Tài liệu Pietroiusti2014

Occupational Medicine 2014;64:319–330 doi:10.1093/occmed/kqu051 In-depth review Engineered nanoparticles at the workplace: current knowledge about workers’ risk A. Pietroiusti and A. Magrini Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Correspondence to: Antonio Pietroiusti, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Tel: +39 06 2090 2204; fax: +39 06 2090 2212; e-mail [email protected] Aims To perform an in-depth review of the state of art of nanoparticle exposure at work. Methods Original articles and reviews in Pubmed and in principal databases of medical literature up to 2013 were included in the analysis. In addition, grey literature released by qualified regulatory agencies and by governmental and non-governmental organizations was also taken into consideration. Results There are significant knowledge and technical gaps to be filled for a reliable evaluation of the risk posed for workers by ENPs. Evidence for potential workplace release of ENPs however seems substantial, and the amount of exposure may exceed the proposed occupational exposure limits (OELs). The rational use of conventional engineering measures and of protective personal equipment seems to mitigate the risk. Conclusions A precautionary approach is recommended for workplace exposure to ENPs, until health-based OELs are developed and released by official regulatory agencies. Key words Engineered nanoparticles; health effects; metrics; occupational exposure limit; workplace exposure. Introduction Nanotechnology is a recognized cross-cutting technology, whose products, called engineered nanoparticles (ENPs), are characterized by a size range between 1 and 100 nm. At this dimension, the material acquires novel physicochemical properties, which are very useful for industrial and biomedical purposes. A growing number of workers are estimated to be involved in work processes directly or indirectly linked with ENPs, and according to a recent projection, 6 million workers will be potentially exposed to ENPs in 2020 [1]. The European Commission (EC), aiming to set a clear definition for nanomaterials for legislative purposes, recently defined nanomaterials as ‘natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm–100 nm [2]’. This definition has implications both for classifying exposed people (i.e. those managing or processing materials with ≥50% ENPs) and for the assessment of exposure (in fact, knowledge of number concentration is needed to establish exposure). As emphasized by the EC, the definition has legislative purposes; therefore, health effects may occur even when nanoparticle percentage is <50%. A literature review commissioned by the European Agency for Safety and Health [3] identified a number of occupational activities with substantial probability of exposure to ENPs (see Box 1). A list of ENPs having relevance in the workplace was released by the Working Party on Manufactured Nanomaterials, established in 2006 by the Organization for Economic Cooperation and Development (OECD) [4]. (see Box 2). Concern about possible adverse health effect of ENPs is raised by previous research on ambient or natural © The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: [email protected] Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 Background The novel physicochemical properties of engineered nanoparticles (ENPs) make them very attractive for industrial and biomedical purposes, but concerns have been raised regarding unpredictable adverse health effects in humans. Current evidence for the risk posed by ENPs to exposed workers is the subject of this review. 320  Occupational Medicine Box  1. Occupational activities with substantial probability of worker exposure to ENPs •• Construction Box  2. ENPs that have relevance in the workplace •• Single-walled carbon nanotubes •• Multi-walled carbon nanotubes •• Fullerene •• Carbon black •• Aluminium oxide •• Dendrimers •• Titanium dioxide, TiO2 •• Zinc oxide •• Cerium oxide •• Iron •• Silver •• Gold •• Layered silicates (nanoclays) •• Silicon dioxide nanoparticles [5,6] and by toxicological in vitro and in vivo studies [7], showing that ENPs have novel biological properties such as the translocation to secondary target organs, poor clearance by macrophages, ability to be transported through the axons of sensory neurons and access to intracellular structures such as mitochondria and nuclei. These properties, not shared by the bulk form of the same material, may cause additional damage or may induce new adverse health effects. Thus, the introduction of ENPs in the work environment may cause unpredictable and possibly serious adverse health effects to exposed workers. Methods Given the relatively recent introduction of nanotechnology, there is comparatively little data about the risk they may pose to workers. Nevertheless, accumulating (i) Evidence of clinically relevant adverse health effects of ENPs in workers (ii) Methods and strategies of ENPs evaluation in the occupational setting (iii) Occupational exposure limits (OELs) (iv) Available data about exposure to ENPs at work (v) Protocols of health surveillance (vi) Control of exposure To identify the pertinent publications, we