The increased production of manufactured nanomaterials (MNMs) and their use in consumer and industrial products means that workers in all countries will be at the front line of any exposure, placing them at risk of potential adverse health effects.
The term "nanomaterials" refers to materials that have at least one dimension (height, width or length) that is smaller than 100 nanometres (10 7 metre), which is about the size of a virus particle. This particular size dimension, which falls between single atoms and their bulk material counterparts, represents a major characteristic of MNMs.
The unique properties of MNMs may result in highly desirable behaviour, including but not limited to increased reactivity, or higher conductivity. As such, the past decade has witnessed the exploitation of these unique properties for industrial and consumer applications, and various types of MNMs have found their way into a plethora of sectors, including aerospace, cosmetics, foods, electronics, construction and medicine, among others.
Significant academic and industrial resources have been dedicated to the field of nanotechnology, increasing the scope and number of MNMs that will be available for future use. However, MNMs may also present health hazards that differ from those of the substance in bulk form, and require different test methods for hazard, exposure and risk assessment from their bulk material counterparts.
The World Health Assembly identified the assessment of health impacts of new technologies, work processes and products as one of the activities under the Global Plan of Action on Workers' Health adopted in 2007, and the WHO Global Network of Collaborating Centres in Occupational Health has selected MNMs as a key focus of its activity.
WHO developed these guidelines with the aim of protecting workers from the potential risks of MNMs. The recommendations are intended to help policy-makers and professionals in the field of occupational health and safety in making decisions about protection against the potential risks of MNMs. These guidelines are also intended to support workers and employers. However, the guidelines are not intended as a handbook or manual for safe handling of MNMs in the workplace, because this requires addressing more general occupational hygiene issues beyond the scope of these guidelines.

# The health burden from manufactured nanomaterials
At the nanoscale, MNMs may exhibit unique characteristics that distinguish their behaviour from bulk materials and may facilitate interaction with their environment. Of particular importance is their small size, which may allow for increased penetration of environmental and biological barriers. In addition, MNMs have far larger surface areas than similar masses of larger-scale materials. A larger surface area provides a larger interface for molecular and chemical interactions within the external environment, potentially promoting their reactivity.
The multiplicity of novel material designs for the same chemical composition with different physicochemical properties presents significant challenges for risk characterization, because toxicological properties may adapt to changes in their physicochemical properties such as size and shape. Nanomaterials are being used in a rapidly growing number of products and industries.
The number of workers exposed to MNMs is not known but is increasing with the industrial production and use of MNMs.
In the workplace, health hazards can result from inhalation, ingestion or skin absorption of MNMs. The human lungs represent an excellent entry portal for MNMs due to their high surface area, thin epithelial barriers and extensive vasculature; and while dermal and oral exposure may occur, inhalation is more likely to result in a larger systemic dose of MNMs. Currently, inhalation of biopersistent particles and fibres with an asbestos-like morphology is the greatest known health hazard possibly resulting in local inflammation and cancer.
Translocation of inhaled MNMs to the circulation and to secondary organs is estimated to be limited to not more than 1% of the mass-based dose. However, this figure is based on extrapolations from animal studies, resulting in a lack of precise information on biokinetics of inhaled MNMs and their long-term fate in humans. Nevertheless, while acute effects from MNMs' translocation to secondary organs are likely to be minimal, it is possible that chronically exposed populations may face greater risks from cumulative, low-dose translocation processes.
While humans have long been exposed to unintentionally produced nanoparticles, such as those from combustion processes, the recent increase in MNM production demands greater investigation into the potential toxicity and adverse health effects of these materials following exposure. Since newly developed MNMs are not tested sufficiently for possible health hazards, it is generally recommended to take a precautionary approach until testing results are available. This means that MNMs should be considered as hazardous unless there is clear proof that they are not.
The toxicity of MNMs may largely depend on numerous physicochemical properties, including size, shape (i.e. size in a particular dimension), composition, surface characteristics, charge and extent of their dissolution. There is currently a paucity of precise information about human exposure pathways for MNMs, their fate in the human body and their ability to induce unwanted biological effects such as generation of oxidative stress. Data from in vitro and animal in vivo MNM inhalation studies are available for only a few MNMs. So far, only a small number of controlled human exposure studies have assessed the fate and health effects of MNM exposure; this is due mainly to ethical concerns.
Even though there are estimates available of the tonnes (t) of nanomaterials produced annually and used worldwide, the GDG did not find convincing evidence of how these estimates can be correlated with worker exposure. The current estimates of the number of workers potentially exposed to nanomaterials in specific countries indicate that they are still a relatively small proportion of all workers (1).
According to one source the volume of MNMs on the market can be ranked as follows (2):
- carbon black (9.6 million t) 2. synthetic amorphous silica (1.5 million t) 3. aluminium oxide (200 000 t) 4. barium titanate (15 000 t) 5. titanium dioxide (10 000 t) 6. cerium dioxide (10 000 t) 7. zinc oxide (8000 t) 8. carbon nanotubes (CNTs) and carbon nanofibres (CNFs), (100-3000 t)

# silver nanoparticles (20 t).
The focus of these guidelines is on low-and middle-income (LMI) countries where nanotechnology is an important means of economic progress. For example, middle-income countries such as Brazil and South Africa produce MNMs and have research laboratories that produce CNTs. LMI countries produce nanosilver that is incorporated in milk packs, fabrics and clothes and MNMs are also produced for use by the pharmaceutical industry.
However, the implementation of health and safety at work regulations is usually less effective in LMI countries, which means that workers in these countries are at greater risk of the potential negative health effects than their counterparts in high-income countries. This is partly because the use of MNMs is often not known about or well understood. Despite the publication of a large number of scientific articles about nanotechnology by authors from LMI countries, only a few are about the potential toxicity of MNMs and very few report on safety or risk assessment (3).

# Scope of the guidelines and key questions
The GDG has identified the following key issues and questions where evidence should be reviewed leading to recommendations that can improve workers' health and safety.

# Risks of MNMs
Which specific MNMs and groups of MNMs are most relevant with respect to reducing risks to workers and which should these guidelines now focus on, taking into account toxicological considerations and quantities produced and used.

# Specific hazard classes
Which hazard class should be assigned to specific MNMs or groups of MNMs and how?

# Forms and routes of exposure
For the specific MNMs and groups of MNMs identified, what are the forms and routes of exposure that are of concern for worker protection?

# Typical exposure situations
What are the typical exposure situations and industrial processes of concern for relevant specific MNMs or groups of MNMs?

# Exposure measurement and assessment
How will exposure be assessed and are there alternatives to current exposure assessment techniques for MNMs that should be recommended in LMI countries?

# Occupational exposure limit (OEL) values
Which OEL or reference value should be used for specific MNMs or groups of MNMs?

# Control banding
Can control banding be useful to ensure adequate controls for safe handling of MNMs?

# Specific risk mitigation techniques
What risk mitigation techniques should be used for specific MNMs, or groups of MNMs in specific exposure situations, and what are the criteria for evaluating the effectiveness of controls?

# Training for workers to prevent risks from exposure
What training should be provided to workers who are at risk from exposure to the specific MNMs or groups of MNMs?

# Health surveillance to detect and prevent risks from exposure
What health surveillance approaches, if any, should be implemented for workers at risk from exposure to specific MNMs or groups of MNMs?

# Involvement of workers and their representatives
How will workers and their representatives participate in the workplace risk assessment and management of handling MNMs?
Initially, the GDG had decided that there would be a question about worker involvement in controlling risks of MNM exposure (see question 11). However, preliminary searches found no studies on this topic and the GDG decided it was better formulated as a best practice statement rather than pursuing a systematic review.
For all other questions, the GDG commissioned systematic reviews from teams of authors found through the WHO Global Network of Collaborating Centres.
The systematic reviews to answer question 1 on risks of MNMs and question 9 on worker training were used to inform section 5 on best practices. In occupational health and safety these describe methods or techniques accepted as being the best in protecting workers and are based on consensus among experts. They should be used when implementing the current recommendations.
The review of the literature on hazards of MNMs revealed that there is a general consensus about grouping them, but this did not lend itself very well to making an evidence-based recommendation. The review on worker training did not find specific studies that showed this would lead to a decrease in exposure or to better availability of controls. Nevertheless, the GDG was of the opinion that there are sufficient arguments that worker training is important. Given the complicated nature of the potential health effects of MNMs, worker training was considered to be necessary and regarded as best practice.

# WHO guidelines relating to this topic
Despite the increase in MNM production, particles at the nanoscale are not a new phenomenon to nature and biology. In the field of air pollution the presence of nanoscale particles has long been recognized, and there are air quality guidelines that also address nanoparticles even though no specific exposure limits are given for ultrafine particles (4,5). Air quality is influenced by small particles that are usually divided into particulate matter smaller than 10 micrometres (PM 10, smaller than 2.5 micrometres (PM 2.5 and ultrafine nanoparticles that are smaller than 100 nanometres. The ultrafine particles are naturally occurring in air and a result of combustion processes. However, these guidelines only address MNMs that are intentionally produced.

