International landscape of limits and recommendations for occupational exposure to engineered nanomaterials

Journal Pre-proof International landscape of limits and recommendations for occupational exposure to engineered nanomaterials ´ Carolina Rodr´ıguez-Ibarra, Alejandro Deciga-Alcaraz, Octavio ´ Estefany I. Medina-Reyes, Norma L. Ispanixtlahuatl-Meraz, Delgado-Buenrostro, Yolanda I. Chirino

PII:

S0378-4274(20)30024-2

DOI:

https://doi.org/10.1016/j.toxlet.2020.01.016

Reference:

TOXLET 10685

To appear in:

Toxicology Letters

Received Date:

23 September 2019

Revised Date:

24 December 2019

Accepted Date:

21 January 2020

´ ´ O, Please cite this article as: Rodr´ıguez-Ibarra C, Deciga-Alcaraz A, Ispanixtlahuatl-Meraz Medina-Reyes EI, Delgado-Buenrostro NL, Chirino YI, International landscape of limits and recommendations for occupational exposure to engineered nanomaterials, Toxicology Letters (2020), doi: https://doi.org/10.1016/j.toxlet.2020.01.016

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

International landscape of limits and recommendations for occupational exposure to engineered nanomaterials Carolina Rodríguez-Ibarra1,2, Alejandro Déciga-Alcaraz1,2, Octavio IspanixtlahuatlMeráz1,2, Estefany I. Medina-Reyes1,2, Norma L. Delgado-Buenrostro1, Yolanda I.

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Chirino1@

Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, Facultad de

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Estudios Superiores, Universidad Nacional Autónoma de México, Av. De los Barrios

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1, Col. Los Reyes Iztacala, Tlalnepantla, CP 54059, Estado de México, México.

Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma

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de México.

@Corresponding author. Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. de Los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, México. Tel.: +52 55

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56231333 Ext. 39817. E-mail address: [email protected]

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Highlights 

Information required for nanomaterials registration is mainly based on tonnage



Sub-nanometric nanomaterials and nanofibers could have different criteria for regulation



For some nanomaterials, limits of exposure are based on the bulk material as a reference Metal oxides and carbon-based are the most regulated nanomaterials

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Measuring airborne nanomaterials concentrations in occupational settings is

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urgent

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Abstract

The increasing concern of possible adverse effects on human health derived from

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occupational engineered nanomaterials (ENMs) exposure is an issue addressed by entities related to provide guidelines and/or protocols for ENMs regulation. Here we

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analysed 17 entities from America, Europe and Asia, and some of these entities provide limits of exposure extrapolated from the non-nanosized counterparts of ENMs. The international landscape shows that recommendations are mostly made

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for metal oxide based ENMs and tonnage is one of the main criteria for ENMs registration, however, sub-nanometric ENMs are emerging and perhaps a novel category of ENMs will appear soon. We identify that besides the lack of epidemiological evidence of ENMs toxicity in humans and difficulties in analysing the toxicological data derived from experimental models, the lack of information on

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airborne concentrations of ENMs in occupational settings is an important limitation to improve the experimental designs. The development of regulations related to ENMs exposure would lead to provide safer work places for ENMs production without delaying the nanotechnology progress but will also help to protect the environment by taking opportune and correct measures for nanowaste, considering that this could be a great environmental problem in the coming future.

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Keywords: engineered nanomaterials, regulatory agencies, nanotoxicology,

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occupational exposure limits.

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1. Introduction

Nanomaterials are natural, incidental or manufactured particles with at least one

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dimension sized in nanometric scale between 1 and 100 nm in an unbound state or as an aggregate/agglomerate and where, 50% or more of the particles are in the

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nanometric distribution, according to the definition adopted by the European Union (EU; https://ec.europa.eu/environment/chemicals/nanotech/faq/definition_en.htm; a number of definitions are already collected by Garduño-Balderas et al., 2015). ENMs

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applications have exceeded expectations of technology innovation in a broad spectrum of fields including biomedicine, food industry, agriculture, wearable electronics, waste water treatment, fuel industry, longer lasting batteries and electronic components in satellites and aircraft (Mirri et al., 2016; Medina-Reyes et al., 2017; Bishoge et al., 2018; Jayathilaka et al., 2019). However, the main concern