consulted the database Pubmed, Scopus and ISI web of knowledge using the following search terms: ‘Nanoparticle (or nanomaterials or manufactured nanoparticles) and: a) work (or workplace, or workers, or occupational setting, b) workplace measurement (or exposure limit), c) adverse health effects in workers, d) health surveillance protocols, e) exposure control’. In some cases, original articles and reviews were identified through the references of recently published papers or by using as search term the name of authors internationally known as being experts in the field. Furthermore, we consulted the positions on the above reported topics of institutions devoted to the assessment of safety at work such as OECD and US National Institute for Occupational Safety and Health (NIOSH). Results Evidence of clinically relevant adverse health effects of ENPs in workers Very few data on health effects of ENPs in workers are currently available, and these data generally refer to very high accidental exposure or to concomitant exposure to other chemicals with a high potential to cause adverse health effects. In 2009, Song et al. [8] reported on seven young female Chinese workers exposed to polyacrylate spray paint who developed unusual pleuropulmonary symptoms, leading to death in two of them. A worksite survey showed emission of ENPs during the activities of these workers, and ENPs were identified in pulmonary and pleural cells, as well as in pleural effusions. In a subsequent report [9], the authors were able to elucidate the chemical nature of the nanoparticles found in the tissue specimens, identifying them as silica ENPs. Of note, silica ENPs were present in the coatings used at these patients’ worksite. Adverse health effects in humans after exposure to ENPs are the subject of two recent case reports. TiO2 ENPs were detected in the pulmonary cells of a 58-yearold man who developed bronchiolitis obliterans organizing pneumonia after working for 3 months with polyester powder paint containing TiO2 ENPs [10]. However, the Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 (e.g. products improving wear resistance and insulation materials) •• Health care (e.g. drug-delivery systems and tissue engineering) •• Energy (e.g. low-wastage storage of energy and new generation photovoltaic cells) •• Automobile and aerospace industry (e.g. reinforced and stronger materials and fuel additives •• Chemical industry (e.g. catalysts and selfcleaning surfaces) •• Electronics and communication (e.g. optical/optoelectronic components and ultra fast compact computers) evidence may allow one to identify some trends in the different steps of the risk evaluation process. Our aim was to highlight these trends, after an extensive review of the available literature. In detail, we examined the following topics: A. Pietroiusti and A. Magrini: Engineered Nanoparticles at the Workplace  321 Methods and strategies of ENPs evaluation in occupational setting Workers’ exposure to ENPs might occur during their production, during their downstream use for further processing or dispersion into products and during further application or treatment of ENP-embedded products [12]. Different degrees of exposure may occur according to the way in which the specific activities are performed: open or closed production process; processing of the ENPs themselves (liquid or powder) or of ENPs embedded in a matrix; removal of produced ENPs through filtration or opening of a reactor; type of handling of removed material (pelleting, cleaning, drying, grinding, milling); and bagging and shipping in liquid suspension or dry powder. Seemingly conflicting findings regarding the workplace evaluation of ENPs exposure may at least in part be explained by the different steps and procedures taken into consideration. The issue of the proper metric for evaluating workers exposure to ENPs is still unresolved [13]. ENP exposure is in fact characterized by a high number of particles with a negligible mass, thus the use of the traditional mass concentration metric may fail to discriminate them from background levels. Several workplace surveys and some proposed OELs are, however, expressed in terms of mass concentration [14]. Two alternative metrics for ENP evaluation in worksites are surface area concentration and number concentration. Surface area concentration is likely to be the best metric for predicting health effects of ENPs in humans, since experimental toxicological studies suggest that their biological effects are mainly related to this parameter. Due to technical reasons, very few reports on the surface area concentration of ENPs in the workplace are currently available. By contrast, the number concentration is the most widely used method and, as stated above, is indirectly supported by the definition of exposure released by the EU Commission. A strategy recently suggested by NIOSH for the evaluation of ENPs at work (nanoparticle emission technical assessment (NEAT)), is based on number concentration [15] and includes three subsequent steps: at the first step (tier 1), information is gathered at the workplace according to established industrial hygiene practices. If release of nanoscale