Safe- and sustainable-by-design: The case of Smart Nanomaterials. A perspective based on a European workshop.

The European Commission's Green Deal is a major policy initiative aiming to achieve a climate-neutral, zero-pollution, sustainable, circular and inclusive economy, driving both the New Industrial Strategy for Europe and the Chemicals Strategy for Sustainability. Innovative materials can help to reach these policy goals, but they need to be safe and sustainable themselves. Thus, one aim is to shift the development of chemicals to Safe- and Sustainable-by-Design, and define a new systems approach and criteria for sustainability to achieve this. An online workshop was organised in September 2020 by the Joint Research Centre and the Directorate-General Research and Innovation of the European Commission, with participants from academia, non-governmental organisations, industry and regulatory bodies. The aims were to introduce the concept of Safe- and Sustainable-by-Design, to identify industrial and regulatory challenges in achieving safer and more sustainable Smart Nanomaterials as an example of innovative materials, and to deliver recommendations for directions and actions necessary to meet these challenges. The following needs were identified: (i) an agreed terminology, (ii) a common understanding of the principles of Safe- and Sustainable-by-Design, iii) criteria, assessment tools and incentives to achieve a transition from Safe-by-Design to Safe- and Sustainable-by-Design, and (iv) preparedness of regulators and legislation for innovative chemicals/nanomaterials. This paper presents the authors' view on the state of the art as well as the needs for future activities, based on discussions at the workshop and further considerations. The case of Smart Nanomaterials is used to illustrate the Safe- and Sustainable-by-Design concept and challenges for its implementation. Most of the considerations can be extended to other advanced materials and to chemicals and products in general.

Advanced materials foresight: research and innovation indicators related to advanced and smart nanomaterials.

Background: Advanced materials are most likely to bring future economic, environmental and social benefits. At the same time, they may pose challenges regarding their safety and sustainability along the entire lifecycle. This needs to be timely addressed by the stakeholders (industry, research, policy, funding and regulatory bodies). As part of a larger foresight project, this study aimed to identify areas of scientific research and technological development related to advanced materials, in particular advanced nanomaterials and the sub-group of smart nanomaterials. The study identified and collected data to build relevant research and innovation indicators and analyse trends, impact and other implications. Methods: This study consisted of an iterative process including a documentation phase followed by the identification, description and development of a set of core research and innovation indicators regarding scientific publications, EU projects and patents. The data was extracted mainly from SCOPUS, CORDIS and PATSTAT databases using a predefined search string that included representative keywords. The trends, distributions and other aspects reflected in the final version of the indicators were analysed, e.g. the number of items in a period of time, geographical distribution, organisations involved, categories of journals, funding programmes, costs and technology areas. Results: Generally, for smart nanomaterials the data used represent around 3.5% of the advanced nanomaterials data, while for each field analysed, they represent 4.4% for publications, 13% for projects and 1.1% for patents. The study shows current trends for advanced nanomaterials at a top-level information that can be further extended with sub-indicators. Generally, the results indicated a significant growth in research into advanced nanomaterials, including smart nanomaterials, in the last decade, leading to an increased availability of information. Conclusion: These indicators identify trends regarding scientific and technological achievements and represent an important element when examining possible impacts on society and policy implications associated to these areas.

Commentary on "Safe(r) by design implementation in the nanotechnology industry" [NanoImpact 20 (2020) 100267] and "Integrative approach in a safe by design context combining risk, life cycle and socio-economic assessment for safer and sustainable nanomaterials" [NanoImpact 23 (2021) 100335].

Commentary on two recent papers published in NanoImpact "Safe(r) by design implementation in the nanotechnology industry" and "Integrative approach in a safe by design context combining risk, life cycle and socio-economic assessment for safer and sustainable nanomaterials".

Developing OECD test guidelines for regulatory testing of nanomaterials to ensure mutual acceptance of test data.