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of ENMs exposure is the potential hazard for workers in occupational settings and through foods, personal care products and medicines containing ENMs for consumers, however even if the safety is still uncertain, the research of novel applications of ENMs is increasing. Furthermore, prediction of ENMs toxicity is still unreachable since risk assessment used for other chemicals is not applicable to ENMs but still efforts for prediction of toxicity are being developed (Choi et al., 2018; Jha et al., 2018; Loret et al., 2018). 3

According to PubMed database, over 25,000 papers published are linked to ENMs applications while less than 3% are related to ENMs occupational safety (Figure 1). However, it has been well described that nanoparticles induce toxicity at subcellular, cellular, tissue and organ level in diverse experimental models. For instance, after exposure to nanoparticles by inhalation these are deposited in the deep lung (Okada et al., 2019; Lee et al., 2019) while microparticles are retained in the bronchial area (El-Sherbiny et al., 2015). In order to clear the airways, the nanoparticles are carried to the blood-stream and consequently are deposited in other organs such as liver,

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spleen and has been described to reach the brain, testis and embryo since nanoparticles are able to cross the blood-brain barrier, the blood-testis barrier and

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placenta (Larson et al., 2014; Wang et al., 2018). Additionally, at cellular level the ENM are able to induce oxidative stress, lipid-peroxidation, alteration of calcium

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homeostasis, decrease on antioxidant systems, DNA damage, and modifications in the gene expression and increase in pro-inflammatory signalling (Roy et al., 2014;

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Heim et al., 2015). Even, it has been showed that exposure to nanoparticles can shift the non-malignance phenotype into a malignant phenotype (Medina-Reyes et

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al., 2019). Based on the above information, the scientific researchers are concerned for ENM exposure and we encourage the policy makers to develop regulations. Indeed, there are already some papers in which the necessities for regulations are

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discussed and the difficulties also addressed (Garduño-Balderas et al., 2014; Lai et al., 2018; Resnik, 2019). Nevertheless, we are aware that regulation for ENM exposure

is

challenging

since

the

shape,

size,

chemical

composition,

physicochemical, electrical and mechanical properties are critical characteristics in their toxicity (Madannejad et al., 2019). In spite of the difficulties some organizations

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have taken under different criteria. For instance, ENMs labelling is mandatory for some cosmetics, medicines and foods in Australia, Canada, EU and United States of America (USA; Lai et al., 2018), however, exposure limits of ENMs in environmental settings and information provided for workers exposed to ENMs produced in industries is not entirely accessible. In this paper, we aimed 1) to identify the minimum information required for ENMs registration and the agencies, institutions or organizations that currently make decisions on regulatory issues or 4

provide guidelines related to ENMs exposure and 2) to examine the type of ENMs regulated by those agencies and the limits of exposure for those ENMs. Then, 3) we identify potential key points to be considered for ENMs regulation.

1.1 Minimum information required for ENMs registration The information required for ENMs registration has different criteria. For instance, Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) is one of the most important entities in charge of regulatory recommendations in the EU.

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For REACH, the tonnage to be produced or imported is the central issue for registration, then, a substance marketed above 10 tons must have chemical safety

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assessment (Mech et al., 2019; Commission Regulation EU 2018/1881). Furthermore, in the EU, ENMs have to follow REACH regulations, this means that

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hazardous properties of nanoforms of substances will have to be assessed, and to

REACH have to be registered.

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be legally manufactured or imported in the EU, all substances within the scope of

For the government of Canada, more than 100 Kg/year of ENMs produced or

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imported will be considered for “Prioritation”, which is related to potential assessment, however, under 100 Kg/year no further actions are needed (Consultation document: prioritization approach for nanoscale forms of substances

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on the Domestic Substances List, https://www.canada.ca/en/environment-climatechange/services/canadian-environmental-protection-act-registry/consultationdocument-prioritization-approach-nanoscale.html). Nanoscaled materials follow the Toxic Substances Control Act (TSCA) according to the Environmental Protection Agency (EPA) in USA since 2017 and specific

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chemical identity, production volume, manufacture methods, processing, use, exposure and release information and, available health and safety data are required. However, there are other types of registries for instance, “Nanomaterial Registry” is a National Institutes of Health (NIH) funded public digital database for nanomaterials from USA that requires 12 characteristics as minimal information about nanomaterials that includes the particle size and distribution, composition, shape,