# Other international programmes on MNM safety
A number of international organizations are active in the area of nanomaterial safety. The most active and influential are the Organisation for Economic Co-operation and Development (OECD) and the International Organization for Standardization (ISO).
The OECD Working Party on Manufactured Nanomaterials (WPMN) has four steering groups. The first steering group on testing and assessment is in the process of publishing dossiers with data on toxicity testing and physicochemical characterization for 11 nanomaterials. It is also responsible for updating safety testing guidelines to make them suitable for nanomaterials. The second steering group on risk assessment and regulatory programmes reviews approaches for risk assessment of nanomaterials. The third steering group on exposure measurement and mitigation focuses on developing guidance for exposure assessment and mitigation of exposure to nanomaterials in the workplace, during consumer use of nano-enabled products and for the environment. Finally, the fourth steering group is looking at environmentally sustainable use of nanomaterials. As of 31 May 2016 the OECD working party had published 58 reports in total. 2 The ISO Technical Committee 229 (TC229) Nanotechnologies has five working groups. Of these, Working Group 3 (WG3) is tasked with developing standards related to the safety of nanomaterials and nanotechnology. As of 22 March 2017 this technical committee had published a total of 55 standards of which 18 were prepared by WG3; they deal directly with the health and safety issues of nanomaterials including specific standards on safe handling of nanomaterials in the workplace aimed at industrial hygienists. 3 The involvement of experts from the WHO GDG in both the OECD and the ISO programme ensures that information is effectively exchanged between the various international organizations. There are also more formal mechanisms for coordination of work among these three organizations. OECD WPMN is a formal participant in ISO TC229, which allows it to review and comment on all ISO TC229 documents under development, while experts from ISO TC229 can reciprocally participate in the development of OECD WPMN documents. A similar status for the WHO GDG with ISO TC229 would further facilitate expert participation in both groups.
WHO and OECD are also members of the Inter-Organization Programme for the Sound Management of Chemicals (IOMC), which coordinates activities among international public organizations with national body memberships on chemicals in general and on nanomaterials specifically.
These links ensure that the knowledge base and expertise developed by these organizations are effectively shared, resulting in the highest quality guidelines, although goals, approaches and stakeholders may differ. For example, ISO aims to develop standards to facilitate commerce, while OECD addresses the needs of government organizations among its 35 member countries; and WHO addresses the needs of government organizations among its 194 member countries including many that are LMI. Despite these differences, recommendations produced by ISO, OECD and WHO are in general very consistent and aim to proactively minimize workers' exposure even though full information about nanomaterial risks is not yet available.

# Target audience
These guidelines are targeted at:
 occupational health professionals and policy-makers at the local, national or international level, who are responsible for the health and safety of workers exposed to MNMs;
 workers and their employers with premises with a potential risk of exposure to MNMs. The project started with the development of a background paper on the development of guidelines for protecting workers from potential risks of exposure to MNMs by the WHO Guideline Steering Group. In 2010-2011 there were several public calls for experts to join the GDG and External Review Group and to identify volunteers to carry out systematic reviews. Once the GDG was formed it worked to identify key questions through several rounds of the Delphi process (6).

# PROCESS FOR GUIDELINE DEVELOPMENT 2.1. Getting started
A first face-to-face meeting of the GDG was held in Johannesburg, South Africa, on 30 September and 1 October 2013 where GDG experts finalized the key questions to be addressed, found authors for systematic reviews of the evidence and agreed on a plan and timeline for completing the work.
Based on decisions made by the GDG, the systematic reviews were commissioned and drafts discussed at evidence review meetings held in:

# Evidence required to address scoping questions
To incorporate significant research undertaken in the area of MNM health and safety, teams of researchers were identified who could carry out systematic reviews of the pertinent literature according to the process outlined in the WHO Handbook for guideline development (7). The systematic review teams are listed in The first step in the evidence search and retrieval procedure was to identify and define the type of evidence required to address the scoping questions. First, the systematic review teams reformulated the key questions posed in section 1.2 so that they could be answered by a systematic review. Then they defined the best available evidence to provide the answers. Owing to the complex nature of the issues being addressed, and the scarcity of experimental studies directly assessing the impact of interventions on occupational health and safety, several distinct areas of evidence were required for each scoping question.

# Summary of evidence review process
Very few existing systematic reviews were found. This is probably because methods for this type of assessment are not very well established in the field of toxicology, occupational health or exposure assessment. Therefore, systematic reviews were commissioned for all questions with the aim of locating studies that could answer the pertinent questions.

# The systematic review process
The systematic review process used for each question varied slightly but followed the principles set out in the WHO Handbook for guideline development. First, for a study to be included it must comprise the four PICO elements: population, intervention, comparator and outcome(s), which are used to assess the exposure or the intervention (7). The PICO approach guarantees that the systematic review process collects the evidence that is needed to answer the question at hand. The searches conducted for the systematic reviews included any observational or experimental study of persons or workplaces exposed to MNMs. For each study, the risk of bias was systematically assessed.
Systematic review conclusions were based on the findings of the included studies. The findings were summarized and provided as support for the recommendations in these guidelines. The summary of findings paragraphs included in the specific recommendations (section 6) contain similar information to the summary of findings tables advocated by the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach, even though we could not provide the summary in the same numerical format.

# Assessment of overall quality of evidence
The systematic review teams determined the quality of evidence for each conclusion (7). The handbook recommends using the GRADE approach for making these assessments (8). GRADE allows the reviewer to systematically and transparently grade the quality of the body of evidence for the effectiveness of medical interventions. At the start of the rating it is assumed that the evidence is of high quality and based on randomized clinical trials. The quality of the body of evidence is then downgraded based on five specific qualifiers including risk of bias and inconsistency of results. This results in one of four quality ratings: high, moderate, low or very low quality of evidence.
However, some of the questions that were used to formulate recommendations in these guidelines were very far from clinical intervention questions, so the GRADE approach for interventions could not be applied. Therefore, a modified GRADE approach was used to assess the overall quality of evidence for the systematic reviews that were conducted to answer the nonintervention questions. The adaptation was based on the existing GRADE guidance for qualitative and prognostic studies (9,10). The guidance on prognostic studies is most applicable also to exposure studies.
The rating process ranked a study design as high quality if it was considered the best for the question at hand. The quality was downgraded if, in one or more domains, criteria for high quality were not met (Table 1). Numerical summaries of findings were not provided in all reviews and in those cases the systematic reviewers used GRADE guidance for qualitative studies as summarized in Table 1. The reviewers did not use any qualifiers for upgrading the evidence, as is possible in the GRADE approach for non-randomized intervention studies. a Based on the GRADE approach for qualitative and prognostic studies; domains and criteria.
Based on these criteria, each systematic review's conclusion was rated for the quality of the evidence. We interpreted the quality levels as proposed by the GRADE working group as follows:
 High quality -further research is very unlikely to change our confidence in the estimate of effect.
 Moderate quality -further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
 Low quality -further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
 Very low quality -any estimate of effect is uncertain.

# From evidence to recommendations

# General process
After the systematic reviews had been conducted, the GDG developed recommendations based on the conclusions. To formulate recommendations and to determine the strength of the recommendations, the GDG used the balance between harms and benefits, values and preferences, monetary costs and the quality of evidence. For most of the recommendations, no numerical values for benefits and harms were available. Therefore, the GDG balanced benefits and harms in a global, qualitative way. Similarly, the costs of an intervention, or the implementation costs of a recommendation, were considered and based on the expert opinion of the GDG members. No formal cost-benefit or cost-effectiveness analyses have been performed.
With each recommendation in these guidelines there is an explanation of how the GDG reached the recommendation based on the evidence. All recommendations were proposed, discussed and based on consensus within the GDG, which was reached through face-to-face meetings. Disagreements were reconciled through adjustments in the recommendations and all GDG members agreed with the final versions.
The strength of the recommendation ranked as either:
 Strong: the GDG agrees that the quality of the evidence combined with certainty about the values, preferences, benefits and feasibility of this recommendation means it should be carried out in most circumstances; or  Conditional: there was less certainty about the combined quality of the evidence and values, preferences, benefits and feasibility of this recommendation meaning there may be circumstances or settings in which it will not apply.

# Workers' values and preferences
Even though the economic benefits of nanotechnology are fully appreciated by all stakeholders, concerns about health and safety risks are especially articulated by workers and their organizations across the globe. The GDG considered the values and preferences of this sector based on the opinion of the groups' members and also conducted a general search for the opinions of key organizations with the following findings.
A few years ago the IUF (International Union of Food, Agricultural, Hotel, Restaurant, Catering, Tobacco and Allied Workers' Associations) called on companies to: adopt a detailed public policy explaining their use of nanomaterials, if any; publish a safety analysis for any nanomaterials being used; issue supplier standards; label all products that contain nanoparticles smaller than 500 nm; and adopt a hierarchy of hazard controls approach to prevent employees' exposure to nanomaterials (11). Similar concerns were also expressed by the ITUC (International Trade Union Confederation), an organization that unites hundreds of trade unions worldwide.
In Europe, the European Trade Union Confederation (ETUC) has expressed its concern about health and safety issues surrounding MNMs. The ETUC emphasizes that to achieve sustainable growth, the innovation resulting from nanotechnologies should include social equity, environmental protection and economic efficiency, while ensuring full health and safety protection and protection of the environment. The ETUC has criticized the failure to fund research on health and safety, ethical, social and environmental issues at the same levels as research and development work on nanotechnologies (12).
In Canada, the Canadian Union of Public Employees recommends following a precautionary approach that prevents workers' exposure until sufficient data can show there are no harmful effects on human health or the environment (13). The Australian Council of Trade Unions has expressed similar concerns (14).