The OECD Working Party on Manufactured Nanomaterials (WPMN) provides a global forum for discussion of nano-safety issues. Together with the OECD Test Guidelines Programme (TGP) the WPMN has explored the need for adaptation of some of the existing OECD Test Guidelines (TGs) and Guidance Documents (GDs) as well as developing new TGs and GDs to specifically address NM issues. An overview is provided of progress in the TGP and WPMN, and information on supporting initiatives, regarding the development of TGs for nanomaterials addressing Physical Chemical Properties, Effects on Biotic Systems, Environmental Fate and Behaviour, and Health Effects. Three TGs specifically addressing manufactured nanomaterials have been adopted: a new TG318 ″Dispersion Stability of Nanomaterials in Simulated Environmental Media", and adaptation of TG412 and TG413 on Subacute Inhalation Toxicity: 28-Day Study/90-day Study. The associated GD39 on Inhalation Toxicity Testing has also been revised. The TGP current develops four new TGs and four GDs. One new TG and six GDs are developed in the WPMN. Six new proposals were submitted to the TGP in 2018. Furthermore, as TGs are accompanied by OECD harmonised templates (OHTs) for data collection, an outline of recently developed OHTs particularly relevant for NMs is also included.

Introducing a new standardized nanomaterial environmental toxicity screening testing procedure, ISO/TS 20787: aquatic toxicity assessment of manufactured nanomaterials in saltwater Lakes using Artemia sp. nauplii.

This paper introduces a new standardized testing procedure for nanomaterial environmental toxicity (International Organization for Standardization/Technical Specification (ISO/TS) 20787): 'aquatic toxicity assessment of manufactured nanomaterials in saltwater lakes using Artemia sp. Nauplii' intended to generate more reliable and repeatable aquatic toxicity data testing manufactured nanomaterials, using Artemia sp., to evaluate their possible ecotoxicity in saltwater lake ecosystems. The principles behind testing with Artemia sp. are reviewed and the paper gives an overview of research published between 2009 and 2018 in which manufactured nanomaterials were tested using Artemia sp.

An inventory of ready-to-use and publicly available tools for the safety assessment of nanomaterials.

Legislation addressing environmental, health and safety aspects of nanomaterials in consumer products and ensuring their safe use is being continuously updated in the European Union and globally. This leads to a growing need for tools to implement this developing legislation. A freely accessible inventory of ready-to-use and publicly available tools that together cover the tasks within a nanomaterial safety assessment process was built in the presented work. This inventory is a unique metadata set in Excel® format: the 'NANoREG Toolbox', which assembles information needed for selecting and accessing instruments that meet specific goals. The recorded tools are categorised according to their purpose, type and regulatory status. The Toolbox covers an unprecedented and broad range of over 500 current tools, developed in Europe and beyond. While NANoREG focussed on safety assessment under the EU Regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), the instruments in the Toolbox are relevant and useful for nanomaterial safety assessments worldwide.

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events. OBJECTIVES: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies. SEARCH METHODS: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention. DATA COLLECTION AND ANALYSIS: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses. MAIN RESULTS: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). AUTHORS' CONCLUSIONS: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

Physico-chemical properties of manufactured nanomaterials - Characterisation and relevant methods. An outlook based on the OECD Testing Programme.

Identifying and characterising nanomaterials require additional information on physico-chemical properties and test methods, compared to chemicals in general. Furthermore, regulatory decisions for chemicals are usually based upon certain toxicological properties, and these effects may not be equivalent to those for nanomaterials. However, regulatory agencies lack an authoritative decision framework for nanomaterials that links the relevance of certain physico-chemical endpoints to toxicological effects. This paper investigates various physico-chemical endpoints and available test methods that could be used to produce such a decision framework for nanomaterials. It presents an overview of regulatory relevance and methods used for testing fifteen proposed physico-chemical properties of eleven nanomaterials in the OECD Working Party on Manufactured Nanomaterials' Testing Programme, complemented with methods from literature, and assesses the methods' adequacy and applications limits. Most endpoints are of regulatory relevance, though the specific parameters depend on the nanomaterial and type of assessment. Size (distribution) is the common characteristic of all nanomaterials and is decisive information for classifying a material as a nanomaterial. Shape is an important particle descriptor. The octanol-water partitioning coefficient is undefined for particulate nanomaterials. Methods, including sample preparation, need to be further standardised, and some new methods are needed. The current work of OECD's Test Guidelines Programme regarding physico-chemical properties is highlighted.