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surface area and charge, purity, agglomeration/aggregation state, solubility, surface reactivity, chemistry and stability (Oberdörster et al., 2005; Ostraat et al., 2013). In spite of the fact that tonnage determines the risk of exposure, we suggest that once a substance fulfils the criteria of ENMs definition, firstly, the minimum information required for registration should embrace an extensive physicochemical characterization plus the interaction with biomolecules (protein corona). Secondly, toxicity studies derived from pertinent in vitro and in vivo models using relevant concentrations and doses must be provided and for this purposes, Organisation for

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Economic Co-operation and Development (OECD) provides guidelines that are helpful to develop the toxicity protocols for ENMs (OECD 2018a, 2018b). However,

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we recommend that together with the registry of ENMs, a measurement for airborne ENMs should be required, regardless of the tonnage produced or handled and there

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are already some methods for this purpose (Kuhlbusch et al., 2011). In addition, the measurement of airborne concentrations of ENMs in workplaces could provide

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information for toxicologist that would help to improve experimental designs.

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1.2 Establishment of occupational exposure limits

The establishment of limits of exposure plays a key role in the regulation and recommendations needed to protect humans from possible adverse effects related

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to ENMs inhalation in occupational settings. For this purpose, quantitative risk assessment (QRA) is made in order to set the occupational exposure limits (OELs) in which QRA estimates the internal dose associated with an adverse health effect in animals or humans (Schulte et al., 2018). This dose is often called the point of departure and can be calculated from the no observed effect level (NOEL), no

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observed adverse effect level (NOAEL) or the lowest observed adverse effect level (LOAEL; Kuempel et al., 2015). It is necessary to carefully extrapolate the point of departure (POD) dose from animals (for example, based on body weight or on the mass, volume, or surface area of an organ) to estimate the human-equivalent dose (Deveau et al., 2015). Also, studies in rodents can be extrapolated to humans through dosimetry models such as the multiple-path particle dosimetry model MPPD model which “calculates the deposition and clearance of monodisperse and 6

polydisperse aerosols in the respiratory tracts of rats and adults and children (deposition only) for particles ranging in size from ultrafine (0.01 µm) to coarse (20 µm)” (Kuempel et al., 2015). For inhaled particles, the equivalent dose in rodents and humans may be estimated by adjusting the differences in the lung surface area. Rodents are the most used animal models in which, in order to have an impact on regulation, the time of exposure must be the one that represents a chronic inhalation exposure. For example, chronic exposure in animals (104 weeks in rats) is treated as equivalent to a full 45 years working lifetime exposure in humans. Data sets

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should be extrapolated to work periods such as 8 h/day, 40 h-work-weeks, for a 45year working lifetime (Schulte et al., 2010).

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However, inhalation of ENMs shaped as fibers in rodents cannot easily be extrapolated to human since deposition of fibers does not follow the same properties

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and breathing behavior as their amorphous counterparts such as biopersistance, aspect ratio, and velocity shear, among others (Sturm and Hofmann, 2006, 2009).

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Independently, measurements of airborne ENMs concentrations in occupational settings should be performed, which is indeed, hard to obtain from industry.

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Nevertheless, some research laboratories have made an effort to estimate exposure levels. The National Enterprise for nanoScience and nanotechnology located in Pisa, Italy which produces ENMs for research, meaning at low scale, made a great effort

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to assess the ENMs exposure using personnel monitors. For that purpose, several facilities were monitored including, graphene synthesis facility, semiconductor nanowires laboratory, transmission electron microscopy facility, NP synthesis laboratory (silicon dioxide and gold NPs) and, lyophilization laboratory. This study reported that the highest mean particle number concentration (4.5 × 103

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particles/cm3) was found in the lyophilization laboratory (Iavicoli et al., 2018). Some of the available exposure limits of ENMs in occupational settings are listed in the table 1.

2. Who provides guidelines and/or protocols for ENMs regulation? Here, we have divided the entities into i) those providing guidelines or protocols, ii) those that provide recommendations and iii) those which are regulatory entities. 7

First, we list the entities by year of foundation (Figure 2). Then, we focused on identifying limits of exposure to ENMs in occupational settings. Moreover, we identified which were the countries with more organizations having an impact on ENMs regulation, we located the entities providing guidelines, recommendations or regulations on ENMs occupational exposure in a world map (Figure 3).

2.1 Entities that provide guidelines These organizations are international entities that gather ENMs information from

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physicochemical properties to toxicity testing to deliver public guidelines for ENMs risk assessment, however, these entities have not established exposure limits for

Organization

for

Economic

(International)

Co-operation

and

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occupational settings.