aerosols cannot be excluded, a basic exposure assessment is performed, using a limited set of easy-to-use equipment (tier 2). Briefly, two portable instruments, an optical particle counter (OPC) and a condensation particle counter (CPC) are used in this step. OPC provides a count concentration in the size range of 300–20 000 nm and allows for the determination of both number concentration and particle size distribution. This instrument is therefore not useful for the assessment of nanoparticles but provides size distribution for particles >300 nm. CPC counts particles >10 nm with an upper limit of about 1000 nm. CPC is useful for detecting particles in the nano-sized range, but it does not provide a size distribution by separating particles into size range. When OPC and CPC are used together, there is an overlap of the two instruments in the range 300–1000 nm, making possible an indirect evaluation of particles <300 nm by subtracting all OPC counts in the size bins ranging from 300 to 1000 nm from the counts between 10 and 1000 nm made by CPC. If ENP concentration is below a certain threshold value in comparison with background levels (increase <20–25% during activity), no further investigations may be necessary; otherwise, the latest state-of-the-art measurement technology should be used to evaluate exposure (tier 3). The limitation of this approach is that it does not allow an evaluation of particles with a size <10 nm and that it includes particles in the size range 101–300 nm, which, strictly speaking, are not nanoparticles. On the other hand, ENPs tend to aggregate or agglomerate in the air, thus forming particles which may exceed 100 nm. For this reason, there is a suggestion that the workplace risk assessment of ENPs should take into account particles and agglomerates with a diameter of ≤300 nm [16]. One problem with the number concentration metric is that ENP number may fluctuate widely on different days, so it is not clear whether mean, cumulative or peak concentration is the most relevant measure. An additional concern is represented by limitations in sensitivity and comparability of currently available instruments. This issue has been extensively reviewed by Khulbush et al. [17] and will not be considered here. More important, instruments measuring workers’ personal exposure are in their infancy, although efforts are in progress. We were able to identify only 11 reports in the literature in which personal exposure data have been obtained [18– 28]. Finally, a problem is posed by the interference of incidental nanoparticles generated by concomitant work processes. Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 actual exposure of the worker remains unknown, and a causal association is not supported by the data provided. In the second case report [11], a young man died from adult respiratory distress syndrome 13  days after exposure to nickel ENPs sprayed onto bushes for turbine bearings. At autopsy, nickel ENPs were detected in the alveolar macrophages of the worker. It was estimated that during the spraying activity the worker inhaled about 1 g of nickel particles, a huge amount, which would had been deleterious for lungs independently from the size of nickel particles. In conclusion, the above reported studies do not allow one to confirm or exclude a particular risk posed by nanoparticles for workers exposed to this material. They suggest, however, that these particles are at least as toxic as their corresponding bulk form. 322  Occupational Medicine Occupational exposure limits Where inadequate information on a product is available, the precautionary principle must be applied (in accordance with EU Communication of February 2000), and the substance must be assumed to have a hazardous effect. This is undoubtly the case for ENPs. However, the ideas on how to make the precautionary principle operational in the case of exposure to ENPs vary widely: it spans the zero exposure option of trade union groups from France and the UK [16], the control banding concepts combining a qualitative evaluation of the hazard posed by the nanoparticle with an estimate of the probability of workers exposure [29–34], and the development of OELs. This latter approach is gaining popularity, and several unofficial OELs for ENPs are being proposed by national organizations. The background upon which these OELs have been developed may differ in some cases, which may explain the different limits for the same ENP recorded in some cases. Another important difference concerns the size range of the particles to which these OELs refer. According to the German Social Accident Insurance (IFA), it should be strictly limited to particles in the range 1–100 nm [35], whereas Safe Work Australia (SWA) suggests also including aggregates and agglomerates having a size >100 nm, leaving however the upper limit undefined [36]. In Table 1, we report a summary of the currently proposed limits for the various ENPs by national institutions. For this purpose, ENPs are classified into different risk groups, which may vary according to different organizations. The concept underlying these classifications is that for almost all of the categories of ENPs identified, it