 3 tasks) Not measured Yes (67%) Not measured

REL exceeding

Not measured Not measured Not measured Yes (SEM) Yes (TEM) Yes (TEM/SEM) Not measured Yes (TEM) No (TEM/SEM) No (SEM) Not measured Not measured Not measured No (SEM) Yes (SEM) No (SEM) Not measured No (TEM) Not measured Not measured Not measured Yes (TEM) Yes (SEM) Yes (TEM) Not measured Yes (SEM) No (SEM)

CNT count (EM)

Moderate Low Moderate Moderate Moderate Moderate Low Moderate Moderate Low Low Low Moderate Low Moderate Moderate Low Low Moderate Low High Moderate Moderate High Moderate Moderate Low

Quality

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Table 2 Instruments and analytical methods used in the reviewed studies for monitoring CNT exposure.

direct-reading instruments. Worth noting that the morphology of CNTs may confound some direct reading instruments, which often depend on an assumption that the particles are compact. Currently, there is no clear-cut understanding of which instruments to use for type of CNTs and in addition, these are expensive instruments, consequently, laboratories usually own a few types. Although direct reading instruments were the preferred measurement tool in the articles we reviewed, they don't reflect a worker's personal exposure. They can, however, be used to assess exposures during a task or find exposure sources. Duration of measurements should correspond to the work activity to rate possible exposures by job tasks. The CNT concentrations need to be anticipated to not overload the direct reading instrument capacity, and the flow-rate adjusted accordingly. The absence of personal sampling devices makes directreading instruments a necessity. These cannot be attached to the worker as a sampling train, but are portable such as CPCs (5–6 kg) while others are more cumbersome to bring in the field such as SMPSs (12–15 kg). These instruments measure any particulates, not only CNTs. A critical step in data analysis in these cases is measuring and adjusting for background aerosol concentrations when assessing occupational exposures. To understand the background corrections made, it is important to describe how (instrument settings), where (indoor, outdoor), when (no production period), and for how long time (seconds, minutes) these measurements were performed. Only eight out of the 27 articles we assessed described background corrections.

representative background data were often noticed along with lack of detailed information on statistical analysis of exposure measurement data (Table S2). For instance, airborne CNT size is often measured as having a broad bimodal distribution (Fromyr et al., 2012); the lowersized mode is attributed to freely suspended nanotubes, and the broader mode to larger particle sizes such as CNT agglomerates, though this would be very material-specific, as in some matrices no free CNT release is expected. The statistical treatment should follow such distributions where they exist, but were rarely discussed in published studies. Rather, we observed a disregard of statistical treatment of the reported CNT exposure measurement values. Exposure metrics were expressed as arithmetic or geometric means without explanation. 3.2. Instrument choice and method considerations from an occupational hygienist's perspective 3.2.1. Direct reading instruments used for CNT in this review Table 2 and Table S3 provide an overview of direct reading instruments used in the reviewed studies. Condensation particle counter (CPC) and scanning mobility particle sizer (SMPS) instruments were the most frequently used to measure airborne nanoparticle size distributions and particle number concentrations in the size range between 10 and 1000 nm. Particle mass concentration size range between 7 nm and 10 μm were often measured using black carbon monitors (BCM) and electrical low-pressure impactor (ELPI). Noteworthy, none of the currently used direct-reading instruments is capable of differentiating granular and fibrous morphologies. In addition, the response to nanofibers and low-density CNT agglomerates is unknown (Simonow et al., 2018). Before taking a direct-reading instrument in the field, we would argue that it is important to have an in-depth understanding of the CNT aerosol morphology. These characteristics should be considered given the limitations of the selected instruments for the particular CNT (Chen et al., 2016). Choice of direct-reading instruments will depend on these characteristics. For example, highly agglomerating CNTs should be measured with instruments in the higher nm range while CNTs that tend to stay separate, an instrument in the lower nano-range should be selected. In our review, we seldom found a reasoning for the choice of

3.2.2. Personal sampling used for CNT in this review Most studies assessed personal exposures for inhalable CNT dust with quartz fiber filter (QFF) or mixed cellulose ester filter (MCE) in a filter cassette attached to a pump with tubing (Table 2). Open and closed (dusty environments) face cassettes were selected depending on the dustiness of the workplace. Respirable dust was sampled with a cyclone or an impactor equipped with QFF or MCE filters. As far as we know, the sampling efficiency of CNTs on these fibers have not been assessed, except some preliminary indications gleaned from work assessing the use of such samplers for fibrous aerosols. This is especially worrisome, as these filters will only collect CNT agglomerates greater 5