Aggression in Psychiatric Wards: Effect of the Use of a Structured Risk Assessment.

Health care workers are often exposed to violence and aggression in psychiatric settings. Short-term risk assessments, such as the Brøset Violence Checklist (BVC), are strong predictors of such aggression and may enable staff to take preventive measures against aggression. This study evaluated whether the routine use of the BVC could reduce the frequency of patient aggression. We conducted a study with a semi-random regression discontinuity design in 15 psychiatric wards. Baseline aggression risk was assessed using the Aggression Observation Short Form (AOS) over three months. The BVC was implemented in seven intervention wards, and the risk of aggressive incidents over three months of follow-up was compared with the risk in eight control wards. The analysis was conducted at the ward level because each ward was allocated to the intervention and control groups. At baseline, the risk of aggression varied between wards, from one aggressive incident per patient per 1,000 shifts to 147 aggressive incidents per patient per 1,000 shifts. The regression discontinuity analysis found a 45% reduction in the risk of aggression (Odds Ratio (OR) = 0.55, 95% confidence interval: 0.21-1.43). The study did not find a significant reduction in the risk of aggression after implementing a systematic short-term risk assessment with the BVC. Although our findings suggest that use of the BVC may reduce the risk of aggression, the results need to be confirmed in studies with more statistical power.

Proinflammatory Effects of Pyrogenic and Precipitated Amorphous Silica Nanoparticles in Innate Immunity Cells.

Amorphous silica nanoparticles (ASNP) can be synthetized via several processes, 2 of which are the thermal route (to yield pyrogenic silica) and the wet route from a solution containing silicate salts (to obtain precipitated, colloidal, mesoporous silica, or silica gel). Both methods of synthesis lead to ASNP that are applied as food additive (E551). Current food regulation does not require that production methods of additives are indicated on the product label, and, thus, the ASNP are listed without mentioning the production method. Recent results indicate, however, that pyrogenic ASNP are more cytotoxic than ASNP synthesized through the wet route. The present study was aimed at clarifying if 2 representative preparations of ASNP, NM-203 (pyrogenic) and NM-200 (precipitated), of comparable size, specific surface area, surface charge, and hydrodynamic radius in complete growth medium, had different effects on 2 murine macrophage cell lines (MH-S and RAW264.7 cells). Our results show that, when incubated in protein-rich fluids, NM-203 adsorbed on their surface more proteins than NM-200 and, once incubated with macrophages, elicited a greater oxidative stress, assessed from Hmox1 induction and ROS production. Flow cytometry and helium ion microscopy indicated that pyrogenic NM-203 interacted with macrophages more strongly than the precipitated NM-200 and triggered a more evident inflammatory response, evaluated with Nos2 induction, NO production and the secretion of TNF-α, IL-6 and IL-1ß. Moreover, both ASNP synergized macrophage activation by bacterial lipopolysaccharide (LPS), with a higher effect observed for NM-203. In conclusion, the results presented here demonstrate that, compared to precipitated, pyrogenic ASNP exhibit enhanced interaction with serum proteins and cell membrane, and cause a larger oxidative stress and stronger proinflammatory effects in macrophages. Therefore, these 2 nanomaterials should not be considered biologically equivalent.

Review of achievements of the OECD Working Party on Manufactured Nanomaterials' Testing and Assessment Programme. From exploratory testing to test guidelines.

