Introduction

Engineered nanomaterials (ENMs) are a broad class of materials that are developed to have at least one dimension between 1 to 100 nm and offer unique, size-dependent properties that are not exhibited by their bulk counterparts. ENMs have gained prominence in technological advancements due to their tunable physicochemical characteristics such as melting point, wettability, electrical and thermal conductivity, catalytic activity, light absorption, and scattering effects resulting in enhanced performance [1]. These materials offer the potential for breakthroughs in various applications in biomedicine, electronics, energy storage, textiles, and cosmetics, as well as high-performance intermediates such as coatings and composites for aerospace, automobiles, and construction [2]. Over the last 15 years, ENMs have also been used in a constantly increasing number of consumer and industrial products [3].

As a result, there have been growing concerns about possible adverse health effects from occupational exposure to ENMs. Previous research on ambient air pollution and naturally occurring nanoparticles, as well as animal studies of fine (diameter less than 2.5 μm) and ultrafine particulates (diameter less than 0.1 μm), has shown potential harmful effects. ENMs could have similar novel biological properties that may cause inflammatory and oxidative stress–induced lung injury and translocate to extrapulmonary tissues [4, 5]. Additionally, the term ENM covers a broad class of materials with various modes of action, mechanisms, and specific characteristics that may drive certain health effects [6]. Therefore, fully understanding the toxicity of these materials is a complex task. Furthermore, there has been limited occupational epidemiologic evidence of human health effects from workplace exposures to ENMs [7]. The introduction of ENMs into the work environment may cause unpredictable and potentially serious adverse health effects to exposed workers [8].

Consequently, sampling methodologies and metrics to assess occupational exposures to ENMs have been at the forefront of discussion over the past decade. Currently, there are no consensus measurement methods or exposure metrics to assess occupational exposures to ENMs, but several multi-metric approaches have been suggested by various researchers and international agencies. These approaches include collecting a combination of exposure data using direct reading or online measurement methods and lab-based, offline analyses. Online methods can assess particle number, particle size distribution, surface area, and mass concentration in real time, while offline methods use laboratory-based electron microscopy or a gravimetric/elemental mass analysis [9,10,11,12]. Online methods can provide a quantitative result with a high time resolution for the exposure metric of choice while offline measurement methods refer to the type of aerosol samples collected on a filter or grid and analyzed by a laboratory at a later date. The lack of specificity of the online measurement methods and potential issues with sample loading and the sensitivity of the offline analytical methods combined with the varying physical, chemical, and physicochemical properties of ENMs preclude the idea of using a single exposure metric [10].

It has been nearly two decades since Maynard et al. (2004) published the first ENM exposure assessment at a primary producer of single-walled carbon nanotubes (SWCNT) [13]. Interest in assessing occupational exposures to ENM has continued to grow over the last two decades with more than 50 studies being published internationally since that time. Recently, several comprehensive reviews and commentaries have been published, which have focused on rating the quality of evidence of an ENM exposure. The reviews evaluated the overall quality of the published studies at that time, their measurement techniques, and examined the most commonly reported processes and tasks that resulted in ENM exposures [14,15,16]. Additionally, reviews by Guseva-Canu et al. (2016; 2020) have focused on evaluating the completeness and reliability of exposure data for use in epidemiology and risk assessments specifically for carbon nanotubes (CNT) [17, 18].

Therefore, the goal of this review was to not duplicate past systematic reviews conducted by Debia et al. (2016), Boccuni et al. (2017), Ding et al. (2017), and Guseva-Canu et al. (2016; 2020), but rather to highlight recently published literature between 2015 and 2020 relevant to assessing occupational exposures to ENMs within workplaces. Additionally, this review pays specific attention to the metrics of exposure and instrumentation used to assess exposures, while offering suggestions for future areas of study that will progress this important field of research. We searched the PubMed database by combining search terms related to nanomaterial exposure assessments (e.g., nanomaterial, nanoparticle, exposure assessment, workplace, occupational) with the names of specific ENMs of interest. We first focused our search on the nine most widely used ENMs based on tonnage which included carbon black, amorphous silica, aluminum oxide, barium titanate, titanium dioxide, cerium oxide, zinc oxide, carbon nanotubes and nanofibers, and nano silver before expanding to other emerging ENM such as graphene [19].

We then reviewed the abstracts identified by these searches and selected relevant articles based on the following criteria: (1) occupational exposure data was collected for ENMs; (2) exposures were assessed within industrial workplaces or laboratories performing daily job tasks; and (3) they provided quantitative data on ENM exposures.