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than 2 μm. However, CNT materials have been reported to be particle agglomerates from 2 to 10 μm (Dahm et al., 2015).

recommending a temperature range between 550 and 920 °C in three stages (EC1 550 °C, EC2 700 °C, EC3 920 °C) (Ono-Ogasawara and Myojo, 2011). Later, Kuijpers et al. modified this protocol for EC2 at 650 °C due to altered oxidation temperatures because of high concentrations of catalyzing metals and the presence of other EC particles (soot) (Kuijpers et al., 2016). They recommend subtracting the mass soot concentration per day/shift per location from the total EC sum to obtain the MWCNT mass concentration of EC. The presence of these artifacts introduces uncertainties in the EC estimation. Thompson et al. recommend accounting for particulate OC by thermal analysis of the specific particulate OC in question to determine onset of oxidation and confirm complete oxidation (Thompson et al., 2015). These authors caution the use of TOA for CNT quantification if they are incorporated in a polymer matrix. Release of free MWCNTs from polymer matrices has been inconsistent due to the variations in method of release and detection (Brame et al., 2018). Polymers that do not fully pyrolyze in the inert atmosphere during TOA would result in a positive bias on EC. Seven studies in our review used MCE filters analyzed with SEM coupled with energy dispersive X-ray spectroscopy (SEM-EDX). Nickelcoated polycarbonate filters can also be used with the SEM-EDX technique. One study used inductively coupled plasma mass spectrometry (ICP-MS) analyzing residual metal impurities in CNTs. This provides a means to distinguish CNTs from other sources of EC in environmental samples (Avramescu et al., 2016). NMAM 5040 (2016 version) recommends the thermal program to adjust to the material, size fraction 85/collected and environmental background. Dahm et al. and Hedmer et al. quantified CNT number concentrations with electron microscopy on samples collected in parallel with samples where concentrations were measured with EC with the 2016 version of NMAM 5040 (Dahm et al., 2012; Dahm et al., 2015; Hedmer et al., 2014a). They concluded that electron microscopy had more sensitivity and selectivity in the measurement of CNT exposure compared to EC analysis.

3.2.3. Grids for electronic microscopy used in this review Transmission electronic microscopy (TEM) coupled with the EDX on a sampling support; a TEM grid, can be used to determine CNT size, morphology, specific surface, and elemental composition. Several types of TEM grids exist (R'mili et al., 2013). TEM grids are small (3 mm diameter) metallic grids (copper, nickel, gold or molybdenum) with a translucent electron beam membrane. This nanometer thick membrane allows the contrast of particles deposited on their surface to be viewed. The TEM grids have operational collection between 5 and 150 nm size ranges. Two of the 27 articles used 3 mm copper TEM grids. Other studies (8/27 articles) chose to follow NIOSH method (7402) for asbestos sampling transferring circular cut sections of the MCE or QFF filters to a TEM for counting. A few studies used less common filter materials (nuclepore filters, and polycarbonate membrane filters (PMF)). The NIOSH method 7402 was modified for CNT analysis in 2016 (NIOSH, 2017), thus articles before and after this time might reference the same method but did not follow the same exact procedure. Air samples were collected on MCE filters having a nominal pore size of 0.8 μm (before 2016 the method 7402 specifies 0.45–1.2 μm), with sampling pumps operated at 5 L/min (0.5–16 L/min specified in 7402). For cutting the filters, the modified NMAM method requires a scalpel to remove a wedge-shaped portion (1/4) from the filter, which is placed on a glass slide. The filter is cleared with acetone vapor in a hot block before coating it with carbon. Three sections from the coated filter are cut and each portion placed on separate TEM grids. Each filter portion has particles sandwiched between the carbon film and collapsed filter. The TEM is then used for identifying the CNT morphology. 3.2.4. Morphology analysis The majority of the studies determined CNT morphology. The analysis technique varied and were either (1) TEM, (2) scanning electron microscopy (SEM), or (3) scanning transmission electron microscopy (STEM) (Table 2). Of the 27 articles we reviewed, the majority chose SEM (33%, n = 9) and TEM (37%, n = 10), while only 11% (n = 3) used STEM (Table 2). Both techniques determine morphology with different approaches but have pros and cons that are associated with the specific imaging techniques: SEM focuses on the sample's surface and its composition, whereas TEM provides the details about internal composition. TEM has much higher resolution than SEM; however, SEM also provides a 3-dimensional image while TEM provides a 2-dimensional projection. TEM is preferred over SEM as CNTs are better visualized in TEM.