This paper charts the almost ten years of history of OECD's work on nanosafety, during which the programme of the OECD on the Testing and Assessment of Manufactured Nanomaterials covered the testing of eleven nanomaterials for about 59 end-points addressing physical-chemical properties, mammalian and environmental toxicity, environmental fate and material safety. An overview of the materials tested, the test methods applied and the discussions regarding the applicability of the OECD test guidelines, which are recognised methods for regulatory testing of chemicals, are given. The results indicate that many existing OECD test guidelines are suitable for nanomaterials and consequently, hazard data collected using such guidelines will fall under OECD's system of Mutual Acceptance of Data (MAD) which is a legally binding instrument to facilitate the international acceptance of information for the regulatory safety assessment of chemicals. At the same time, some OECD test guidelines and guidance documents need to be adapted to address nanomaterials while new test guidelines and guidance documents may be needed to address endpoints that are more relevant to nanomaterials. This paper presents examples of areas where test guidelines or guidance for nanomaterials are under development.

Grouping and Read-Across Approaches for Risk Assessment of Nanomaterials.

Physicochemical properties of chemicals affect their exposure, toxicokinetics/fate and hazard, and for nanomaterials, the variation of these properties results in a wide variety of materials with potentially different risks. To limit the amount of testing for risk assessment, the information gathering process for nanomaterials needs to be efficient. At the same time, sufficient information to assess the safety of human health and the environment should be available for each nanomaterial. Grouping and read-across approaches can be utilised to meet these goals. This article presents different possible applications of grouping and read-across for nanomaterials within the broader perspective of the MARINA Risk Assessment Strategy (RAS), as developed in the EU FP7 project MARINA. Firstly, nanomaterials can be grouped based on limited variation in physicochemical properties to subsequently design an efficient testing strategy that covers the entire group. Secondly, knowledge about exposure, toxicokinetics/fate or hazard, for example via properties such as dissolution rate, aspect ratio, chemical (non-)activity, can be used to organise similar materials in generic groups to frame issues that need further attention, or potentially to read-across. Thirdly, when data related to specific endpoints is required, read-across can be considered, using data from a source material for the target nanomaterial. Read-across could be based on a scientifically sound justification that exposure, distribution to the target (fate/toxicokinetics) and hazard of the target material are similar to, or less than, the source material. These grouping and read-across approaches pave the way for better use of available information on nanomaterials and are flexible enough to allow future adaptations related to scientific developments.

Assessment of causal associations between illness and criminal acts in those who are acquitted by reason of insanity.

BACKGROUND: The court proceedings after the terrorist attacks on 22 July 2011 reignited the debate on the justification for having a rule that regulates the insanity defence exclusively on the basis of a medical condition ­ the medical principle. The psychological principle represents an alternative that requires a causal relationship between the psychosis and the acts committed. In this article we investigate rulings made by the courts of appeal where the accused have been found legally insane at the time of the act, and elucidate the extent to which a causal relationship between the illness and the act appears to be in evidence. MATERIAL AND METHOD: Data have been retrieved from rulings by the courts of appeal published at lovdata.no, which include anonymised rulings. Searches were made for cases under Section 39 (verdict of special sanctions) and Section 44 (acquittal by reason of insanity) of the General Civil Penal Code. Court rulings in which a possible causal relationship could be considered were included. The included rulings were carefully assessed with regard to whether a causal relationship existed between the mental disorder of the accused at the time and the criminal act. The search returned a total of 373 rulings, of which 75 were included. RESULTS: The vast majority of the charges referred to serious crimes. Diagnoses under ICD-10 category codes F20-29 (schizophrenia, schizotypal and delusional disorders) were the most frequently occurring type. In 17 of the 75 rulings (23%), it was judged that no causal relationship between the illness and the act existed. In 25 of 26 cases that involved homicide, a causal relationship between the illness and the act was judged to be evident. INTERPRETATION: The data may indicate that the medical principle results in impunity in a considerable number of rulings where the illness of the accused apparently has had no effect on the acts committed.