is a reasonable assumption that they have a hazardous potential greater than that of the bulk form of the same material. In the British Standard Institute (BSI) approach [37], four groups provide a basis for categorization of nanomaterials (see Box 3). Box 3. Categorization of nanoparticles •• Fibrous: a high aspect ratio insoluble nanomaterial; •• CMAR: any ENP already classified in its larger particle form as carcinogenetic, mutagenic, asthmagenic or reproductive toxin; •• Insoluble: insoluble or poorly soluble nanomaterials not in the fibrous or CMAR category; and •• Soluble: soluble nanomaterials not in fibrous or CMAR category. The value of 10 000 fibres/m3 recommended by BSI for fibrous ENPs is derived from the British guide value for asbestos during remediation work and is expressed as number concentration only. By contrast, for CMAR ENPs (whose bulk form has recognized carcinogenic, mutagenic, asthmagenic or reproduction toxic effects), the recommended limits are expressed as mass concentration only, and a general safety factor of 0.1 (10 times lower) compared with the existing OEL for the bulk form is suggested. For insoluble, biopersistent nanoparticles, BSI indicates limits based on both mass and number concentrations. For mass concentration values, a general safety factor of 0.066 (15 times lower) compared with the existing OEL for the bulk form is suggested, whereas the proposed number concentration has as reference 20 000 particles/ml, which is the lower end of the UK urban pollution range (20 000–50 000 particles/ ml). Mass-based limits are suggested for soluble ENPs, and a safety factor of 0.5 (i.e. 2 times lower) compared with the existing OEL for the bulk form is suggested. The IFA and the Dutch Minister of Social Affairs and Employment (DMSAE) [16] proposed OELs are mainly based on number concentration. For fibrous ENPs (i.e. carbon nanotubes (CNTs)) the limit is the same as that of BSI. However, the limit for non-rigid CNTs, for which, according to the manufacturer, asbestos-like properties can be excluded, is the same as that of biopersistent ENPs; in this group, two distinct ENP subgroups are identified: those having a density higher or lower than 6000 kg/m3. For the group having the higher density, the proposed limit is 20 000 000 particles/m3, whereas a limit of 40 000 000 particles/m3 is proposed for the other subgroup. The rationale underlying these suggested OELs resides in the fact that the proposed limit of number concentration for low- and high-density nanoparticles corresponds to a mass concentration of 0.1 mg/m3. Of note, no distinct group of CMAR ENPs is provided in the IFA and DMSAE classification: based on their density, some of them are included in the low density group and some others in the high-density group. Finally, no safety factor is proposed by IFA and DMSAE for soluble and liquid ENPs, for which the OEL is the same as that of the bulk form. Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 In summary, despite the progress made in recent years on measurement techniques and strategies for exposure assessments, several gaps need to be filled. At the current state of knowledge and technical development, a multiparametric approach including the assessment of mass concentration, surface area concentration and number concentration, followed by physicochemical characterization would be ideal. Clearly, this costly and technically demanding strategy cannot be transferred to the real world, and probably a measurement approach based on number concentration seems the most practical one. Another urgent step is the development and testing of personal monitoring devices delivering reliable results that can be used in health studies and/or for risk management. The development of realistic exposure scenarios is also needed for comparative assessments of different tasks and processes. A. Pietroiusti and A. Magrini: Engineered Nanoparticles at the Workplace  323 Table 1.  Proposed workplace exposure limits for different ENPs (all data refer to concentration per cubic metre, when not otherwise specified) ENPs BSI (UK) IFA (Germany) DMSAE (The NIOSH Netherlands) (USA) SWA (Australia) AIST (Japan) KML (Korea) Fibre-like ENPs   Rigid, biopersistent 104 f 104 f CNTs   Fibre-like metal oxides 104 f 4 × 107 p   CNTs with explicitly excluded asbestos-like effects Biopersistent granular ENPs with a density <6000 kg/m3   Titanium dioxide 4 × 107 p 0.066× WEL* 4 × 107 p   Carbon black 4 × 107 p 0.03× Australian inhalable 0.61 mg or 0.1× Australian respirable WEL 3 mg 3.5 mg 4 × 107 p 2 mg (fumed silica) 4 x 107 p 0.03× Australian inhalable 0.39 mg or 0.1× Australian respirable WEL 0.03× Australian inhalable or 0.1× Australian respirable WEL  Fullerene   Zinc oxide, aluminium 0.066× WEL* or 4 × 107 p oxide, dendrimers, 2 × 107 p polystyrene, nanoclay Biopersistent granular ENPs with a density >6000 kg/m3   Cerium oxide, gold, 0.066× WEL* or 2 × 107 p iron, iron oxide, silver, 2 × 107 p cobalt, lanthane, lead, antimony oxide, tin oxide Insoluble ENPs for which WEL* is not available CMAR ENPs 2 × 107 p   Nickel, cadmium 0.1× WEL* containing quantum dots, chromium VI 4 × 107 p   Beryllium, arsenic, 0.1× WEL* zinc