3.2.6. Recommendations for In the US, the National Institute for Occupational Safety and Health (NIOSH) proposed a recommended exposure limit (REL) for CNTs and carbon nanofibers of 1 μg/m3 EC as an 8-h time weighted average (TWA) respirable mass concentration with the recommended analytical method NIOSH 5040 (NIOSH, 2013). The NIOSH REL was designed to protect against pulmonary fibrosis. Based on maximum crosswise dimensions, the majority of CNT agglomerates will likely fall in the thoracic or inhalable aerosol fractions (Dahm et al., 2018; Dahm et al., 2015; Kuijpers et al., 2016). Bishop et al. are skeptical to this respirable fraction limit as recent findings suggest adverse health effects in conductive airways (bronchiolitis obliterans) (Bishop et al., 2017). Another drawback, is if the respirable fraction is not measured (i.e., a filter is used instead of a cyclone) but calculated (Dahm et al., 2018), this value should be interpreted with caution, as the ratio between respirable and inhalable fraction may vary considerably depending on the workplace. The British Standards Institute has suggested a benchmark exposure limit of 0.01 fibers/cm3, which is 1/10 of the asbestos exposure limit (BSI, 2007). This benchmark exposure limit has now been established in the UK, Germany and Switzerland (Ellenbecker et al., 2018). A fiber is defined as a particle with an aspect ratio > 3:1 and length > 5 μm, and the quantification performed with SEM or TEM. Dahm et al. counted the total number of CNT/nanofibers per cm3; however, CNT/nanofibers materials were typically particle agglomerates from 2 to 10 μm, and do not fit the traditional definition specified by this benchmark limit (Dahm et al., 2018; Dahm et al., 2015). Furthermore, this benchmark limit is based on analogy to asbestos rather than direct evidence of risk. We therefore need to better characterize this aspect of exposure (Brame et al., 2018). In South Korea, an OEL of 6 μg/m3 was estimated for MWCNT based on data from a 13-week inhalation study in rats, which enabled deriving a no observed adverse effect level (NOAEL) of 0.98 mg/m3 (Lee et al., 2019). The authors calculated deposition fractions of MWCNTs in

3.2.5. Elemental carbon analysis Half of the studies (48%) used elemental carbon analysis (EC) to analyze CNTs (Table 2). Personal sampling with QFF and MCE filters are used for elemental composition and the choice of filters depend on the analytical techniques. CNT filter deposition could result in uneven deposits and thus invalidate the assumption that the ~1.5 cm2 punch analyzed is representative of the entire filter (Miller et al., 2013). QFF filters analyzed with thermal-optical analysis (TOA) using flame ionization detector (FID) was used in nine studies. NIOSH method 5040 quantification of EC was cited as a method used. In 2016, this method was expanded to include carbon nanomaterials. The method recommends analyzing bulk material to determine thermal profiles for the material used in the workplace. This will assist manual assignment of the OC-EC split, which in turn will result in more accurate CNT measurements. Carbons that are difficult to oxidize (e.g., graphite) may require a longer period and higher temperature during the oxidative mode to ensure that all EC is removed. Known sampling artifacts are caused by the adsorption of gaseous organic compounds (OC) onto the quartz filter and an analytical artifact in the thermal–optical determination. Ono-Ogasawara and Myojo published a protocol for MWCNT 6