# INDIVIDUALS AND PARTNERS INVOLVED IN GUIDELINE DEVELOPMENT

# WHO Guideline Steering Group
Members of the WHO Guideline Steering Group are listed in Table A.2.1, Annex 2. They include WHO staff members who are involved in work relevant to the topic of MNM and associated health outcomes. The Guideline Steering Group was involved at all stages of planning, selecting members of the GDG and external review group, review of the evidence and developing potential recommendations at the main expert meetings as well as ongoing consultation on revisions following peer review.

# Guideline Development Group (GDG)
The GDG consists of content experts gathered to investigate all aspects of evidence contributing to the recommendations. This group defined the key questions and priorities of the research, chose outcomes and provided advice on any modifications of the scope as established by the WHO Steering Group. The GDG interpreted the evidence, with explicit consideration of the overall balance of benefits and harms, and ultimately formulated the final recommendations, taking into account diverse values and preferences. The group also determined the strength of the recommendations and responded to external reviews. The complete list of GDG members, their affiliations and geographical locations, can be found in

# Systematic review teams
Systematic reviews were commissioned by WHO staff using external contractors. WHO issued public calls for volunteers to carry out reviews including via the WHO Global Network of Collaborating Centres for occupational health. In addition, the GDG recommended several authors to conduct the systematic reviews based on their knowledge of the field.

# External Review Group
The external review group is composed of technical experts, end-users and stakeholders with a geographical and gender balance. Technical content experts and end-users were selected for their expertise in the subject at hand. The group also includes representatives from professional groups and industry that will be implementing the guidelines. Members were asked to review the material at the end of the development process and they provided extensive comments that were used to further improve the recommendations and the wording of the text. The list of group members and their affiliations is provided in

# Management of conflicts of interest
All members of the GDG and systematic review authors completed WHO declaration of interest forms that were accompanied by Annex B (code of conduct for WHO experts) and Annex C (confidentiality undertaking). These were reviewed by the WHO Focal Point and the Ethics, Risk and Compliance office for potential conflicts of interest. Based on their statements there were two requests for further information until finally all of the GDG members and the authors of the systematic review teams were accepted by WHO in their respective roles.
In addition, at the start of each meeting, all members received a briefing about the nature of all types of conflict of interest (i.e. financial, academic/intellectual and non-academic) and were asked to declare to the meeting any conflicts they may have. No member of the GDG or the systematic review team was excluded from his or her respective role.
For transparency purposes only, also the External Review Group members provided declaration of interest forms, as well as confidentiality statements.

# FORMULATING THE RECOMMENDATIONS

# Focus of the recommendations
The specific recommendations 1 to 3 aim to define specific nanomaterials and their health hazards and recommendations 4, 5 and 6 focus on assessing exposures that impact on workers' health and safety. In addition, recommendations 7 to 11 focus on interventions that are generally used to protect workers' health. Finally, the GDG reached conclusions regarding health surveillance for workers and worker training and involvement. These recommendations are listed in sections 6.4 and 6.5.

# Guiding principles

# Precautionary approach
The GDG decided early on that in cases where a health concern is identified but scientific data do not permit an evaluation of the magnitude of the risk based on data from studies in humans, recourse to precaution should be used to reduce or prevent exposure as far as possible. This was seen as an important underlying approach in the interest of protecting workers' health, especially given previous experience with asbestos. Several definitions of a precautionary approach exist. All include a component that urges acting despite uncertainty when there are reasonable indications to do so (15).
For MNMs, potentially adverse effects have been identified for a number of materials. New MNMs are constantly being developed but the ability to predict their hazardous properties is still limited (16). Therefore, as a precautionary approach, the GDG considered that in the absence of toxicological information, workers should not be exposed. This means that in these cases the strictest control measures to prevent workers' exposure should be in place. Only when toxicological information is available can there be a more tailored control strategy. Along similar lines, the control-banding strategy elaborated in these guidelines is based on the same principles.

# Hierarchy of controls
The hierarchy of controls is a concept of risk management that is generally accepted in occupational health and safety. It stipulates that the implementation of controls to reduce workers' exposure should be considered the goal of a successful industrial hygiene programme. The hierarchy of controls is an approach to risk reduction or elimination of hazard or exposure (17).
The first step should be to try and eliminate the hazard. If that is not possible, the hazardous material should be substituted by a less harmful agent. Then, engineering controls should be applied such as isolation, local exhaust ventilation or dust suppression techniques. If all these are not feasible, then administrative controls should be considered such as worker education, and training or scheduling. As a last resort, personal protective equipment (PPE) can be used, but reducing the exposure at source provides better protection for workers and better cost-benefit for employers.
Often, there will be a combination of control measures to minimize the risk. For instance, it might be possible to eliminate or reduce the hazardous properties of nanomaterials without altering their beneficial properties. However, in the case of MNMs, substitution is a control measure that will be difficult to realize, because it is all about the very use of the MNMs. Some have argued that substitution is too limited and should be replaced by process change to reduce worker exposure (18). Changing the process in such a way that no MNMs will be released into the air should therefore always be one of the first control measures to consider.

# BEST PRACTICE
The GDG considers it best practice to class MNMs into the following three groups: those with specific toxicity, those that are respirable fibres and those that are granular biopersistent particles.

# Classification of MNMs
The specific toxicity group consists of (i) MNMs with high dissolution rates through the release of ions or amenable to biodegradation and, (ii) MNMs with low dissolution rates but with high specific toxicity. The latter are MNMs with specific toxicity, which is mediated by the specific chemical properties of their components (19).
The respirable fibres group consists of MNMs that are rigid, biopersistent or biodurable and respirable, which have dimensions agreed upon by a WHO working group for man-made mineral fibres in the past. These dimensions are a fibre length (FL)>5 m, fibre diameter (FD)3 (20). Although this group of fibres is characterized as being rigid, it should be kept in mind that there is no consensus on specific criteria for rigidity even though some have proposed crystallinity as a measure of rigidity for MNMs (21).
The granular biopersistent particles (GBP) group consists of respirable granular biodurable particles that are characterized by both low dissolution rates and lack of high specific toxicity. GBP are respirable granular and biopersistent but not fibrous (as defined above) and these particles are also known as poorly soluble particles or poorly soluble, low-toxicity particles (19).
Forming groups of MNMs with similar properties is important in the absence of information on the hazards of many new materials. This enables the transfer of hazard information, also called bridging or read across, from one material to another. Because there is no general accepted approach on how to do this, the GDG commissioned a systematic review of possibilities to group MNMs based on toxicological considerations. The systematic review was undertaken by Zienolddiny & Skaug (2017) (22). The systematic review team located 22 reviews of grouping MNMs, or approaches to transfer hazard information from one MNM to another. To be included in the overview the authors of the reviews had to have considered which mechanisms of action could lead to toxicity of nanomaterials. The systematic review team authors concluded that there is evidence that there are three main mechanisms of toxicity of nanomaterials: specific toxicity of the material, inhalation and biopersistence in the lungs, and one mediated specifically by the fibre structure. For other potentially hazardous properties, such as genotoxicity, there was no consistency in the included reviews that this is inherent to the nanoscale size of the MNMs.
Given that the grouping of MNMs is based on expert opinion, the GDG considered that changes are likely when more research becomes available.

# Worker involvement
The GDG considers it best practice that workers should be involved in health and safety issues and that this will lead to more optimal control of health and safety risks.
In most countries, worker involvement in health and safety issues is mandatory. Article 19 of the International Labour Organization (ILO)'s C155 Occupational Safety and Health Convention, 1981, stipulates that representatives of workers in the undertaking cooperate with the employer in the field of occupational safety and health. In many other ILO conventions and European Union (EU) directives, the term "worker participation" is frequently used.

# Additional training and education of workers
The GDG considers it best practice that workers potentially exposed to MNMs should be educated on the risks of MNMs and trained in how they can best protect themselves.
MNMs have risk aspects that are specific to being a nanomaterial and that are not self-evident.
For proper control measures to be well implemented, workers need information about these risks. Safety data sheets (SDS) do not always provide reliable information on MNMs and users should be aware of this. In addition, MNMs require specific control measures that can be different from those for the bulk material. This is also recognized by the EU, which has provided specific guidance for workers (23).
There are good training materials available, for instance from the National Institute of Environmental Health Sciences in the United States of America (USA) and from the Health and Safety Executive in the United Kingdom of Great Britain and Northern Ireland, which can easily be adapted to local circumstances (24,25).
Education and training should focus on those aspects of MNMs that are dealt with in these guidelines and that are additional to, or different from, education and training in the safe handling of bulk material chemicals. Topics should include which hazards are specific to MNMs and different from the bulk material; which hazard classes are assigned to MNMs; which routes of exposure are important; which workplace exposures have been measured and which tasks put workers most at risk; how proposed OELs can be interpreted; when and how control banding, specific controls and PPE for MNMs can be used.
ILO Convention 155 concerning Occupational Safety and Health and the Working Environment also states that there should be a national policy to provide information and education and implement training for workers, including necessary further training, qualification and motivation of persons involved, in one capacity or another, in the achievement of adequate levels of safety and health. This also holds for workers exposed to MNMs.