Results of the Literature Search

Our initial literature review identified 37 publications assessing occupational exposure to ENMs that were published between 2015 and 2020. Twenty-two of which were not included in the four most recent ENM review articles and are discussed within this review [14, 16,17,18]. The three ENMs that generated the highest volume of new research include titanium dioxide (TiO2), the graphene family of ENMs, and aluminum oxide (Al2O3). We identified ten TiO2 studies and nine graphene studies published between 2015 and 2020. Seven of the studies for each material were not previously covered in other reviews. Six new Al2O3 studies are also included in this review, while recent review articles only included two. ENMs with the fewest recent publications included cerium oxide, zinc oxide, nano clays, nano iron, nano nickel, and nano palladium, each of which only had one exposure assessment publication each.

Carbonaceous Nanomaterials

Carbon Nanotubes and Nanofibers

CNTs have been the most assessed ENM to date, with 27 articles being published on the topic between 2004 and 2018 [18]. Since that time, one additional manuscript has been published that met our inclusion criteria and assessed exposures to MWCNT at a primary manufacturing facility (Table 1). Bressot et al. (2018) collected particle size distribution and particle number concentration (PNC) using a fast mobility particle sizer (FMPS), scanning mobility particle sizer (SMPS), and condensation particle counter (CPC) coupled with the offline analysis method of electron microscopy to verify airborne occupational exposure [20]. However, this site assessment did not use any form of offline mass-based measurement, such as elemental carbon mass which has been successfully utilized by other recent studies and is the exposure metric for the US National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) [18, 21].

Table 1 Carbonaceous nanomaterials: exposure metrics and results
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Graphene

There have been seven new peer-reviewed publications that assessed occupational exposures to graphene (Table 1). Of the seven publications identified, one was conducted at a laboratory/research & development (R&D) facility, five were conducted at primary production facilities, and one assessed exposure at two secondary manufacturing companies associated with the conductive inks and coatings industries.

Two of the recently published graphene studies used online instrumentation to assess the exposure metric of mass, while five reported surface area ranges, and all studies used at least one online measurement instrument to assess PNC ranges. Four of the recently published studies also conducted an offline gravimetric mass analysis, while three of the studies conducted an offline elemental carbon mass analysis. The presence of aerosolized graphene was confirmed via offline electron microscopy analysis in five publications, but no quantitative estimates were provided. However, Vaquero et al. (2019) used electron microscopy to assess morphology but could not confirm the presence of graphene due to the size of agglomerates observed [22•]. Lavicoli et al. (2018) solely focused their assessment on the use of online instrumentation to assess surface area, PNC, and aerosol size distribution information [23].

Carbon Black

Two recent peer-reviewed publications assessed occupational exposure to carbon black and were included in this review (Table 1). Both exposure assessments were conducted at secondary production facilities within the rubber and conductive inks industries. Both studies used online instrumentation to assess mass and PNC, while Loven et al. (2020) used an aethalometer to collect online measurements for carbon black mass [24]. Loven et al. (2020) also collected air samples at the inhalable size fraction for the mass of elemental carbon and confirmed the presence of carbon black via an offline electron microscopy analysis.

Krieder et al. (2015) used an innovative method which involved an online analysis for PNC using the electrical low pressure impactor (ELPI). The study also analyzed the particles collected from the ELPI impactor stages by using an offline electron microscopy method following NIOSH method 7400 to determine the percent of carbon black particles collected per stage [25••]. The percentage was then multiplied by the stage-specific online particle counts to provide an estimate of the PNC for carbon black per size bin.

Nanometal Oxides

Titanium Dioxide

This review includes seven recent peer-reviewed publications that assessed occupational exposures to titanium dioxide (TiO2; Table 2). Two of the exposure assessments were conducted at primary manufacturing facilities that were producing industrial-scale quantities. Three assessments were conducted at secondary manufacturing facilities (metals production, cosmetic retailers, and conductive inks) and two assessments were conducted at laboratory/R&D facilities. Lee et al. (2020) used a novel biological monitoring approach to assess exposures to TiO2 and zinc oxide (ZnO) that measured oxidative stress within cosmetic retail clerks using the urinary biomarker 8-hydroxy-2′-deoxyguanosine (8-OHdG) [26•]. Additional details on Lee et al. (2020) can be found in the ZnO portion of the results section.