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standardized method for their quantitative measurement is not yet available. Compared to the first wave of studies (Guseva Canu et al., 2016a), new studies identified in this review add to the consistency of these results, since for each of above-mentioned operation, several studies from different countries and settings yield rather similar exposure results and conclusions. Moreover, most recent studies are notably of better quality, compared to those of the first wave. Our quality assessment grid was particularly useful to remain neutral during the quality rating and identifying drawbacks. Although, systematic review guidelines recommend using well-recognized methods and tools for quality appraisal and evidence grading, we found no convenient tool for our review. The quality assessment method developed by Boccuni et al. (2017) based on the GRADE methodology (Balshem et al., 2011) is applicable regardless nanomaterial type. However, given the importance of the above-mentioned CNT properties for the choice of sampling and analytical methods and for the result interpretation, we found this method unsatisfactory. Therefore, we adapted it specifically for CNT characterization quality in exposure assessment studies. However, instead of applying the Delphi technique (Rowe and Wright, 2011) for developing a CNT specific quality assessment method based on expert consensus, we asked one expert in CNT physics-chemistry and toxicology to validating our approach. To generalize the use of our method, a more formal approval would be suitable. Noteworthy, the authors provide increasingly more detailed descriptions including supplementary digital files and raw data, enabling generating meta-estimates of measured exposure values, once the measurement methods are standardized. We would suggest that this practice is encouraged, in particular in studies with more than ten workers. When accompanied by detailed contextual information, such as detailed task and time schedule description, these data constitute a precious material for constructing job exposure matrices (JEMs) (Guseva Canu et al., 2016b, 2017). Thus, studies by (Dahm et al., 2018; Shvedova et al., 2016), are already good premises for such an approach, as they defined standardized job titles according to the exposure estimates at corresponding workstations and classified them by decreasing CNT exposure level: technicians > engineers > chemists. One could expect this approach becomes generalizable with standardization of the exposure assessment methods between studies and between countries. Furthermore, it could form the basis for a predictive model to estimate worker exposure using facility, workstation, and job as exposure determinants, as well as facilitate the establishment of within-company medical and epidemiological surveillance programs (Guseva Canu et al., 2016b; Guseva Canu et al., 2019). The costs of the instruments and analysis for an accurate exposure assessment study in the field are still high. Moreover, entering in companies manufacturing CNT and CNT-bearing composites and products for conducting such studies is challenging, especially in small companies with limited resources (Guseva Canu et al., 2018). Therefore, JEM and exposure modelling represent a relevant alternative for launching a prospective cohort study in frame of an international research collaboration. With this respect, identification of facilities with important workforce involved in the CNT industrial applications in the USA, South Korea, Russia, Finland, Belgium and France constitutes an important progress. Indeed, the identification of the CNT-exposed workers and their registration in view of a passive or active monitoring of their health status in the frame of a prospective medical and/or epidemiological follow-up is the first and the most critical step in epidemiological research and surveillance (Gulumian et al., 2016). According to the numbers of workers reported in the reviewed studies, the minimal size of a pooled CNT-exposed worker population is currently around 200 individuals. However, the true number should be far greater as the studies available have not systematically covered all the CNT applications but focused on some selected tasks. Several of the reviewed articles documented that administrative workers can also be exposed to cross-contaminations or the settling of

the alveolar region of rats and humans as 0.0527 and 0.0984, respectively, using the multi-path particle dosimetry model. A human equivalent exposure concentration of 0.17 mg/m3 was then calculated, based on the NOAEL in rats and adjusted for uncertainty by applying an uncertainty factors of 3 for species differences (rats to humans), 2 for an experimental duration (subchronic to chronic), and 5 for inter-individual variations among workers to obtain the OEL (Lee et al., 2019). This new MWCTN mass-concentration based approach is however contrasting with the benchmark exposure limit adopted in some European countries, based of CNT-fiber count and sustains the question around toxicological relevance of different CNT exposure metrics. 3.2.7. Novel exposure metrics Kato et al. and Kim et al. have suggested to use the direct reading instrument for respirable size (BCM) concentration instead of EC (Kato et al., 2017; Kim et al., 2016). In our review, eight studies used BCM, and of these five studies measured both (Table 2). However, none of these studies compared the methods. Tromp et al. suggest using personal sampling and combining EC and SEM-EDX to measure MWCNT number concentration (Tromp et al., 2017). This might be the better option but would require additional instruments and incur laboratory labor costs. A promising direct reading instrument is an acoustic dispersion system, which Chen et al. used to characterize aerosolized MWCNTs (Chen et al., 2012). MWCNT structures were categorized into two fractions, fibrous particles and isometric particles, which were MWCNT agglomerates having an aspect ratio of < 3. Thompson et al. rated these results as “fairly representative” of the MWCNT observed in their exposure assessment (Thompson et al., 2015). Instead, they proposed to use a personal nanoparticle sampler, named PENS (Thompson et al., 2015). PENS was found to be an effective device for sampling MWCNTs in the workplace for 100 nm to 4 μm. PENS use a micro-orifice impactor with a nozzle array with a diameter of 6.8 mm (Tsai et al., 2012). Furthermore, Thompson et al. (2015) describes the advantages of the PENS as: “If one were to use a filter punch which was the same size as the impactor deposition area and a 25 mm after filter, the PENS would be capable of simultaneously detecting concentrations of 0.034 μg EC/ m3 in the PM0.1–4 size range and 0.36 μg EC/m3 in the PM0.1 size in a worker's PBZ over an 8-h workday.“. 3.2.8. Quantitative data available and their relevance from the epidemiologist's perspective Given the challenges associated with the usage of direct reading instrument for CNT exposure assessment we focused our analyses of quantitative measurement results on mass concentration, including EC mass measurement, and counts of the CNT-structures, that could be compared with currently available OELs for CNTs. Table S4 summarizes the results of these measurements. EC measurements were performed in 48% of the studies (n = 13) (Table 1, Table S4). Although this metric was used by NIOSH to set the recommended CNT occupational exposure limit in 2013 (NIOSH, 2013), six studies published after 2013 did not measured it, though some of them (Fonseca et al., 2015; Sirven et al., 2017) estimated the EC mass concentration through conversion of other measurements such as metal catalyst mass concentration. Noteworthy, a majority of the studies (85%) reported values exceeding the NIOSH REL (1 μg/m3) (Table 1 and Table S4). Most of these study were of moderate quality and one of high quality. The above-discussed heterogeneity of methods and analyses used still preclude any quantitative data summary and meta-analysis. Therefore, only narrative synthesis of results is possible for the moment. Work activities with the greatest mean CNT mass concentrations (Table S4) were powder conditioning, manual recovery/harvesting of SWCNTs and MWCNTs, cleaning and maintenance of the reactor, packaging and bagging, extrusion, and pelletizing. Confirmatory findings of CNTs aggregates and agglomerates using electronic microscopy analyses in all of these situations is also a valuable result, even though the 7