# SPECIFIC RECOMMENDATIONS

# Assess health hazards of MNMs
Recommendation 1: The GDG recommends assigning hazard classes to all MNMs according to the Globally Harmonized System (GHS) of Classification and Labelling of Chemicals for use in safety data sheets. For a limited number of MNMs this information is made available in these guidelines (Table 2) (STRONG, moderate quality evidence).

# Recommendation 2:
The GDG recommends updating safety data sheets with MNM-specific hazard information, or indicating which toxicological end-points did not have adequate testing available (STRONG, moderatequality evidence).
Recommendation 3: For the respirable fibres and granular biopersistent particles' groups, the GDG suggests using the available classification of MNMs given in Table 2 for provisional classification of nanomaterials of the same group (CONDITIONAL, low-quality evidence).
A list of selected nanomaterials and their up-to-date hazard classes, according to the GHS and as assigned by the systematic review team, is available in

# From evidence to recommendation
The animal and genotoxicity studies, as collected and reviewed by the OECD and reported in the specific nanomaterial dossiers, formed the evidence for the assignment of hazard classes to the various MNMs. In addition to the OECD data, the evidence for carcinogenic properties was based on assessment of a limited number of MNMs by the International Agency for Research on Cancer (IARC). Based on an assessment of study limitations, the quality of the evidence was rated as moderate to high for the various MNMs.
Recommendation 3 to bridge the hazard classes from specific materials within a group to other materials within that same group, is based on low-quality evidence that the respirable fibres or GBP materials have similar toxicological properties (see Best practice, Classification of MNMs, section 5.1).

# Benefits and harms
The benefits of having MNMs properly classified and labelled according to their hazards, in terms of focus on risk and control measures, clearly outweigh the possible harm that the classification might be overly cautious given the lack of information about the hazards of MNMs in general. In some cases, the classification system could also result in underestimation of the hazard.

# Values and preferences
The hazard classification forms the basis for labelling products according to their hazards. In many countries, this is legally binding. This information is also included in the SDS informing workers and employers about the safety and hazards of the products they use. Even though the GHS might not be optimal for MNMs, and is being continually developed, it is a systematic approach that is generally recognized globally.
Grouping MNMs with similar properties is important, especially in the absence of information on the hazards of many new materials.

# Net benefits worth the costs
Assigning hazard classes to MNMs is not a very costly procedure if data from studies are available.

# Strength of the recommendation
Based on the above considerations, the GDG makes a strong recommendation for the assignment of hazard classes to MNMs. For bridging from specific materials within the same group, the recommendation is conditional.

# Summary of findings: MNMs and hazard class assignment
Systematic review question: Which hazard classes can be assigned to specific MNMs according to the UN GHS and making use of MNM-specific dossiers as developed by the OECD? The MNM dossiers compiled by the OECD give an overview of the available toxicological data for a number of specific MNMs.

# Evidence summary
The systematic review was undertaken by Lee et al. (2017) (26) and was published by WHO.

# Number of studies and participants
There were 11 OECD dossiers containing toxicity testing information. These were used by the systematic review team to assign one or more hazard classes, according to the GHS, to the following nanomaterials: fullerene, single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT), silver, gold, silicon dioxide, titanium dioxide, cerium dioxide, dendrimer, nanoclay and zinc oxide in nanoparticle form. For the assessment of carcinogenicity, the review team also used the evidence summaries compiled by IARC on SWCNTs, MWCNTs and titanium dioxide.

# Data in the dossiers
Dossiers mostly contained results of in vivo animal studies and in vitro genotoxicity studies supplied by member countries and nongovernmental organizations such as the Business and Industry Advisory Committee to the OECD.

# Risk of bias in the included dossiers
The main limitations to the studies included in the dossiers were that they did not fulfil the OECD criteria for good methodological quality, such as being published in a peer-reviewed journal and complying with good laboratory practice (GLP). For some studies, the GLP test data were not fully disclosed because of the company's intellectual property rights. Studies were classified at low risk of bias if they were in the OECD category 1 or 2, complied with GLP, were based on test guidelines and resulted in a peer-reviewed publication; at medium risk of bias if the above applied but there was no compliance with GLP; and at high risk of bias if none of the above applied.

# Classification of MNMs
The MNMs were classified as having a specific hazard according to the GHS, having no hazard according to the available studies, or as having no data when these were not available for classification. "No hazard" does not necessarily imply that there is no hazard but only that this was not found in the studies used in the OECD dossiers.
For fullerene, there was evidence that there is no hazard for acute toxicity, skin-, eye-or respiratory damage, germ cell mutagenicity or specific target organ toxicity after repeated exposure but, for the other hazard classes, data were missing.
For SWCNT, there was evidence of a hazard for germ cell mutagenicity (Cat 2) and specific organ toxicity after repeated exposure (Cat 1). For reproductive toxicity no clear hazard could be established based on the available data. There was also evidence of no hazard in acute toxicity, skin damage, respiratory/skin sensitization, or reproductive toxicity. For specific target toxicity after single exposure, there were no data. For carcinogenicity there were no data but there is an IARC classification 3, meaning not classifiable.
For MWCNT, there was evidence of a hazard for eye damage (Cat 2), germ cell mutagenicity (Cat 2), carcinogenicity (Cat 2, IARC 2B/3) and specific organ toxicity after repeated exposure (Cat 1). There was also evidence of no hazard in acute toxicity, skin damage, respiratory/skin sensitization, or reproductive toxicity. For specific target toxicity after single exposure, there were no data.
For silver nanoparticles, there was evidence of a hazard for respiratory/skin sensitization (Cat 1B) and specific target organ toxicity after repeated exposure (Cat 12). For acute toxicity, skin corrosion, eye damage, germ cell mutagenicity and reproductive toxicity there was evidence of no hazard. For carcinogenicity and specific target organ toxicity after single exposure, there were no data.
For gold nanoparticles, there was evidence for specific target organ toxicity after repeated exposure (Cat 1). There were no data for the other classes.
For silicon dioxide, there was evidence for specific target organ toxicity after repeated exposure (Cat 2), but no hazard for acute toxicity, skin or eye damage, respiratory or skin sensitization, germ cell mutagenicity and reproductive toxicity. For carcinogenicity and specific organ toxicity after single exposure, there were no data.
For titanium dioxide, there was evidence for possible carcinogenicity ((IARC Cat 2B), reproductive toxicity (Cat 1), and specific organ toxicity after repeated exposure (Cat 1), but also evidence of no hazard for acute toxicity, skin or eye damage, respiratory or skin sensitization or germ cell mutagenicity. There were no data for specific organ toxicity after single exposure.
For cerium dioxide, there was evidence of specific target organ toxicity after repeated exposure (Cat 1), but also evidence of no hazard for acute toxicity. There were no data for the other hazard classes.
For dendrimer and nanoclay, there were no animal toxicity or genotoxicity data to use for classification.
For zinc oxide, there was evidence for specific organ toxicity after repeated exposure (Cat 1) but also evidence of no hazard for acute toxicity, skin or eye damage, germ cell mutagenicity and reproductive toxicity. There were no data for respiratory/skin sensitization, carcinogenicity and specific organ toxicity after single exposure.
For physical hazards, there was evidence that silicon dioxide and titanium dioxide were not flammable or explosive. There was no evidence for the other MNMs.

# Quality of the evidence
The evidence was rated as high quality if there was at least one study at low risk of bias; as moderate quality if there was at least one moderate-quality study; and as low quality if there were only studies at high risk of bias. The quality of the evidence for all but one of the classifications of hazards was in the moderate or high category (Table 2).

# Implementation guidance, research recommendation

# Implications for research
There is high to moderate-quality evidence for 11 specific MNMs to be classified according to the GHS. This exercise should also be undertaken for other MNMs not mentioned here. Where data are available, they should be used for the development of SDS.