Table 2 Nanometal oxides: exposure metrics and results
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The remaining TiO2 exposure studies used a combination of online and offline measurement methods to assess occupational exposures. Two studies used online instrumentation to assess TiO2 mass while three reported exposures using the exposure metric of surface area. Meanwhile, six studies used at least one online instrument to assess PNC ranges or provide information on the aerosol size distribution. Additionally, three studies collected aerosol samples at the respirable or ultrafine/fine particle size fractions for offline gravimetric mass analysis; the metric and sampling method was used for comparison to the US NIOSH Recommended Exposure Limit [27]. The presence of airborne TiO2 was confirmed via offline electron microscopy analysis in six of the seven publications. Additionally, Loven et al. (2020) provided a quantitative exposure estimate via electron microscopy and also examined TiO2 presence or absence on work surfaces [24].

Aluminum Oxide

An additional six peer-reviewed publications that assessed occupational exposures to aluminum oxide (Al2O3) were identified in the literature and included in this review (Table 2). Three of the published site assessments were conducted within laboratory/R&D facilities, while two assessed exposures within primary manufacturers, and one study was conducted at a secondary facility that specialized in lacquering and anodizing aluminum surface treatments.

Four of the included studies used online instrumentation to assess the exposure metric of mass, three assessed exposures using online surface area measurements, and all six reported data on PNCs through the use of multiple instruments. Brenner et al. (2016) used inductively coupled plasma atomic emission spectroscopy (ICP-OES) to assess aluminum particles in the air, under the assumption that all aluminum detected was in the form of Al2O3 [28]. Meanwhile, Brenner et al. (2015) and Glassford et al. (2020) also collected offline mass-based measurements, but did not fully describe the analysis methods [29, 30]. The presence of airborne Al2O3 was confirmed via offline electron microscopy analysis coupled with a chemical microanalysis technique in all six assessments. However, Brenner et al. (2016) also performed a quantitative electron microscopy analysis [28].

Zinc Oxide

Lee et al. (2020) assessed occupational exposures to zinc oxide (ZnO) within cosmetic retail clerks (Table 2) [26]. The study used the urinary biomarker 8-hydroxy-2′-deoxyguanosine (8-OHdG) to quantify oxidative stress. The researchers began by examining commercially available cosmetic products available in Taiwan that contained ZnO and TiO2. They analyzed the content, concentration, and size of the nanoparticles in the cosmetic products using single-particle ICP-MS.

They recruited participants, collected demographic information, exposure surveys, and collected two urine samples from each participant on four separate occasions. This information was used in conjunction with single-particle ICP-MS to calculate daily exposure doses and cumulative risk calculations. The results linked a higher likelihood of chronic occupational cosmetic exposures containing ZnO and TiO2 with higher urinary 8-OHdG levels, but additional research on dermal exposures to these ENMs is needed.

Ferric Oxide

Two recent peer-reviewed publications assessing occupational exposure to ferric oxide (Fe2O3) were identified (Table 2). Both publications used online methods to investigate relationships between number, surface area, and mass concentrations of nanoparticles at primary production facilities. However, Zou et al. 2015 also reported the ratio of cumulative PNC and percentage by mass to assess which of the two characteristics were dominant in two nanometals (Fe2O3 & Al2O3) [31]. Xing et al. (2015) and Zou et al. (2015) both confirmed the presence of Fe2O3 using scanning electron microscopy [31, 32].

Cerium Oxide

Brenner et al. (2015) assessed occupational exposures to cerium oxide (CeO2) within a laboratory/R&D facility that processed wastewater from semiconductor production (Table 2). The assessment focused on the use of online instrumentation to assess exposures using the metric of PNC and collected information on aerosol size distributions. Brenner et al. (2015) also collected samples at the inhalable aerosol fraction for an offline gravimetric mass analysis, but results were below the detection limit [29]. Additional offline analyses were completed by electron microscopy to confirm the presence of aerosolized CeO2 at the facility.

Zirconium Dioxide

Exposures to zirconium dioxide (ZrO2) were assessed by two peer-reviewed publications included in this review (Table 2). Both exposure assessments were conducted at primary production facilities. Glassford et al. (2020) assessed exposures using online instrumentation for PNCs and mass, while Bressot et al. (2018) also assessed exposures using online instrumentation for PNC and to determine aerosol size distributions [20, 30]. Glassford et al. (2020) reported the collection of an offline analysis at the inhalable aerosol size fraction for the airborne mass concentration of Zr, but the method was not clearly described. However, the presence of airborne ZrO2 was confirmed using offline electron microscopy analyses in both publications.