Development

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The Organization for Economic Co-operation and Development (OECD) has recollected the information of 17 countries about their interest for nanoparticles

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regulation, this includes information on i) fullerenes (C60) ii) single-walled carbon nanotubes iii) multi-walled carbon nanotubes iv) silver nanoparticles v) titanium dioxide vi) cerium oxide vii) zinc oxide viii) silicon dioxide ix) dendrimers x) nanoclays

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and xi) gold nanoparticles. The countries included are Australia, Austria, Belgium, Canada, Chile, Denmark, France, Germany, Italy, Japan, Korea, The Netherlands, Sweden, United Kingdom, USA, EU countries and Thailand. Those countries are concerned to regulate titanium dioxide, carbon nanotubes, silver, carbon black, titanium dioxide, aluminum, zinc oxide or silica although not all of them have

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regulation yet. In addition, Australia is worried for “nano-enabled pesticides” and Austria for the role of “nanomaterials and advanced materials in the circular economy” and started the EC4SafeNano project that aimed to network existing nanosafety platforms. Furthermore, the OECD has more than ninety documents about

nanosafety

and

information

helpful

for

future

regulation

(http://www.oecd.org/chemicalsafety/nanosafety/publications-series-safetymanufactured-nanomaterials.htm). 8

2.1.2 World Health Organization (International) The

World

Health

Organization

(WHO)

has

developed

guidelines

with

recommendations for protecting workers from the potential risks of ENMs, these guidelines include a definition for ENMs and specify equipment as well as preventive measures

to

reduce

occupational

exposure

to

ENMs

(https://apps.who.int/iris/bitstream/handle/10665/259671/9789241550048-

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eng.pdf;jsessionid=3D095B49840A563A36A63ECAE405D4F5?sequence=1).

2.2 Entities that provides recommendations

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Some of these entities provide documents in which limits of exposure to some ENMs can be found. In addition, recommendations can be supported by pre-existent data

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from bulk materials or materials considered as “fine particles”, which can be defined

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as particles with greater diameter than 100 nm.

2.2.1 American Conference of Governmental Industrial Hygienists (USA)

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The American Conference of Governmental Industrial Hygienists (ACGIH) does not include a definition for ENMs but establishes Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) that are recommendations for exposure limits for

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chemicals and some ENMs, these are available at ACGIH web page (https://www.acgih.org/tlv-bei-guidelines/policies-procedures-presentations/tlv-beidevelopment-process). Also, the ACGIH has available books and monographs regarding ENMs toxicity, such as Nanoscience and Nanotechnology: Environmental and Health Impacts, Nanotoxicology: Toxicity Evaluation, Risk Assessment and

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Management, Exposure Assessment and Safety Considerations for Working with Engineered Nanoparticles and Nanoparticles and Ultrafine Aerosol Measurements. These

are

all

available

at

ACGIH

web

page

for

a

cost

(https://www.acgih.org/forms/store/ProductFormPublic/).

2.2.2 French Agency for Food, Environmental and Occupational Health & Safety (France) 9

The French Agency for Food, Environmental and Occupational Health & Safety (ANSES) mentions the definition for ENMs and recommends implementing multidisciplinary projects to develop knowledge of the characteristics and hazards of nanomaterials, throughout the product life cycle. This mainly involves promoting the development of appropriate safety tests for assessing the health risks of products containing ENMs intended to be placed on the market. The ANSES proposes a control banding approach for ENMs according to their toxicity as an alternative method to conduct a qualitative risk assessment and taking measures to protect exposed

to

manufactured

nanomaterials

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(https://www.anses.fr/fr/system/files/AP2008sa0407RaEN.pdf).

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workers

2.2.3 Health Canada (Canada)

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Health Canada includes the definition of ENMs and takes a case-by-case approach to assessing the safety of products and substances that may either be or contain

Information

on

ENMs

is

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nanomaterials in Canada and is based on the recommendations from the ACGIH. available

at

Health

Canada

web

page

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(https://www.canada.ca/en/employment-social-development/services/healthsafety/reports/engineered-nanoparticles.html).

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2.2.4 International Organization for Standardization (International) The International Organization for Standardization (ISO) has established many standards on nanotechnologies such as the ISO/TS 800004-2:2015 Nanotechnologies Vocabulary and the ISO/TS 18637:2016 which was published with the aim of providing an overview of available methods to calculate OELs and

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applying control banding tools for ENMs, these standards include definition for ENMs. However no normative references are included in this document. Additionally, ISO has published other documents describing the use of a control banding approach for controlling the risks associated with occupational exposures to ENMs, such as the ISO/TS 12901-2:2014. ISO has available standards on ENMs at ISO web page (https://www.iso.org/standard/53375.html).