chromate CMAR ENPs for which WEL* is not available Liquid and soluble ENPs   Fat, hydrocarbons, Same WEL* syloxane   Sodium chloride 0.5× WEL* Same WEL*   Other soluble ENPs 0.5× WEL* Same WEL* Soluble ENPs for which WEL* is not available 0.007 mg 105 f 0.03 mg 105 f 4 × 107 p 4 × 107 p 2 × 107 p 0.3 mg 0.03× Australian inhalable or 0.1× Australian respirable WEL 0.3 mg 2 × 107 p 0.1× WEL* 4 × 107 p 0.1× WEL* 0.003 mg Same WEL* Same WEL* Same WEL* 0.5× WEL* 0.5× WEL* 1.5 mg f, fibres; p, particles; WEL*, work exposure limit of coarse material. The SWA [36] proposed OELs are mainly based on mass concentration, except for fibrous ENPs. The proposed number concentration limit for this ­material (100 000 particles/m3) is 10 times higher than that proposed by BSI, IFA and DMSAE. This is due to the fact that 100 000 particles/m3 is the exposure limit for asbestos in Australia. Furthermore, technical reasons underlie this difference: the Australian association argues that in this way ‘a higher number of fibres will be counted by electron microscopy which is needed to resolve fine fibres, e.g. carbon nanotubes’. For CMAR ENPs, SWA suggests the same safety factor of 0.1 proposed by BSI, except for CMAR ENPs for which no worker exposure limit (WEL) is available for the bulk form: in this case, a fixed exposure limit of 0.03 mg/m3 is suggested. For insoluble biopersistent ENPs, a fixed limit Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014  Silica 0.066× WEL* or 4 × 107 p 2 × 107 p 0.066× WEL* or 4 × 107 p 2 × 107 p 0.066× WEL* or 4 x 107 p 2 × 107 p 104 f 324  Occupational Medicine 0.33  μg/m3 or 4000 particles/cm3, chronic exposure 0.098  μg/m3 or 1200 particles/cm3; effects on liver: 0.67 μg/m3 or 7000 particles/cm3); and titanium dioxide (17 μg/m3). All of the above reported OELs are 8-h time-weighted average standard except for the NIOSH exposure limit for titanium dioxide, which refers to 10 h/day (40 h/week). It should be considered, however, that the most probable exposure in the workplaces is represented by transient spikes occurring during some workplace procedures and that short-term peaks of natural or ambient nanoparticles have been found to be associated with cardiovascular effects [43]. Taking this into account, the American Conference of Governmental Industrial Hygienists established that a nanotechnology process could be considered to require further assessment if (i) short-term exposures exceed 3 times the particle control value for more than a total of 30 min per 8-h working day or (ii) a single shortterm value exceeds the particle control value by 5 times [44]. This issue was also considered at a recent international workshop in which participants agreed on the need of risk assessment for exposure to ENPs over a 15-min TWA (time weighted average) period equal to twice the 8-h OEL [16]. A strategy for the utilization of the available OELs has been suggested by SWA [36]. This strategy includes six steps, listed in order of priority (see Box 4). In conclusion, the rational use of provisional OELs proposed for ENPs may be advisable in occupational settings where exposure to this material is possible. OELs represent a warning level: when they are exceeded, exposure control measures should be taken. As such they may help the employer to ensure his compliance with his legal duty to manage the health and safety aspects of ENPs in the workplace according to the state of the art in technology and science. Box 4. Strategy for utilization of the available OELs A. Company’s control limits, if they are more stringent than other proposed regulatory limits. B.  National workplace exposure limits, if available. C.  Workplace exposure limits released by another country. D. Proposed workplace exposure limits derived from research results. E. Benchmark exposure levels which have some consideration of health effects. F. Local particle reference values derived from characterizing background particle levels. Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 is proposed by SWA for fumed silica, carbon black and ENPs for which WEL for the bulk form is not available, whereas a safety factor of 0.03 or 0.1 (in reference to the Australian WEL for inhalable and respirable particles, respectively) is suggested for the other ENPs. Similarly to BSI, the SWA proposes a safety factor of 0.5 for soluble ENPs. A fixed value of 1.5 mg/m3 is suggested for soluble ENPs for which no WEL is available for the bulk form. The NIOSH, the Japanese New Energy and Industrial Technology Development Organization (AIST) and the Korean Ministry of Labour (KML) propose mass concentration-based OELs for a limited number of ENPs. In the case of CNTs, the exposure limit proposed by NIOSH is 0.007 mg/m3 and is based on risk estimates developed from animal data indicating that workers may have >10% excess risk of developing early-stage pulmonary fibrosis if exposed over a full working lifetime to these concentrations [38]. Another ENP for which NIOSH developed an exposure limit is titanium dioxide [39]. The proposed limit of 0.3 mg/m3 is based upon toxicological findings for the avoidance of lung cancer. Of note, the number concentration of 40 000 000 particles/ m3 