# Assess exposure to MNMs
Recommendation 4: The GDG suggests assessing workers' exposure in workplaces with methods similar to those used for the proposed specific OEL value of the MNM (CONDITIONAL, low-quality evidence).
Recommendation 5: Because there are no specific regulatory OEL values for MNMs in workplaces, the GDG suggests assessing if workplace exposure exceeds a proposed OEL value for the MNM. A list of proposed OEL values is provided in Annex 1 of these guidelines. The chosen OEL should be at least as protective as a legally mandated OEL for the bulk form of the material (CONDITIONAL, low-quality evidence).
Recommendation 6: If specific OELs for MNMs are not available in workplaces, the GDG suggests a stepwise approach for inhalation exposure with, first an assessment of the potential for exposure; second, conducting a basic exposure assessment and third, conducting a comprehensive exposure assessment such as proposed by OECD or CEN (CONDITIONAL, moderate-quality evidence). For dermal exposure assessment, there was insufficient evidence to recommend one method of dermal exposure assessment over another.
Knowledge about exposure and subsequent risk assessment forms the basis for measures to control exposure. However, without an exposure level that can serve as a benchmark or guideline level that indicates a risk for adverse health effects, it will be difficult to make decisions about control measures.
There are several alternative ways to measure MNM exposure such as the number concentration or the mass concentration of an MNM, where it is unclear which method is best for assessing health risks. Therefore, the GDG recommends using the same method as has been used for proposed OEL values. This determines the measurement method and at the same time enables a comparison with a benchmark level that probably indicates a safe exposure level.
Only when no proposed OEL is available for an MNM does the GDG recommend using a more generic exposure assessment that consists of a tiered approach. In the first tier, a qualitative assessment is made of possible absence or presence of exposure. In the second tier, called a basic measurement, a quantitative assessment is made of the exposure concentration. In the third tier, called a comprehensive measurement, the size distribution, morphology and chemical composition of particles is characterized.
The recommendations are based on the evidence compiled in two systematic reviews on the quality of exposure assessments in studies and on OELs proposed for various MNMs.
A comprehensive and up-to-date list of proposed OEL values for MNMs is available in Annex 1, Table A.1.1. The values proposed come from a wide range of institutions and countries. Some authors propose one value for all MNMs (general approach), others propose one value for a group of MNMs (categorical approach), but most propose a value for one specific MNM (specific approach).
The user should be aware that these OELs do not imply a safe level below which adverse health effects do not occur, because they are all based on extrapolation from animal research, or other fields such as air pollution, since there are only very limited data available on long-term humanhealth effects. Users should make their own choice of the best applicable OEL value. This is similar to the selection of OELs for bulk materials, where a range of values may be available and the user has to make a choice.
Deveau et al. provide a practical framework for how to find the best applicable OEL for a particular problem from a list of varying OELs for one chemical. This approach can also be used for the list of OELs for MNMs (27).
The exposure assessment and measurement strategy as proposed by OECD and the Comite Europeen de Normalisation (European Committee for Standardization: CEN) distinguishes the following three levels of assessment that can be used as stand-alone modules or embedded in a harmonized tiered approach (28).
 The initial assessment provides information on the likelihood of MNMs being released during an activity or process, and usually does not comprise any measurements.
 The basic assessment, using hand-held or personal devices or samplers, measures exposure as particle number concentration(s) or as respirable mass, or both, in the breathing zone or the workstation air and in the background air. These measurements are supported by laboratory analysis of the samples to characterize the MNM(s) either by chemical composition or morphology.
 In addition to the basic assessment, the comprehensive assessment provides a characterization of the aerosols in the breathing zone that enables, for example, estimation of the dose of MNMs that is deposited in the gas-exchange region of the lung.

# From evidence to recommendation
The evidence for these recommendations is based first on a systematic review of all available proposed OELs (29). Since there is no consensus on a valid way of deriving OELs for MNMs, the GDG could not take the quality of the evidence into account and therefore has only formulated conditional recommendations.
Second, the recommendation is informed by a systematic review of exposure measurement methods that shows there is moderate-quality evidence that basic and comprehensive inhalation exposure assessment methods are feasible in practice (30). There was only very low-quality evidence about feasibility of measurements for dermal exposure assessment.

# Benefits and harms
The benefits of OELs are that they can constitute a benchmark against which local measurements can be compared. The drawback is that many associate the OEL with a safe level below which no adverse health effects will occur. Since both measurements and adverse health effects are uncertain, the OELs can give a false sense of security. However, balancing the two, the GDG decided that the benefits outweigh the harms.
Comprehensive assessment can be time consuming and requires expert knowledge and instrumentation. Many countries would struggle to carry out comprehensive exposure assessments and few companies would be able to pay for such assessments, especially small and medium-sized enterprises (SMEs). Therefore, the GDG recommended the tiered approach.

# Values and preferences
The OEL is a familiar concept to stakeholders and widely used for assessing bulk materials. The same holds for the exposure assessment approach, which is used in general for chemicals.

# Net benefits and costs
The costs of derivation of an OEL depend on the method, but it is not necessarily expensive.
The GDG considers the measurement of MNMs and comparison with OELs to be an important strategy and its costs to be a useful investment in prevention.
The costs for the measurement instruments are considerable -at least several thousand dollars for hand-held particle measurement devices. However, in many countries it is possible to rent the equipment for short periods. The benefit of measuring is that it enables comparison with an OEL and evaluation by means of a before-after comparison to determine whether measures to control exposure are successful.

# Strength of the recommendation
Given the difficulty of establishing the quality of the OELs, the recommendation for using them is conditional. Given the complexities and the costs of measurements, the GDG makes a conditional recommendation for the assessment of exposure.

# Summary of findings: systematic review of proposed OELs
Systematic review question: Which specific OEL values that should protect workers are proposed for workers or workplaces with potential exposure to an MNM or a group of MNMs based on studies that proposed a value underpinned with empirical research or arguments.

# Evidence summary
The systematic review by Mihalache et al. (2017) was published as a journal article (29).

# Number of studies and participants
Twenty studies from a wide range of countries and institutes that proposed 56 OEL values were included in the systematic review. Of these, two proposed one value for all MNMs, 14 proposed one value for a group of MNMs and 40 proposed a value for a specific MNM.

# OELs in studies
All studies that considered inhalation exposure proposed OELs for chronic exposure. One study proposed OELs for dermal and oral exposure for CNTs and fullerenes and two studies derived OELs for acute/peak exposure.
In 15 of the studies the exposure values were derived by extrapolation from animal studies. Two studies derived the OEL from the background level or from an environmental exposure limit. Six studies used a bridging approach to derive an OEL for a group of MNMs, arguing that the risks will similarly apply to members of the whole group (fibres, GBPs, MNMs with specific toxic bulk material with an OEL, soluble MNMs and non-biopersistent MNMs).
Two studies proposed limits for all MNMs. Six studies proposed OELs for a group of MNMs. The rest proposed OELs for specific MNMs: seven for titanium dioxide (TiO2) nanoparticles, six for CNTs, three for fullerenes, three for silver nanoparticles and one study each for silicon dioxide nanoparticles, low-toxicity dust consisting of GBP, nanocellulose fibres and nanoclays.

# Risk of bias in the included studies
One of the study limitations was that the authors did not always give sufficient information about the specific MNM or group of MNMs and the way the OELs were derived. Also, it was unclear if the proposed OELs, especially the number-based OELs for primary nanoscale particles, can be matched with measurements at the workplace where mostly micro-sized agglomerates of MNMs are assessed.

# Proposed OELs that are publicly available
Four studies proposed the asbestos OEL of 0.01 fibres/cm 3 for nanofibres.
Four studies proposed values for GBP, of which two studies each had two proposals. One study proposed 500 g/m3 and 1250 g/m 3 for the respirable fractions dependent on whether particles exhibited specific toxicity or not. In the other study, the proposals for metal and metal oxide nanoparticles are 20 000 particles/cm 3 and 40 000 particles/cm 3 dependent on particle density.
One study proposed the same OEL for non-biopersistent material as for their bulk material.
For carbonaceous material, proposed OELs ranged from 0.67 g/m 3 for MWCNT to 390 g/m 3 for fullerenes.
For nanosilver there are six proposals varying from 0.098 g/m 3 up to 50 g/m 3.
There are 10 proposals for TiO 2 nanoparticles from the lowest, 17 g/m 3 to the highest, 2000 g/m 3. Some variations in reported OELs for nanomaterials that are chemically the same are due to different models used to derive OELs and some are due to different physicochemical properties including specific toxicity of nanomaterials.

# Quality of the evidence
The GDG did not consider the limitations in the studies because there is no generally accepted way of deriving OELs. There were multiple studies with consistent proposals for fibres only. For all other MNMs there was considerable variation. Therefore, the GDG considered the quality of the evidence as low.

# Implementation guidance, research recommendation

# Implications for practice
Workplace exposure studies indicate that in most situations, exposure exceeds the majority of the proposed OELs. This should be a strong incentive for exposure control measures.

# Implications for research
More studies are needed to derive OELs for specific MNMs. Harmonization of OELs requires agreement about interspecies and intraspecies' adjustment factors and exposure values.

# Summary of findings: systematic review on exposure assessment and measurement
Systematic review question: In workers potentially exposed to MNMs or workplaces with exposure to MNMs, which exposure measurement techniques to assess MNMs are feasible based on studies that assessed and measured exposure?

# Evidence summary
The systematic review was published by Boccuni et al. (2017) as a journal article (30).

# Number of studies and participants
The systematic review included papers on exposure through inhalation and dermal absorption. There were no papers identified on exposure through ingestion. The systematic review identified 59 articles that described 53 measurement techniques. Among these, four papers analysed both inhalation and dermal exposure. Three studies of dermal exposure were conducted in the workplace and one in the laboratory setting. These papers reported very poor data on specific techniques for dermal exposure measurements. Therefore, systematic review conclusions were focused on measurements of exposures through inhalation.