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2.2.5 National Institute for Occupational Safety and Health (Japan) The National Institute for Occupational Safety and Health (JNIOSH) contributes to protect workers, safety and health by publishing documents from Labour Standard Bureau, Ministry of Health, Labour and Welfare that explain preventive measures to reduce worker exposure to ENMs since they represent an unknown risks to human health and the prevention of exposure to nanomaterials at workplaces, these documents include the definition for ENMs and are available at JNIOSH web page (https://www.jniosh.johas.go.jp/publication/doc/houkoku/nano/files/mhlw/Notificatio

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n_0331013_en.pdf#zoom=100).

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2.2.6 National Institute for Occupational Safety and Health (USA)

The National Institute for Occupational Safety and Health (NIOSH) established a

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nanotechnology research center that provides guidance on the occupational safety, health implications and applications of nanotechnology in workplace or in research

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laboratories. Also, NIOSH supports epidemiological studies for ENMs workers and establishes OELs for some ENMs. NIOSH published different solutions in the

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workplace design for protect the workers during the handling, intermediate and downstream processing of ENMs, these include the definition for ENMs. It also provides accessible information for general public about controlling health hazards

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and recommends the use of respiratory protection for workers handling ENMs, such as a particulate respirator N100 from 3M (Cat. No. 8233), these information is available

at

NIOSH

web

page

(https://www.cdc.gov/niosh/docket/review/docket312/pdfs/NTRC-Strategic-Plan-

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2018-2025_February-2018.pdf)

2.2.7 New Energy and Industrial Technology Development Organization (Japan)

The New Energy and Industrial Technology Development Organization (NEDO) provides a definition for ENMs and the Japan Ministry of Economy, Trade and Industry (METI) through the NEDO project reported risk assessments of three ENMs (titanium dioxide, fullerene and carbon nanotubes). The three reports on the risk 11

assessment

include

OELs

and

direction

on

risk

management

methods

recommended by the project.

2.2.8

SAFENANO.

Centre

of

Excellence

in

Nanotechnology

Safety

(International) SAFENANO provides expertise to enable effective risk management for ENMs, it also provides the definition for ENMs. Although SAFENANO has the vision of being the leading multidisciplinary independent authority on nanosafety, it has not

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established any limits for ENMs yet. Information on risk assessment for ENMs is available at SAFENANO web page (https://www.safenano.org/services/risk-

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2.2.9 Safe Work Australia (Australia)

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assessment).

Safe Work Australia (SWA) provides safety hazards for ENMs, information about of

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emissions during machining process, occupational health and safety assessment tools for handling ENMs. Also, SWA publishes reports of ENMs toxicity and

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occupational health hazards and the advances in the development of an automated high-throughput screening procedures for nanomaterials genotoxicity assessment

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(https://www.safeworkaustralia.gov.au/resources-publications).

2.3 Regulatory entities

These are governmental entities that establish limits of exposure with some exceptions, however, none of them have sanctions for exceeding OELs.

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2.3.1 Environmental Protection Agency (USA) The Environmental Protection Agency (EPA) does not propose exposure limits to ENMs, but has developed an approval process to manufacture or use ENMs which includes the definition for ENMs. EPA has received and reviewed over 160 new chemical notices under the TSCA for ENMs. EPA has taken actions to control and limit exposures to ENMs, including: a) limiting the uses of the nanoscale materials, b) requiring the use of personal protective equipment and engineering controls, c) 12

limiting environmental releases, and d) requiring testing to generate health and environmental effects data. Also, EPA has also allowed the manufacture of new chemical nanoscale materials under the terms of certain regulatory exemptions. The information

on

the

TSCA

for

ENMs

is

available

at

EPA

web

page

(https://www.epa.gov/reviewing-new-chemicals-under-toxic-substances-control-acttsca/control-nanoscale-materials-under).