proposed by IFA and DMSAE for this ENP would correspond to a mass concentration of 0.011 mg/m3 for a TiO2 particle 50 nm in size, which is substantially below the value proposed by NIOSH. The mass-based OELs for CNTs and titanium dioxide also developed by AIST [40] refer to a subchronic exposure period of 15  years and are in both cases less stringent than those proposed by NIOSH: 0.03 mg/m3 for CNTs and 0.6 mg/m3 for TiO2. AIST also proposed an exposure limit for fullerenes of 0.39 mg/m3. Finally, the only exposure limit proposed by the KML [19] regards carbon black and is slightly higher than the comparable limit released by SWA: 3.5 mg/m3 versus 3 mg/m3. In addition to these national workplace exposure limits, other OELs have been developed by some companies and by research groups. BASF adopts an internal no observed effect level for CNTs of 0.1 mg/m3 based on a subchronic inhalation study on Wistar rats; Nanocyl in Belgium reports a value of 0.0025 mg/m3 for the multiwalled CNTs which it manufactures, and Bayer Material Science states a manufacturer’s recommendation of 0.05 mg/m3 in the material safety data sheet for Baytubes C 150 P [41]. As far as research group data are concerned, a series of derived no effect levels have been proposed as outcomes of the ENRHES project (Engineered Nanoparticles: Review of Health and Environmental Safety) [42]. They concern fullerene (44  μg/m3 for acute exposure and 0.27  μg/m3 for chronic exposure), CNTs (effects on the lung: acute exposure 201  μg/m3, chronic exposure 33.5  μg/m3; effects on the immune system: acute exposure 4 μg/m3, chronic exposure 0.67 μg/m3), silver (particle size 18–19 nm, effects on lung: acute exposure A. Pietroiusti and A. Magrini: Engineered Nanoparticles at the Workplace  325 Exposure to ENPs at work (i) Personal breathing devices may show quite different values than those detected by static devices [22]. This finding supports the need for the development of such detection techniques in order to obtain a more accurate assessment of the true risk for workers. (ii) In the vast majority of the cases, the surveys were performed in low-size manufacturing facilities producing relatively low amounts of material. With the expected increased production, the exposure risk for workers might increase. (iii) Number concentration was by far the more frequently used metric. Until reliable, easy-to-use and cheap devices are developed, this metric should be the reference, in order to allow comparability of the data. It should be noted, however, that some of the proposed OELs are expressed as mass concentration, so this metric may represent an alternative or an integration to number concentration. Surface area concentration still has limited use, and, overall, no proposed OEL has been developed in relation to this metric. Its use should therefore be reserved to the research field. (iv) Analysis of size distribution, frequently associated with morphological characterization, showed that agglomerated nanoparticles, sized >100 nm in their lowest dimension, were dominant in the aerosol. Control of exposure There is preliminary inference that ENPs follow the classical laws of aerosol physics, fluid dynamics and filtration theory and that enclosure of the process with efficient ventilation may be an effective means to reduce exposure [59]. In fact, during nanometal oxide reactor cleanout, the average percent reduction in airborne particulate was close to 100% by use of local exhaust ventilation and custom-fitted flange [61,62]. In a laboratory case study, the use of benchtop enclosures prevented the release of carbon nanoparticles during the procedure of dispersion in a liquid [63]. The enclosure was placed on a ventilated benchtop (100 ft/min). Before installation of exposure controls, airborne multi-walled carbon nanotubes bundles were observed by transmission electron microscope, and none were detected in the samples collected after the enclosure was installed. A study of laboratory fume hoods showed that the hood design affects the nanoparticle release, and an aircurtain hood design (with a different airflow pattern) significantly reduced workers’ exposures [64]. As far as personal exposure protective equipment is concerned, a study of the filtration performance of a NIOSH N95 respirator showed that it meets the NIOSH respirator certification criteria (>95% filtration efficiency), although the most penetrating particle size was 50 nm in diameter (~2% filter penetration) [65]. A more recent investigation of the same group showed that a mechanical filter would offer a relatively higher filtration performance for nanoparticles than an electrostatic counterpart rated for the same filter efficiency [66]. Thus, it seems that traditional engineering control measures may remove ENPs as effectively as they do fine particles. However, further confirmatory data are needed. Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 Three literature reviews on ENPs occupational exposure have been published by Kaluza et al. [3], Brouwer et al. [45] and Kuhlbusch et al [17]. The most recent review took into account 25 studies covering a wide range of ENPs, including the majority of those prioritized by the OECD. However, most examined studies do not refer to OELs or to NEAT, making interpretation of the data difficult in terms of workers risk. After the publication of the above mentioned reviews, 21 workplace surveys regarding possible workplace exposure to 26 ENPs have been published. Some of these articles refer to proposed OELs or to NEAT and are listed in Table 2. The present analysis shows that under certain circumstances (maintenance activity, open gas-phase production process, open handling of nanopowders) a release of ENPs may occur. Although the possible exposure to 26 ENPs was analysed, CNTs/carbon nanofibres were by far the most frequently studied ENPs, a finding in keeping with previous reviews. Personal exposure was evaluated in seven studies regarding nine ENPs, whereas no information on this detection technique was available in previous reports. Some of the reviewed surveys explicitly refer to proposed OELs. Once again, no such information was available in previous reviews. The following considerations are elicited by the analysis of these surveys: This fact raises the possibility that workers’ exposure to ENPs is actually an exposure to the bulk form, therefore exempt from the possible peculiar toxic effects linked to their size. On the other hand, ENPs may undergo de-agglomeration processes once they come into contact with pulmonary cells [60], so local and systemic size-related effects are possible. (v) Traditional engineering processes (chemical fume hoods, enclosed production processes, custommade gloveboxes and high-efficiency particulate air-filtered vacuums) generally allowed good control of workers’ exposure, although in some cases their improper use (or non use) has led to workers’ exposure exceeding the proposed OELs. (vi) The pattern of exposure is generally characterized by transient high peaks, linked to specific operations. The recently proposed limits for short-term exposure are therefore of great relevance in this context. 326  Occupational Medicine Table 2.  ENPs, methods and main findings of the analysed workplace surveys No. of reports Personal sampling Metrics No. of reports showing exposure Remarks References CNTs/CNFs 12 4/12 NC: 12/12 MC:8/12 SAC:2/12 9/12 Transient high peaks of mainly aggregated ENPs Titanium dioxide 5 2/5 NC: 5/5 MC:3/5 SAC:1/5 4/5 Low-level exposure, in all cases below the proposed OELs Silver 4 2/4 3/4 Silicon 2 0/2 Silica 2 1/2 Transient high peaks of single (non-aggregated) ENPs in one case. Transient peaks of both aggregated and nonaggregated ENPs Transient high peak in one case Aluminium 2 0/2 NC: 4/4 MC: 2/4 SAC: 0/4 NC: 2/2 MC: 0/2 SAC: 0/2 NC: 2/2 MC: 1/2 SAC: 0/2 NC: 2/2 MC: 0/2 SAC: 0/2 Lee et al. [19], Birch et al. [22], Dahm et al. [27], Lee et al. [28], Morawska et al. [36], Debia et al. [46], Fleury et al. [47], Ling et al. [48], Methner et al. [49], Ogura et al. [50], Ogura et al. [51], Ogura et al. [52] Curwin and Bertke [21], van Broekhuizen et al. [24], Morawska et al. [36], Yang et al. [53], Koivisto et al. [54] Lee et al. [26], Lee et al. [28], Ling et al. [48], Zimmermann et al. [55] Zimmermann et al. [55], Wang et al. [56] Copper 2 0/2 NC: 2/2 MC: 0/2 SAC: 0/2 2/2 Nanocellulose 1 0/1 1/1 Zinc oxide 1 0/1 Nanoclays 1 0/1 Cerium oxide 1 0/1 Chromium 1 0/1 Cobalt 1 0/1 Aluminium oxide 1 1/1 Zinc 1 0/1 Germanium 1 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 1/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 1/1 SAC: 1/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 2/2 2/2 2/2 Transient high peaks of single (non agglomerated) ENPs in one case. Transient high peaks of single (nonagglomerated) ENPs in one case. Very slight increase van Broekhuizen et al. [24], Tsai et al. [57] Debia et al. [46], Zimmermann et al. [55] Debia et al. [46], Zimmermann et al. [55] Vartiainen et al. [58] 1/1 Slight increase, well below proposed OELs Ling et al. [48] 1/1 Transient high peaks Morawska et al. [36] 1/1 Transient high peaks of aggregated ENPs Leppänen et al. [59] 1/1 Transient high peaks of single (non-aggregated) ENPs Transient high peaks of single (non-aggregated) ENPs Transient peaks of aggregated ENPs, below proposed OELs Transient high peaks of single (non-aggregated) ENPs Transient high peaks of single (non-aggregated) ENPs Zimmermann et al. [55] 1/1 1/1 1/1 1/1 Zimmermann et al. [55] Curwin and Bertke [21] Zimmermann et al. [55] Zimmermann et al. [55] Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 ENPa A. Pietroiusti and A. Magrini: Engineered Nanoparticles at the Workplace  327 Table 2.  (Continued) ENPa No. of reports Personal sampling Metrics No. of reports showing exposure Remarks References NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 1/1 SAC: 1/1 NC: 1/1 MC: 1/1 SAC: 1/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 1/1 SAC: 0/1 NC: 1/1 MC: 0/1 SAC: 0/1 NC: 1/1 MC: 1/1 SAC: 1/1 NC: 1/1 MC: 1/1 SAC: 1/1 1/1 Transient high peaks of single (non-aggregated) ENPs Transient high peaks of single (non-aggregated) ENPs Transient peaks of aggregated ENPs, below proposed OELs Transient peaks of aggregated ENPs, below proposed OELs Transient high peaks of single (non-aggregated) ENPs Transient peaks of aggregated ENPs Zimmermann et al. [55] 1 0/1 Nickel 1 0/1 Calcium oxide 1 1/1 Iron oxide 1 1/1 Platinum 1 0/1 Carbon black 1 0/1 Calcium carbonate 1 0/1 Magnesium oxide 1 1/1 Yttrium oxide 1 1/1 1/1 1/1 1/1 1/1 1/1 1/1 1/1 1/1 Transient high peaks of single (non-aggregated) ENPs Transient peaks of aggregated ENPs, below proposed OELs Transient peaks of aggregated ENPs, below proposed OELs Zimmermann et al. [55] Curwin and Bertke [21] Curwin and Bertke [21] Zimmermann et al. [55] Tsai et al. [57] Tsai et al. [57] Curwin and Bertke [21] Curwin and Bertke [21] CNTs/CNFs, carbon nanotubes/carbon nanofibres; NC, number concentration; MC, mass concentration; SAC, surface area concentration; OEL, occupational exposure level. Several ENPs were sometimes concomitantly analysed in the same study. a Health surveillance Occupational health surveillance consists of hazard surveillance and medical surveillance and can occur at the workplace or at population level. At the current stage of knowledge, hazard surveillance would involve collecting information on which ENPs are being manufactured or handled and where in the workplace exposure might occur. This determination is mostly a matter of management judgment, supplemented by environmental measurements and worker input. Assessing the health of nanomaterial workers is a critical component of responsible development of the technology, and both exposure registries and development of epidemiological studies are recommended [67]. Exposure registers involve the enrolment of workers to collect information about their exposure so that research can eventually be conducted and timely and targeted risk communication, intervention or advice can be provided. Exposure registers may serve as the basis for conducting prospective studies of workers exposed to ENPs. However, carrying out epidemiologic studies of nanotechnology workers will be difficult because of the diversity of the workplaces and types of ENPs. In spite of these limitations, NIOSH recently began a study of US workers in facilities that produce or use engineered carbon nanoparticles [68,69]. Collected data include respirable particle mass, number and active surface area; personal fullshift daily exposure and targeted sampling of the tasks associated with the highest exposures. A similar study is being developed in France [70]. Currently, it is not clear that, beyond hazard surveillance and routine medical surveillance, there is any specific medical testing that is warranted for workers potentially exposed to ENPs. According to the American College of Occupational and Environmental Medicine [71], it is uncertain whether screening methods commonly used in medical surveillance, such as spirometry, will have the sensitivity and specificity to detect potential early adverse effects from exposure to nanoparticles. Other more sensitive tests, such as cytokine measurements might be more reliable. However, specific biological markers of exposure or response to ENPs suitable for surveillance have not been identified. A  promising approach may come from the utilization of ‘omics’ which consist of the mapping of Downloaded from http://occmed.oxfordjournals.org/ at University of Hawaii at Manoa Library on August 17, 2014 Gold 328  Occupational Medicine Conclusions Uncertainties still exist regarding several aspects of the risk posed by ENPs for workers. The main grey areas are the development of reliable and easy-to-use instruments for their measurement in the workplace, the possibility of obtaining personal exposure evaluations and the quantification of the additional health risk they may pose to workers in comparison with the bulk form of the same material. In spite of these limitations, provisional OELs have been developed by non-official organizations. Although different limits have been proposed in different countries, they may nevertheless provide a good reference to check the reliability of existing engineering and personal protective measures for exposed workers. In fact, available data coming from workplace surveys indicate that substantial exposure may occur whenever the implementation of protective measures is inappropriate or neglected. Key points •• Release of engineered nanoparticles may occur in the workplace. of exposure is still far from optimal, given the uncertainties in metrics and the relatively poor performance of currently available instruments. •• More severe adverse health effects than those caused by larger particles may be expected, although no evidence of this is yet available in humans. •• A precautionary approach, possibly based on provisional occupational exposure levels, is probably the best way to minimize the risk in potentially exposed workers. •• Assessment Funding The authors are supported, in part, by the European Commission (FP7-MARINA: grant agreement 263215; FP7 NANoREG: grant agreement 310584) and the Italian Ministry of Health (“Finalizzato Salute” project RF-2009-1536665). Conflicts of interest None declared. References 1. Roco MC. The long view of nanotechnology development: the National Nanotechnology Initiative at 10 years. Journal Nanopart Res 2011;13:427–445. 2. EC. 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