# Measurements in studies
There were 53 descriptions of a basic measurement technique and of these there were 13 additional descriptions of a comprehensive technique to assess the presence or absence of MNMs in workplace air. All 53 techniques measured exposure by inhalation; of these, four studies also considered exposure by dermal absorption.

# Outcomes in studies
The studies used either a basic assessment technique or a comprehensive technique.

# Risk of bias in the included studies
The basic exposure assessment was rated as moderate quality in 40 studies and as high quality in two studies.
The comprehensive exposure measurement was rated as moderate quality in 11 studies and as high quality in two studies.

# Exposure measurements carried out
A basic exposure measurement that assesses the presence or absence of MNMs in the workplace air was demonstrated in 53 studies.
A comprehensive exposure measurement was demonstrated in 13 studies.
Comprehensive measurement techniques are more expensive than basic measurement techniques.

# Quality of the evidence
The quality of the evidence is moderate for both basic and comprehensive assessments because the majority of the studies demonstrate at least a moderate-quality exposure assessment. There was very low quality and inconsistent evidence on specific techniques of dermal exposure measurement.

# Implementation guidance, research recommendation

# Implications for practice
The GDG concludes that there is moderate-quality evidence that both basic and comprehensive measurement techniques are feasible in the workplace.

# Implications for research
Studies to validate basic and comprehensive measurement techniques including techniques to assess dermal exposure are needed.

# Control exposure to MNMs

# Focus on prevention of inhalation of MNMs
Recommendation 7: Based on a precautionary approach, the GDG recommends focusing control of exposure on preventing inhalation exposure with the aim of reducing it as much as possible (STRONG, moderate-quality evidence).

# Recommendation 8:
The GDG recommends reduction of exposures to a range of MNMs that have been consistently measured in workplaces especially during cleaning and maintenance, collecting material from reaction vessels and feeding MNMs into the production process. In the absence of toxicological information, the GDG recommends implementing the highest level of controls to prevent any exposure of workers. When more information is available, the GDG recommends taking a more tailored approach (STRONG, moderate-quality evidence).
Sometimes, specific types of MNMs are processed in a specific way, such as in an open or closed system during synthesis, and thus this determines the likelihood of exposure. The GDG recommends that under these circumstances, the distinctive processes related to the type of MNM are taken into account in the evaluation of workers' likelihood of exposure and the routes of exposure.
The GDG further notes that there is a need to perform high-quality evaluations of worker exposures to nanomaterials in LMI countries.

# From evidence to recommendation
The evidence for these recommendations is based on two systematic reviews of studies that measured exposure to specific MNMs in the work environment. One review assessed what the most likely routes of exposure were and during which tasks these exposures occurred. This review was published by Basinas et al. (2017) (31). The other review assessed the levels of exposure to MNMs, how well the exposures were measured and during which tasks the exposures occurred. This review by Debia et al. (2016) was published as a journal article (32). The studies on inhalation were considered of high quality, but those on dermal and ingestion exposure contained assumptions that reduced the quality of the evidence. The studies on workplace exposure measurements mostly used well elaborated exposure assessment strategies and were rated as high-quality studies.

# Benefits and harms
To be able to implement an effective control strategy, it is important to know if there is exposure to MNMs and what the most important route of uptake is. The recommendation aims at preventing potential harmful effects of MNMs through a focused control strategy.

# Values and preferences
The routes of uptake form an important part of the occupational hygiene strategy to reduce exposure to chemicals. There are no specific values or preferences connected to this issue.

# Net benefits and costs
It is important to know the routes of exposure. For inhalation exposure, the methods of measurement are well-defined, but for dermal and ingestion exposure this is more complicated
and not yet standardized. Certainty about the dermal route of exposure would imply more specific exposure assessment and involve considerably more work and cost.

# Strength of the recommendation
For inhalation exposure, based on the above considerations, the recommendation is strong. For dermal exposure, the quality of evidence is low and thus the recommendation is conditional.

# Summary of findings: routes of exposure to MNMs
Systematic review question: In workers with potential exposure to MNMs, what are the most likely routes of exposure for specific MNMs and during specific tasks based on workplace measurements of MNMs?

# Evidence summary
The systematic review was published by Basinas et al. (2017) (31).

# Number of studies and participants
There were 107 studies reporting a total of 424 exposure assessment situations, i.e. combinations of activity and type of MNM with workers' potential exposure to MNMs and sufficient data to allow assessment of the likelihood of exposure by route.

# Exposures in studies
The exposure assessment situations related to potential workers' exposure to CNTs and CNFs (N = 63), Si-based (N = 42), TiO 2 (N = 43), other metal oxides (N = 77), metals (N = 38), and other nanomaterials (N = 61).

# Outcomes in studies
For every exposure assessment situation, the likelihood of a route of exposure was assessed by applying specific criteria. For inhalation exposure, an adapted set of criteria was used based on the CEN Standard (PREN 17058) Workplace exposure -Assessment of inhalation exposure to nano-objects and their agglomerates and aggregates (33). Dermal exposure was based on an established sourceto-reception model. For each combination of activity and type of MNM, the likelihood of exposure by a particular route was derived by aggregating across the relevant individual assessments.

# Risk of bias in the included studies
The main limitations of the studies are listed below:
 The data that were available from studies included in the review comprised measurement in small and research scale-productions and therefore may not adequately represent the exposure conditions in industrial workplaces.
 For the inhalation route, there was a lack of harmonized methods to measure personal exposure at the workers' breathing zone. Most of the evaluated exposure assessments were based on stationary sampling, not necessarily representative of workers' exposure via inhalation.
 For the dermal route only, there were limited indirect measurement data available that resulted from the analysis of collected surface samples.
 No measurement data are available on ingestion exposure.
 Protection provided by PPE was not considered in the review because it is not relevant to determine the route and form of exposure.
There is high-quality evidence that, in general, the form and route of exposure depends mainly on the activity (i.e. process and operational conditions), rather than just on the type of MNM handled (Annex 3).
There is also high-quality evidence that the likelihood of exposure is affected by the presence of risk management measures and the scale of production. In principle, both inhalation and dermal exposure are less likely when the process is enclosed. For example, CNTs, Si-based and various metal oxides are processed within enclosed reaction vessels, which makes exposure unlikely during production. Other materials such as TiO2 and metals can be synthesized with flame pyrolysis and mechanical reduction in a not fully enclosed process, which makes exposure more likely to occur.
When a worker can possibly inhale MNMs, potential for dermal exposure also exists. However, for some forms (e.g. when an MNM is in suspension/liquid form), dermal exposure or ingestion exposure can be possible even when inhalation exposure is unlikely.
For the following situations and MNMs, exposure was unlikely:
For CNTs and CNFs, there is high-quality evidence that inhalation exposure usually does not occur in the reaction phase of synthesis and handling and transfer of liquids. There is high-quality evidence that dermal exposure does not occur in the reaction phase of synthesis.
For Si-based nanomaterials, there is high-quality evidence that inhalation and dermal exposure do not occur in the reaction phase of synthesis.
For other metal oxides and mixtures, there is high-quality evidence that inhalation and dermal exposure do not occur in the reaction phase of synthesis.
For other MNMs, there is high-quality evidence that inhalation and dermal exposure do not occur in the reaction phase of synthesis.

# Quality of the evidence
Quality of the studies was dependent on the methods used to quantify release and the applicability or not of the adapted set of criteria described in the CEN Standard (PREN 17058) Workplace exposure -Assessment of inhalation exposure to nano-objects and their agglomerates and aggregates (33).
Conclusions reached using the adapted CEN criteria and both off-line and online data, were considered to be based on high-quality data. For some MNMs there is an established exposure assessment method based on chemical analysis, e.g. for CNT and TiO2. When this chemical analysis was used to quantify the release, the quality was considered high even if no online measurements were available or if the available online measurements for the activity involving MNMs were not considerably higher than background.
For dermal exposure, evidence was considered as high quality if surface contamination was clearly established and/or if release was confirmed through both online and off-line measurements and a transparent description of the process and operational conditions was provided.

# Implementation guidance, research recommendation

# Implications for practice
The GDG concludes that there is high-quality evidence for workers' inhalation exposure and lowquality evidence for dermal exposure to MNMs in general.
There is also high-quality evidence that in some situations inhalation exposure is unlikely, such as for CNTs and CNFs during handling and transfer of liquid intermediaries and ready-to-use products, and high-quality evidence that dermal exposure does not occur during the reaction phase of synthesis for most MNMs.
There were no studies of ingestion exposure. However, established conceptual models imply that where dermal exposure occurs, ingestion exposure is likely.

# Implications for research
There is a need to conduct more representative studies to better estimate workers' inhalation exposure by assessing MNMs at the personal breathing zone, rather than in the near-field. Studies that directly measure dermal and ingestion exposure of workers to MNMs are needed. For all routes of exposure more measurements are needed under real industrial production conditions. More research should be conducted to characterize exposures to nanomaterials in a broad range of industries where nanomaterials are used.