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Acknowledgment

suspended CNT aerosols in general areas, outside of production or manufacturing areas. Regularly opening and closing doors that separated the production and office area enhanced CNT dispersion. Especially two activities increased the CNT exposures outside of the production area: during office cleaning, and when production workers had office related jobs bringing in CNT contamination from their clothing into the office (Dahm et al., 2018; Kouassi et al., 2017; Kuijpers et al., 2016). This clearly indicates that these types of administrative workers must be included in the prospective surveillance and followed up as part of exposed population instead of being by default considered as unexposed (control) participants. Eventually, it would increase the sample size even more and allow a reasonably powerful study being launched in the near future. Opponents of epidemiology and observational studies blaming its long-lasting expensive follow-up and bias potential could be reassured by the newly offered possibilities of active and passive health surveillance at little cost, thanks to the health data access and facilities in big-data analysis, as exemplified by the French EpiNano program (Guseva Canu et al., 2013; Schulte et al., 2016).

The authors thank Dr. Paul Schulte and Prof. Ivo Iavicoli for their invitation to realize and present this review at the ICOH CS Nanotechnology workers symposium in April 2018 in Dublin. We also acknowledge Dr. Emmanuel Flahaut from the CIRIMAT, University Paul Sabatier, France, for his help in selecting the most relevant CNT physical-chemical properties for this review. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijheh.2020.113472. REL, NIOSH Recommended Exposure Limit (1 μg/m3 of Elemental carbon mass concentration (respiratory fraction)); (S/MW)CNT, (single-/multi-wall) carbon nanotube; EM, electronic microscopy; NR, not reported; PBZ, personal breath zone; LOD, limit of detection; TEM/ SEM, Transmission/Scanning Electron Microscopy. * No EC measurement was performed, REL was compared with EC estimates calculated from CO measurements.

4. Conclusion

References

For the responsible development of nanotechnology, it is important to know and control the risks associated with engineered nanomaterials. Imposing disproportionate measures of exposure control or evoking the precautionary principle is suitable neither for companies nor for workers. Rather, an objective and realistic risks assessment should be preferred, where relevant exposure data are paramount. Our review of occupational exposure to CNTs provided a moderate evidence that currently reported CNT values exceed the NIOSH REL in most workplaces where EC concertation has been measured and reported. Moreover, a moderate evidence was provided on the presence of CNTstructures on TEM/SEM in personal breath zone of workers, which confirms the CNT release and occupational exposure potential in the majority of studies addressing these parameters. Health monitoring of the exposed workers at least, according to a basic medical surveillance scheme, is thus required and should not be delayed while waiting for solving uncertainties on the long- and medium-term effects of the CNTs in humans and the most suitable exposure metric. More standardization in instrumental and analytical choice is warranted as well as in standardization of statistical treatment and reporting of background and workstation exposure levels along with task and job description. The counting of CNTs is consensually recognized as priority in terms of method standardization and automation. The alignment of the UK, Germany and Switzerland in establishing the benchmark value in terms of the CNTs count is evidence of this, as is the necessary confirmatory microscopy analysis when less specific exposure assessment methods are used. Reporting of the exposure results by standardized job titles is also warranted as in risk assessment, exposure assessment and hazard identification are of equal importance and must evolve together. The already initiated harmonization of CNT exposure assessment and result reporting need to continue to favor not only studies in the field, but also to identify companies and workers using CNTs to characterize their exposures as well as monitor their health. This will enable an objective and realistic evaluation of risks associated with CNT applications and an appropriate risk management.

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Funding I. Guseva Canu's professoral allocation provided by the University of Lausanne and research grant No. LIFE17 ENV/GR/000285 provided by the European Union for the NanoEXPLORE project. Declaration of competing interest None to declare. 8

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