2.3.2 Occupational Safety and Health Administration (USA)

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The Occupational Safety and Health Administration (OSHA) provides a definition for ENMs and sets standards for protecting workers from exposure to nanomaterials in

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section 5(a)(1) of the Occupational Safety and Health Act of 1970 (29 U.S.C. 654) that requires employers to "furnish to each of his employees a place of employment

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which is free from recognized hazards that are causing or are likely to cause death or serious physical harm to his employees”. Likewise, in section 5(a)(2) that requires

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employers to "comply with occupational safety and health standards" promulgated under the OSHA General Industry standards. OSHA also made public the OSHA Sheet

for

working

safely

with

ENMs

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Fact

(https://www.osha.gov/Publications/OSHA_FS-3634.pdf).

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2.3.3 European Chemicals Agency (EU)

The European Chemicals Agency (ECHA) works closely with the OECD by participating and contributing to ongoing international regulatory activities such as the OECD Working Party on ENMs. ECHA hosts the EU Observatory for Nanomaterials and the Nanomaterials Expert Group (ECHA-NMEG), this advisory

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group supports the implementation of ECHA Workplan for Nanomaterials 2016-2018 and provides information and advice on scientific and technical issues regarding the implementation of REACH legislation in relation to ENMs. This agency has no established exposure limits for ENM and delivers only recommendations in the European Union.

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2.3.3.1 Registration, Evaluation, Authorization and Restriction of Chemicals (European Union) Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) is a regulation of the EU, created to improve the protection of human health and the environment from the risks that can be posed by chemicals. REACH covers substances at the nanoscale according to regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 and the normal

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REACH provisions apply.

2.3.4 Secretary of Economy (Mexico)

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The Secretary of Economy (SE) publishes legal documents including NMX-R-129011-SCFI-2015, a non-mandatory regulation that establishes OELs the limits of

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exposure for ENMs and uses definitions and criteria from ISO and NIOSH (SEGOB,

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2017), however, the SE does not include a definition for ENMs.

3. Key Points For ENMs Regulation

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3.1 What are the challenges? The knowledge of ENMs physicochemical properties and toxicity has substantially advanced in the last decade, however, real estimations of airborne ENMs concentrations in occupational settings and individual personnel

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exposure are one of the biggest challenges. Besides ethical concerns related to the responsibility of employer to inform workers of ENMs possible risk, another challenge is having the workers aware of potential health adverse effects, particularly those with susceptibilities for respiratory diseases.

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3.2 What is the impact of precise exposure estimations? In the last decade, ENMs contained in products for oral consumption have been quantified. Food products such as chewing gums, coffee creamer, coating and tooth paste used analytical methods such as Raman spectroscopy, transmission electron microscopy, and X-ray diffraction, for ENMs recovery and quantification (Dudefoi et al., 2018; Peters et al., 2014; Sohal et al., 2018). Then, real estimations of ENMs intake are available which for food-grade titanium dioxide ranges from 0.19 μg/kg bw/day in 14

elderly, to 2.16 μg/kg bw/day in young children (Rompelberg et al., 2016). European Food Safety Agency (EFSA, established in 2002 and located in Parma) is aware of potential adverse effects and has been counselling for periodical revision of foodgrade titanium dioxide (labelled as E171 in Europe). Since occupational exposure is at the present a clear concern by ENMs inhalation, attention must be kept on dietary exposure considering at least mandatory labelling for some medicines, foods and cosmetics (Lai et al., 2018).

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3.3 Are other ENMs should be included? Regardless to known difficulties, some other ENMs need to be included in the regulation based on the current or potential

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manufacture at industrial scale. In this regard, nanotextile market is expected to reach US$ 14.8 billion by 2024 according to the Trends Market Research and zinc

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oxide is one of the ENMs used for this technology. The market of carbon nanotubes is expected to reach $9.84 billion by 2023 according to Carbon Nanotubes (CNT)

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Market worth (https://www.marketsandmarkets.com). Perhaps an eye must be kept on any type of ENMs shaped as fibers since its toxicity may be higher when

Forest et al., 2017).