Nanometals

Silver

Three recent peer-reviewed publications assessed occupational exposures to nano silver (Ag) and silver nanowires at primary production facilities (Table 3). Two studies used online instrumentation to assess mass, while three studies used online instruments to assess PNC using a combination of condensation particle counters and optical particle sizers. Garcia et al. (2017) reported airborne silver mass concentrations at the inhalable aerosol size fraction using NIOSH Manual of Analytical Methods (NMAM) 7303 (ICP-AES) and used NMAM 9102 (ICP-AES) to assess silver concentrations from surface samples [33]. Glassford et al. (2020) reported silver mass concentrations at the inhalable aerosol size fraction and collected samples to assess silver concentrations from surfaces, but the analysis methods were not clearly described in the publication [30]. The presence of airborne Ag was confirmed via offline microscopy analysis in all three publications, while Garcia et al. (2017) reported quantitative exposure data [33].

Table 3 Nanometals and other nanomaterials: exposure metrics and results
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Nano Iron, Nickel, and Palladium

Garcia et al. (2017) assessed occupational exposures to nano iron, nickel, and palladium at a single primary production facility by using a combination of online instruments and offline analysis methods to assess the exposure metrics of mass and PNC [33]. The study used NMAM 7303 as an offline analysis method to assess the airborne mass concentrations of iron, nickel, and palladium at the inhalable aerosol size fraction. Garcia et al. (2017) also collected workplace surface samples for offline mass analysis using NMAM 9102 [33]. The presence of all three materials in the air was confirmed and quantified using an offline electron microscopy analysis method.

Other Nanomaterials

Amorphous Silica

Five recent peer-reviewed publications assessed occupational exposures to amorphous silica (SiO2) and were subsequently included in this review. Of the five publications identified, three assessed exposures at laboratory/R&D facilities, one was at a primary manufacturer of amorphous silica, and the other included two secondary manufacturing facilities in the rubber manufacturing industry (Table 3). Four of five studies used a combination of online and offline exposure assessment metrics and methods with the exception of Lavicoli et al. (2018), which did not conduct any offline analyses [23].

Two of the recently published studies used online instrumentation to assess the exposure metric of mass, while two reported surface area measurements, and all five studies used at least one online instrument to assess PNC ranges (Table 3). Krieder et al. (2015) used the ELPI as both an online instrument to collect PNC by size bin and collected the counted particles via offline microscopy analysis that confirmed the presence of SiO2 in 32% of the particles counted [25••]. Boccuni et al. (2020) also collected samples from an impactor but performed a gravimetric mass analysis on the samples and confirmed the presence of SiO2 via microscopy [34•]. Brenner et al. (2016) used NMAM 7501 (X-ray powder diffraction) to report the airborne mass concentration of silica at the inhalable size fraction [28]. The presence of airborne SiO2 was confirmed in all four publications that conducted offline morphology analysis via electron microscopy. Brenner et al. (2016) also used an offline quantitative analysis method to assess airborne PNC via an electron microscopy analysis [28].

Alumino-Silicate Clay

One new peer-reviewed publication was identified that assessed occupational exposures to alumino-silicate clay within a research laboratory using a combination of online and offline methods to assess exposure (Table 3). Koivisto et al. (2018a) used a single online instrument to assess the exposure metric of surface area and PNC simultaneously [35]. The authors also conducted a gravimetric analysis on aerosol samples collected at the respirable aerosol size fraction. The presence of alumino-silicate clay collected from air samples was confirmed using a modified version of NMAM 7402, originally developed for asbestos [35].

Nanocellulose

Two recent peer-reviewed publications assessing occupational exposure to nanocellulose were identified in this review (Table 3). Between the two studies, exposures were assessed at two primary manufacturers of nanocellulose and two laboratory/R&D facilities. Both studies used a combination of online and offline instrumentation and exposure metrics to assess occupational exposures.

Each study used online instrumentation to assess mass and both studies used a condensation particle counter along with an optical particle counter to assess PNC ranges and particle sizes. Glassford et al. (2020) conducted a mass concentration analysis at the inhalable size fraction that used a cesium marker as indication of exposure [30]. Ogura et al. (2020) conducted an offline gravimetric mass analysis at the respirable aerosol size fraction and included an offline elemental carbon analysis using a modified version of NMAM 5040 [36]. Both studies used electron microscopy to confirm the presence of airborne nanocellulose.