# Summary of findings: workplace exposures to MNMs
Systematic review question: In workplaces where MNMs are in use according to the OECD list, does comprehensive measurement of exposure lead to confirmation of exposure to MNMs and if so during which tasks? Any study type in which exposure to MNMs was comprehensively measured was included.

# Evidence summary
The systematic review was published by Debia et al. (2016) as a journal article (32).
GRADE had to be considerably adapted to fit the type of studies reviewed. Consistent results in several studies with comprehensive measurements were considered high-quality evidence.
The GDG judged that given the comprehensiveness of the measurements and the consistency of the results, there was overall high-quality evidence that workers are exposed to micro-sized agglomerated MNMs in workplaces during production and use of products. For the same reasons, the evidence for handling tasks was rated as high quality.

# Implementation guidance, research recommendation

# Implications for practice
The GDG concludes that there is high-quality evidence that workers are exposed to micro-sized agglomerated nanoparticles and that exposure occurs mostly during handling tasks, cleaning operations and machining of products. There was low-quality evidence of exposure to nanoscale primary airborne nanoparticles in workplaces. There were no studies, and therefore there was no evidence of exposures in LMI countries.

# Implications for research
Longitudinal studies evaluating workers' exposure over time are needed. Studies of workers' exposure in LMI countries are also needed. Recommendation 11: When assessment and measurement by a workplace safety expert is not available, the GDG suggests using control banding for nanomaterials to select exposure control measures in the workplace. Owing to a lack of studies, the GDG cannot recommend one method of control banding over another (CONDITIONAL, very lowquality evidence).

# Use controls to reduce the level of exposure
The GDG considered that in the absence of toxicological information on MNMs, the most stringent control measures should be applied to prevent workers from being exposed. This is also called a no-exposure policy.
Control banding is an approach to risk management for SMEs that can be applied to prevent worker exposures in cases of incomplete information about a nanomaterial. Control-banding strategies are often found in toolkits with categories, or bands, of health hazards, that are combined with exposure scenarios to determine the desired controls. This approach allows users to make meaningful inferences about likely exposures and to make decisions about necessary controls, reducing the exposures within four or five hazard bands (34).
When there is only limited toxicological information available for MNMs, or when analogies can be made with hazard properties of similar materials in broad groups, this should lead to control banding. When full toxicological information is available, this should lead to full risk assessment.
The GDG therefore notes that control banding does not replace risk assessment, but it can still be beneficial for communication and better risk management.

# From evidence to recommendation
The evidence for these recommendations is based on two systematic reviews, both of which were published as journal articles. The first, by Myojo, Nagata & Verbeek (2017), reviewed the effects of control measures (35). The other, by Eastlake, Zumwalde & Geraci (2016), assessed the effects of the control-banding approach (36). For the control measures varying levels of evidence were found and therefore parts of the recommendation are conditional. Overall the risk of bias across studies was low but precision was unclear. For PPE the quality of the evidence was further downgraded because of indirectness, meaning that there were only laboratory studies and no field studies. For control banding there were only two studies, with a high risk of bias.
Control-banding tools such as those listed in the systematic review (36) can be used proactively as a low-cost intervention to reduce exposures to nanomaterials in the workplace.

# Benefits and harms
There are clear benefits of preventing and decreasing exposure by engineering controls.

# Values and preferences
The hierarchy of controls is a generally accepted concept in occupational hygiene, in which increased value is given to what are known as "more preventive" solutions (see Hierarchy of controls). Control banding is an approach that is well understood by employers and employees and seems feasible with bulk materials (37).

# Net benefits and costs
The costs for full enclosure or process change can be considerable but decrease with the hierarchy of controls. The GDG attaches much weight to more preventive solutions. Control banding requires training but no considerable investments (38).

# Strength of the recommendation
Based on the above considerations, the GDG makes a strong recommendation for control measures for inhalation exposure but a conditional recommendation for full body protection to prevent dermal exposure and a conditional recommendation for control banding.

# Evidence summary of controls to reduce exposure to MNMs
Systematic review question: In workers or workplaces with exposure to MNMs, what is the effect of workplace ventilation, PPE or organization of work aimed at reducing exposure, on the level of exposure to MNMs compared to no controls or protective equipment based on studies that compared a situation with the intervention to a situation without the intervention?
The effect of the controls was expressed as the protection factor (PF), which is defined as the ratio of exposure level (either mass-based or particle-based) without the controls divided by the exposure level with the controls. If the PF is >1 controls reduce exposure. A PF of 10 indicates that controls reduce exposure by 90%.

# Evidence summary
The systematic review by Myojo and Nagata (2017) was published as a journal article (35).

# Number of studies and participants
There were 50 studies with 55 workplaces/participants. Of these studies, 27 were before-after comparisons.

# Controls evaluated in studies
There were 14 studies with 27 workplaces that evaluated ventilation, 19 studies with 23 participants evaluated PPE, 16 studies evaluated other control strategies: five on suppression with fluids, two on automation of a process with five workplaces, eight on other organizational strategies, and one on the use of SDS. All studies were about MNM exposure and 15 of these were on exposure to carbon nanotubes.

# Outcomes in studies
All outcomes were expressed as a PF.

# Risk of bias in the included studies
The main limitations were no control group for the studies on engineering controls and no fieldwork for the respiratory protection studies. Risk of bias in the studies was 2 to 3 on a scale that ranged from 3 to 3, in which 3 meant a very high risk of bias and +3 a very low risk of bias.

# Effects of exposure
For engineering controls, enclosure achieved the highest PFs of > 100 (seven cases).
For ventilation, PFs varied from 0.12 to 55 (20 cases) with 15 cases providing PFs >3. For ventilation of fume cupboards, the PF was influenced by the face velocity of the air and the movements of workers. Face velocity is the inward airflow velocity measured in several specific locations across the plane of the fume cupboard sash opening.
in this area. Specifically, effectiveness of control banding to reduce exposures to MNMs should be evaluated by carrying out measurements selected through the use of control-banding tools (against more comprehensive risk assessment and risk management approaches). Controlbanding tools should be further evaluated for use with MNMs. Control-banding tools should be calibrated against exposure measurements and guidance for selection of the appropriate tool for specific situations should be developed.

# Health surveillance
The GDG cannot make a recommendation for targeted MNM-specific health surveillance programmes over existing health surveillance programmes that are already in use, due to the lack of evidence.
The GDG further notes that existing occupational health surveillance systems could be implemented to monitor health outcomes possibly associated with MNM exposure where there are health concerns. Given that knowledge of MNMs and their adverse health effects is increasing rapidly, this recommendation should be updated in five years to take into account new findings.

# From evidence to recommendation
The evidence for this recommendation is based on a small number of non-randomized studies at high risk of bias that did not show the benefits of health examinations.

# Benefits and harms
The benefits of health examinations could not be assessed. Setting up a health surveillance system for workers exposed to MNMs would be costly. In addition, it would be difficult, with the current lack of knowledge, to ascribe adverse health effects to MNM exposure.

# Values and preferences
It is well known that general health examinations are highly valued by consumers and this is probably also the case for workers (39).

# Net benefits and costs
Since the GDG could not assess any benefits of health examinations that are specific for MNMs, only considerable costs remain.

# Strength of the recommendation
Based on the above considerations, there is no recommendation for specific health examinations.

# Summary of findings: health examinations of workers exposed to MNMs
Systematic review question: In workers exposed to MNMs, what is the effect of health surveillance on any adverse health outcome compared to no health surveillance or an alternative form of health surveillance based on any study that described or evaluated health surveillance?
The systematic review was published by Gulumian et al. (2016) as a journal article (40).

# IMPLEMENTATION OF THE GUIDELINES
Given the current high exposures to MNMs documented in the exposure review, considerable efforts are needed by all stakeholders to ensure country implementation of these guidelines with a particular focus on LMI countries.
WHO will officially launch these guidelines with its partners from the Collaborating Centres for Occupational Health and nongovernmental organizations in official relations with WHO, in addition to presenting the guidelines for further distribution at diverse forums.
With regard to a corporate launch, discussions will be held internally with the Director Public Health, Environmental and Social Determinants of Health, Department of Communication and the WHO regions to devise a communications plan. This can be achieved through stakeholder networks including those of GDG members and the WHO Global Network of Collaborating Centres.
In addition to this document, simplified summaries will be prepared for employers and workers to ease implementation and monitoring.

# Implications for research
More research needs to be conducted to (i) identify biomarkers specific to nanomaterial exposures; (ii) identify potential early signs predicting potential long-term adverse health effects, and (iii) validate current medical tests for use in asymptomatic nanomaterial-exposed workers. It is important to emphasize to workers participating in health surveillance that these programmes at this point are research efforts with unproven benefit and health significance to participants.
Exposure registry studies, based on which workers can be followed over time to validate candidate biomarkers, are needed.

# Number of studies and participants
Over the reviewed period (January 2000-January 2015), 50 studies in 72 workplaces with 306 exposure situations were eligible and included in the review. Studies were mainly located in the Republic of Korea and the United States, but none in LMI countries. Most studies (62.5%) were in research laboratories or pilot plants.

