2.1. Getting Started
According to established WHO procedures, the Interventions for Healthy Environments Unit in the Department of Public Health, Environmental and Social Determinants of Health, obtained planning approval in 2010 to develop guidelines and established a WHO Guideline Steering Group and a Guideline Development Group (GDG). The GDG was composed of leading experts and end-users responsible for the process of developing the evidence-based recommendations.
Members of the WHO Guideline Steering Group and the GDG are listed in Tables A.2.1 and A.2.2 of Annex 2. Funding for meetings and the costs of the methodologist were provided by the WHO Department of Public Health, Environmental and Social Determinants of Health. Experts participated in the GDG on an in-kind basis and systematic reviews were conducted by volunteer teams.
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).
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:
Paris, France, on 9 and 10 February 2015
Brussels, Belgium on 4 and 5 September 2015
Dortmund, Germany on 18 and 19 April 2016.
2.2. 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 Table A.2.3 of Annex 2.
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.
2.3. 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.
2.3.1. 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.
2.3.2. 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 non-intervention 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 (). 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 . The reviewers did not use any qualifiers for upgrading the evidence, as is possible in the GRADE approach for non-randomized intervention studies.
Grade Adaptation: Domains and Criteria to Assess the Quality of The Evidence.
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.
2.4. From Evidence to Recommendations
2.4.1. 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.
2.4.2. 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).