Conclusions and Future Research Directions

ENM uses will continue to grow as industries refine their processes and find new applications for these unique materials. As demonstrated throughout this review, a considerable amount of research has been completed since 2015. As more exposure assessment research is conducted, this information will further guide the establishment of consensus sampling and analysis methods for different types of ENMs. This portion of the review will discuss the most prevalent methods applied, provide suggestions for future research, and highlight research methods that were particularly influential to ENM exposure research.

Online instruments are an essential component for assessing exposures in the workplace since they can report data in real time, but as mentioned previously, are not comprehensive due to their lack of particle specificity. These instruments allow safety professionals to expeditiously locate sources of exposures, evaluate control technologies, and monitor concentration profiles in order to better understand workplace exposures [14]. The online instrumentation most frequently used to characterize the exposure metric of mass within the reviewed studies was the DustTrak while the DiSCmini and the AeroTrak were most commonly used to characterize surface area exposures. Meanwhile, the CPC was the instrument most used to assess PNC, and the OPS was commonly used to characterize particle size distributions.

Previously, several authors have considered surface area and particle number counts as important factors in determining potential adverse health effects to ENM exposure [37, 38]. The major disadvantage of using the surface area and particle number count methods reside in the difficulty of distinguishing the target ENM from the background of natural and incidental nanoparticles that may interfere with measurements in the workplace [39, 40]. Considering this critical point, Kreider et al. (2015) used a novel method that can be used to assess all types of ENM by combining the direct reading and low-pressure cascade impactor of the ELPI with offline electron microscopy analysis methods. Krieder et al. (2015) followed NMAM 7400 (asbestos and other fibers by phase contrast microscopy) to determine the percent of carbon black and amorphous silica particles collected per impactor stage [25••]. This unique technique allowed for the quantitative measurement of the nanoparticle of interest in mixed dust environments where many particle types are present.

Meanwhile, offline exposure assessment methods may allow for more ENM-specific quantitative and qualitative exposure data but do not provide real-time data and some analyses can be prohibitively expensive or time consuming to conduct. Currently, there are few established methods for the offline quantitative measurement and analysis of ENMs beyond the US NIOSH Current Intelligence Bulletins for TiO2, Carbon Nanotubes, and a NMAM method for the analysis of CNT by transmission electron microscopy [21, 27, 41]. The use of offline scanning or transmission electron microscopy to either identify the ENM of interest or even quantify exposure to the ENM of interest was nearly ubiquitous among all the recent literature found in this review. Traditionally, manual microscopy-based analysis and classification methods have been cumbersome. However, recent studies have shown that the automatic detection and classification of complex ENM structures are possible and should be a continued area of future research [42].

Several recent studies assessing occupational exposures to carbonaceous nanomaterials (i.e., graphene) and nanometals (i.e., TiO2) reported the concentration of elemental mass associated with the ENM of interest [24, 43,44,45]. This approach was generally applied for TiO2 exposure studies but was also used for other nanometals. The recent inclusion of elemental mass concentrations can provide additional quantitative data and could help progress ENM sampling harmonization assuming that the limits of detection are sufficient.

It is evident that the harmonization of measurement strategies and exposure metrics for ENMs is still under development. Although it appears that for some of the more commercially established ENMs, such as CNT and TiO2, researchers are moving toward consensus on sampling methods and exposure metrics as additional literature is published. For example, there has been a growing number of recent studies for CNT that have used the offline analysis method of elemental carbon mass, coupled with either a confirmatory electron microscopy or a quantitative microscopy analysis method, to associate exposure to CNTs with early biological markers of effect [46,47,48,49]. Additionally, a recent study that found immunological effects due to CNT exposure concluded that the quantitative electron microscopy analysis method was the most sensitive exposure metric [50].

The use of ENMs will continue to be incorporated into consumer and commercial products. They are a broad class of materials that have vastly different material characteristics and potential toxicities. Several general multi-metric exposure assessment approaches have been suggested and are continuing to be used throughout the recently published ENM exposure assessment literature. It is important to continually assess and harmonize ENM exposure assessment approaches, which will enable data pooling and comparison, while also carefully considering the unique material attributes of each individual ENM. Consensus methods for assessing exposures to specific ENMs will continue to emerge as exposure research continues.