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compared to the same amorphous ENMs (Stoehr et al., 2011; Zhang et al., 2017;

IARC classified

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3.4 How lack/insufficiency of data can be interpreted?

multiwalled carbon nanotubes (MWCNT-7) in the group 2B while other types of carbon nanotubes were classified in the group 3 as non-carcinogen to humans based on the limited information available from mechanistic data but not in the evidence of absence of carcinogenic effects (Grosse et al., 2014). On the other hand,

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carbon nanotubes were included in Tier 2 by ACGIH in 2018 and it means that these ENMs “will not move forward, but will either remain on or be removed from the under study list for the next year”. Policy makers should attend the fact that absence of evidence of toxicity of ENMs is not equivalent to safe ENMs exposure. Indeed, some chemicals seem to exhibit low genotoxicity signs but we need to consider that many of these chemical agents can be carcinogenic even in absence of noticeable DNA damage (Nohmi, 2018; Hernández et al., 2009). Lack, insufficiency or inadequate 15

data regarding to ENMs effects must be taken as a priority to advance in studies of ENMs toxicity including genotoxicity, which is one of the most worrying adverse effects (Corvi and Madia, 2017). For lack of data that comes from inadequate doses of exposure, again, priority to measurement of airborne ENMs concentration in occupational settings is decisive.

3.5 Better estimation of occupational exposure would help to predict nanowaste delivering? The estimation of real ENMs exposure would help for

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estimation of nanowaste prediction generated ENMs production but it would be restricted to environmental settings since there are other sources that contribute to

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the environmental nanowaste such as nanopesticides, nanofertilizers (Kah et al., 2018), cosmetics (Silpa et al., 2012) and electronics (Ruffino and Grimaldi, 2019).

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It is estimated that between 63% to 91% of the global emission of ENMs would end up in landfills, 8% to 28% in soil, 0.4% to 7% in water and less than 1.5% in air

Containing

Nanomaterials

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according to the Assessment of Impacts of a European Register of Products published

in

2014

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(https://www.umweltbundesamt.de/sites/default/files/medien/378/publikationen/text e_23_2014_assessment_of_impacts_of_a_european_register_of_products_contai ning_nanomaterials-schwirn.pdf). However, better estimations of nanowaste could

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be done with real estimations of airborne ENMs in occupational settings. We suggest that policy makers might encourage occupational settings to measure size and airborne ENMs concentrations to estimate ENMs airborne concentrations that will impact experimental designs avoiding overdosed models and, the work places would have the opportunity to take action, for instance, reducing working

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hours in places that exceed limits of exposure, and offering a better protection equipment for workers including respirators and clothing. In addition, some countries claim to have important ENMs production but limits of exposure are difficult to track down. This is the case of China, that apparently is the second largest manufacturer of titanium dioxide having produced 1.28 million tons in 2007 (Luo et al., 2014), but limits of exposure and regulations are unavailable for non-Chinese speakers.

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No matter how big are the steps in terms of experimental models since without real data of human exposure, the interpretation of those studies remains limited and priority should be given to estimations of inhalation, ingestion and dermal and ocular exposure in working settings. The knowledge of real human exposure to ENMs would impact not only on regulations, but for nanoscience on improvement of experimental designs to predict not only the outcome of exposure, but also the contribution of ENMs exposure as enhancer of other diseases. Experimental designs should be designed as a representation of worker exposure that occurs under 8-hour

of

shifts per day and also considering that previous diseases might be present in these

ro

workers (Jonasson et al., 2013; Mishra et al., 2016).

4. Concluding remarks

-p

The information required for ENMs registration in the EU follows the REACH criteria while in the USA, nanoscale materials follow the TSCA according to the EPA. Some

re

important criteria to register novel ENMs include tonnage, physicochemical properties, production volume, exposure information, and available health and safety

lP

data. In addition, based on the information delivered by 17 entities analysed here, we identified that there are some entities that do not establish limits of exposure of ENMs but consider the bulk material as a reference for recommendations. For

ur na

instance, limits of exposure recommended for titanium dioxide, are based on limits established for microsized or fine particles according to ACGIH (USA), NEDO (Japan), NIOSH (USA) and the SE (Mexico). These limits might be applicable to nanosized titanium dioxide manufactured nowadays. In general terms, the metal oxide ENMs and carbon based ENMs are the most advanced in terms of limits of

Jo

exposure.

We identified possible key points for regulation that include, 1) to uniform the criteria for

registration.