# Exposures in the studies
Exposures to carbonaceous and metallic nanomaterials and nanoclays were evaluated in the studies.

# Outcomes in studies
Authors reported weight-based concentrations (mass concentration), count-based concentrations (number concentration) and off-line qualitative analysis.

# Risk of bias in the included studies
The main limitations in the studies were that the exposure measurements were not real breathing zone sampling and not as comprehensive as would be advisable.

# Confirmed exposure
Of the 306 exposure situations, there was confirmed exposure in 233 (76%) ranging from 100% for nanoclays, 83% for carbonaceous MNMs and 73% for metallic MNMs.
In 233 of the exposure situations, confirmed workers' exposure was mainly confined to microsized agglomerated MNMs with only a few studies reporting the sampling of nanoscale airborne MNMs.
Exposures to carbonaceous MNMs ranged from not detected to 910 g/m 3 of elemental carbon (EC) with local engineering controls and from not detected to 1000 g/m 3 EC without controls.
Carbon nanofibre exposure ranged from not detected to 1.6 CNF structures/cm 3 with local engineering controls and from 0.09 CNF structures/cm 3 to 193 CNF structures/cm 3 without controls. Titanium dioxide nanoparticle exposure ranged from 0.24 to 0.43 g/m 3 with local engineering controls and from 0.09 to 33 g/m 3 without controls. Aluminium oxide nanoparticle exposure was not detected with local engineering controls and ranged from not detected to 0.157 g/m 3 without controls.
Silver nanoparticle exposure ranged from 0.09 to 4.99 g/m 3 during dry synthesis with no controls (only general ventilation) and from 0.38 to 0.43 g/m 3 during wet synthesis (with fume hood). Reactor cleaning activities yielded the highest exposure, up to 33 g/m 3 (with local exhaust ventilation).
Iron nanoparticle exposure ranged from 32 g/m 3 with local engineering controls to 335 g/m 3 without controls.
In 231 of the exposure situations, workers were exposed to micro-sized agglomerated MNMs and in two of the exposure situations to nanoscale MNMs.
For process automation, the PFs varied between 2.5 and 8.2 (five cases) but, owing to interruption of the process by handling material, one case yielded a PF of 0.073. The studies on dustiness and fluid-dust suppression did not provide before-after measurements and did not allow for a PF calculation.
For respiratory protection, masks rated at the protection level of N95 respirators provided a PF of more than 10 in 11 cases. Higher rated P100 respirators provided higher PFs of around 100. One study evaluated a cloth mask which yielded a PF of 1.1 to 1.35. One study reported on a loosefitting powered air-purifying respirator with PFs over 1.1 million. Most studies were performed in the laboratory under ideal conditions with exposure to sodium chloride as a proxy for MNM because of its size. However, it is unclear whether these results can be extrapolated to mask performance in real workplaces.

# Quality of the evidence
Risk of bias in the studies was low. Except for the respiratory protection studies the evidence was direct. The results were consistent across studies. Precision of the effects was unclear because the authors did not provide estimates of statistical precision. Publication bias can be expected, but could not be assessed owing to a lack of data.
The rating of the evidence was defined as low quality at the outset because all studies were nonrandomized and non-controlled. The evidence was not upgraded or downgraded.

# Implementation guidance, research recommendation

# Implications for practice
The GDG concludes that there is only low-quality evidence that exposure to MNMs can be decreased with engineering controls such as enclosure and ventilation, when the specific exposure situations are taken into consideration. There is also only low-quality evidence that respiratory protection can considerably decrease exposure, if the proper type is used and fittesting is performed for each wearer.

# Implications for research
Field studies that evaluate dust control techniques, such as modification and suppression are needed. In addition, studies on the effectiveness of respiratory protection under real workplace conditions are needed.

# Evidence summary: control banding for safe handling of manufactured nanomaterials
Systematic review question: In workers or workplaces with potential exposure to MNM, what is the effect of the use of a control-banding tool on controls in place or level of exposure compared to no risk assessment tool or an alternative risk assessment tool based on any type of controlled study?

# Evidence summary
The full review was published by Eastlake, Zumwalde & Geraci (2016) as a journal article (36).

# Number of studies and participants
There were two studies that evaluated 32 different exposure situations. One study was conducted in two MNM research laboratories with exposure to metal and ceramic nanoparticles and CNTs in the United States. The other study reported an additional 27 cases of potential exposure to a variety of MNMs, but did not provide details of the geographical location or the worksite.

# Interventions in studies
Both studies were about evaluating potential exposure to a variety of MNMs using the controlbanding nanotool developed by Paik, Zalk & Swuste (38).
The use of the control-banding nanotool was compared to assessments performed by an experienced occupational hygienist.

# Outcomes in studies
The outcome in both studies was the recommendation of an engineering control.

# Risk of bias in the included studies
The main limitations were that there was only a qualitative analysis and no exposure measurements. One of the studies did not provide details of the work situations.

# Effects of exposure
In the two studies, the recommendations provided using the control-banding nanotool concurred with those of the occupational hygienist in 59% (19/32) of cases. The control-banding nanotool recommended a lower level of control than the occupational hygienist in 28% (9/32) of cases. The control-banding nanotool recommended a higher level of control than the occupational hygienist in 13% (4/32) of cases.
No exposure assessment data were provided to verify that engineering controls recommended by the occupational hygienist reduced exposure potential.

# Quality of the evidence
According to GRADE, observational studies start as low-quality evidence, unless they can be upgraded. Based on the limitations of the studies (qualitative analysis, no exposure assessment data, no details about workplaces), the evidence found in this systematic review was downgraded to very low quality.

# Implementation guidance, research recommendation

# Implications for practice
The GDG concludes that there is only very low-quality evidence that use of the control-banding nanotool leads to similar control measures to those an experienced occupational hygienist would recommend. Professionals, employers and workers would all need training to be able to use the tool.

# Implications for research
The low quality of evidence on the effectiveness of control-banding approaches to reduce worker exposure to nanomaterials to safe levels, suggests that more research needs to be conducted

# Number of studies and participants
There were seven studies of which six compared health indicators between exposed and unexposed workers, with 1278 participants. One study described a programme, but did not report any health outcomes. Studies showed that workers were exposed to a mixture of MNMs (3), CNTs (2), nanosilver (1) and TiO 2 (1).

# Health examinations in studies
Studies reported on biomarkers from exhaled breath condensate, blood and urine such as markers of oxidative stress and antioxidant enzymes; early health effects such as pulmonary and neurobehavioural test results; and self-reported health outcomes.

# Risk of bias in the included studies
The main limitations were that there were no controlled studies with a longitudinal design; all of them were cross-sectional.

# Effects of exposure
Two studies found biomarker levels (exhaled breath condensate concentrations of malondialdehyde, 4-hydroxy hexenal (4-HHE) and n-hexanal/aldehyde) elevated in exposed groups compared to unexposed groups.
Early health indicators (lung function parameters) did not deviate from physiologically normal parameters or did not differ between groups.
The prevalence of allergic dermatitis and sneezing was higher among workers exposed to MNMs in one study.

# Quality of the evidence
According to GRADE, observational studies start as low-quality evidence unless they can be upgraded. The evidence found in this systematic review was further downgraded because of limitations in study design. There were no reasons to upgrade the evidence.

# Implementation guidance, research recommendation

# Implications for practice
The GDG concludes that there is only very low-quality evidence on whether targeted nanomaterial health surveillance might reveal early signs of adverse health effects. There was no evidence on specific items that should be included in a surveillance programme.

# Training and involvement of workers
The GDG considers training of workers and worker involvement in health and safety issues to be best practice, but cannot recommend one form of training of workers over another, or one form of worker involvement over another, owing to the lack of studies available.
The GDG commissioned a systematic review to answer the question "what training should be provided to workers?". The question was reformulated to look at the effects of additional training and education on workers potentially exposed to MNMs. The systematic review by von Mering & Schumacher (2017) was published by WHO (41). The GDG also conducted preliminary searches to answer the question about worker participation in the workplace risk assessment and management of MNMs. However, no studies were found on this topic.

# Summary of findings: training and involvement of workers

# Evidence summary
The systematic review did not locate any studies on the effects of worker training. There were no studies that established specific workers' training needs related to MNMs.

# Research recommendation

# Implications for research
The GDG recommends evaluating the effect of worker and employer training on the level of MNM exposure and the installation of controls compared to alternative forms of training, preferably with a controlled before-after design. Similarly, the GDG recommends evaluating the effect of different forms of worker involvement on level of exposure and implementation of controls.

# UPDATING THE GUIDELINES
The field of MNM safety is evolving rapidly. A research agenda set by Stone et al. in collaboration with stakeholders in 2014, foresaw considerable progress in validated measurement methods and the assessment of routes of exposure and monitoring strategies in the short term (42). Therefore the GDG proposes to update these guidelines in 2022.

# ANNEX 1: LIST OF PROPOSED OCCUPATIONAL EXPOSURE LIMIT (OEL) VALUES FOR MNMS