In

this

regard,

perhaps

an

exhaustive

physicochemical

characterization plus tonnage might be considered together. 2) Priority for the potential ENMs to be produced at industrial scale, for instance, all types of carbon based ENMs, any type of ENMs shaped as fibers. 3) To encourage occupational settings to measure airborne ENMs in the occupational settings and make public this 17

information. This information will also be necessary for toxicologists in order to improve experimental designs. 4) To speculate about safety of future ENMs for instance, sub-nanometric ENMs, which are already under development, at least gold and graphene (Alves et al., 2011; Sakaguchi et al., 2014). In addition, the benefits of regulating ENMs in occupational settings could impact three important sectors including industrial economy, occupational health and environmental safety (Figure 4).

of

5. Aknowledgements

This project was supported by Programa de Apoyo a Proyectos de Investigación e

ro

Innovación Tecnológica (PAPIIT IN224119). CRI, ADA, OIM and EIMR are doctoral students from Programa de Doctorado en Ciencias Biomédicas de la Universidad

-p

Nacional Autónoma de México (UNAM) and received fellowships 626239, 582547, 599447 and 576227 respectively, from CONACYT. We thank Natalie Jimenez

lP

re

Barrios for her contribution to this paper.

ur na

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Figure legends

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Figure 1. Articles available in PubMed database. The number of published papers related to concerns of ENMs exposure (toxicity, risk assessment and occupational safety) is 2.7 times lower than papers related to applications. ENMs: Engineered nanomaterials. Last update: September 2019.

28

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Figure 2. Foundation timeline of entities that currently provide guidelines, recommendations or regulations related to limits of ENMs exposure. From the 15 entities analysed, 4 entities (green) are federal authorities, 9 entities provide recommendations (blue) and 2 international entities deliver guidelines (purple).

Jo

Figure 3. Location of entities providing guidelines, recommendations/ regulations of ENMs exposure. Entities in USA provide recommendations and regulations with exposure limits, while in the European Union, the recommendations and regulations not necessarily include limits of exposure.

29

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Figure 4. Benefits of regulating exposure to ENMs. Regulations concerning to ENMs exposure in occupational settings would reduce the health risk of personnel exposed to ENMs providing at the same time, safer workplaces. In addition, it would help for selecting safer ENMs for production and for making nanowaste estimation. Later, it could contribute to decrease the health expenses for companies and governments.

30

of

Do the documents include a definition for ENMs? No

Health Canada (Canada)

Yes

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National Institute for Occupational Safety and Health (NIOSH; USA)

re

American Conference of Governmental Industrial Hygienists (ACGIH®; USA)

Jo

New Energy and Industrial Technology Development Organization (NEDO; Japan) and The Japan Ministry of Economy, Trade and Industry (Japan)

Safe Work Australia (Australia)

Yes

Exposure limits

TiO2: 10 mg/m3 8-h time-weighted average Carbon black: 3 mg/m3 Silver metal dust 0.1 mg/m3 Rigid, biopersistent nanofibers: 0.01 fibre/cm3. Biopersistent granular nanomaterials: 20000 particles/cm3. Biopersistent granular and fibre form nanomaterials: 40000 particles/cm3. Non-biopersistent granular nanomaterials: Applicable occupational exposure limit Carbon nanotubes and carbon nanofibers: 1 µg/m3 8-h timeweighted average Fine TiO2: 2.4 mg/m3 10-h time-weighted average Ultrafine TiO2: 0.3 mg/m3 10-h time-weighted average Silver metal dust 0.01 mg/m3

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Entities

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Table 1. Limits of exposure to engineered nanomaterials by regulatory entities

Yes

TiO2: 0.6 mg/m3 Carbon nanotubes: 0.03 mg/m3 Fullerene: 0.39 mg/m3

Yes

Proposes Benchmark Exposure Levels (BEL) for following nanomaterials: Carbon nanotubes (fibrous): 0.01 fibers/mL Zinc oxide (insoluble): 20,000 particles/cm3 Manganese oxide (insoluble): 0.013 mg/m3 Cobalt oxide (insoluble): 0.0033 mg/m3 Silver oxide (insoluble): 0.0066 mg/m3 Silver oxide (soluble): 0.005 mg/m3 Alumina: 20,000 particles/cm3

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Other nanomaterials (soluble or insoluble): 0.2 mg/m3 or 20,000 particles/cm3

No

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Yes

Secretary of Economy (SE; Mexico)

Carbon black: 3.5 mg/m3 TiO2 total dust: 15 mg/m3 8-h time-weighted average Silver metal dust: 0.01 mg/m3 Amorphous silica inhalable particles: 10 mg/m3 Carbon dusts: 2 mg/m3 Fine TiO2: 2.4 mg/m3 UltrafineTiO2: 0.3 mg/m3

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Occupational Safety and Health Administration (OSHA; USA)

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ENMs: Engineered nanomaterials. Fine: particles greater than 100 nm in diameter. Ultrafine: defined as the fraction of respirable particles smaller than100 nm.

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