Hydroxyethyl starch reduces coagulation competence and increases blood loss during major surgery: results from a randomized controlled trial.

OBJECTIVE: This study evaluated whether administration of hydroxyethyl starch (HES) 130/0.4 affects coagulation competence and influences the perioperative blood loss. BACKGROUND: Artificial colloids substitute blood volume during surgery; with the administration of HES 130/0.4 (Voluven, Fresenius Kabi, Uppsala, Sweden) only a minor effect on coagulation competence is expected. METHODS: Eighty patients were scanned for enrollment in the study, and 40 patients fulfilled the inclusion criteria. Two patients withdrew their consent to participate in the study, and 5 patients were excluded. Thus, 16 patients were randomized to receive lactated Ringer's solution and 17 to receive HES 130/0.4. RESULTS: Among the patients receiving HES 130/0.4, thrombelastography indicated reduced clot strength (P < 0.001) and blinded evaluation of the perioperative blood loss was 2.2 (range 0.5 to 5.0) versus 1.4 (range 0.5 to 2.4) L in the patients who received HES 130/0.4 or lactated Ringer, respectively (P < 0.038). The patients in the lactated Ringer's group, however, received more fluid (P < 0.0001) than those in the HES 130/0.4 group. There was no significant difference between the 2 groups with regard to frequency of reoperations or the length of hospital stay, but use of HES 130/0.4 was both more expensive and less efficacious than the use of lactated Ringer. CONCLUSIONS: Administration of HES 130/0.4 reduced clot strength and perioperative hemorrhage increased by more than 50%, while administration of lactated Ringer's solution provoked an approximately 2.5 times greater positive volume balance at the end of surgery.

European experience in chemicals management: integrating science into policy.

The European Union (EU) adopted the first legislation on chemicals management in 1967 with the Dangerous Substances Directive (DSD). Over time the underlying concepts evolved: from hazard identification over risk assessment to safety assessment. In 1981 a premarketing notification scheme was introduced. Approximately 10 years later a risk assessment program started for existing substances following a data collection and prioritization exercise. Integration of science into EU chemicals legislation occurred via several technical committees managed by the European Chemicals Bureau (ECB) and resulted in the Technical Guidance Document on Risk Assessment (TGD), which harmonized the risk assessment methodology. The TGD was revised several times to adapt to scientific developments. The revision process, and the risk assessments for new and existing substances, led to scientific research on chemical risk assessment and thus increased in complexity. The new EU chemicals policy REACH (Registration, Evaluation, Authorization and Restriction of CHemicals) builds on previous experiences and aims to further enhance health and safety. REACH places the burden of proof for chemical safety on industry focusing on managing risks. REACH formalizes the precautionary principle. Furthermore, it underlines a continued scientific underpinning in its implementation, also via stakeholder involvement, and a focus on aligning with international fora.

Forensic issues in intellectual disability.

PURPOSE OF REVIEW: The present paper reviews some of the most significant findings in the field of forensic issues related to intellectual disability over the last 2 years. RECENT FINDINGS: Recent publications have explored the prevalence and assessment of intellectual disabilities in the criminal justice system, as well as individual characteristics of intellectual disabled offenders. Service by the criminal justice system and treatment of intellectual disabled offenders have also been explored. New insights into violence and sexual offences have been achieved, however identification and evidence-based treatment of intellectual disabled offenders are not widely explored issues. SUMMARY: Progress in treatment studies, studies of the function of the criminal justice system and risk assessments have resulted in improvements in these aspects during recent years. The wide range of services involved in successful initiatives has been addressed, but some crucial aspects still receive too little attention. Differences between countries and cultures have not been emphasized, and the progress that has been achieved seems to be confined to countries with a clear policy and organized services for offenders with intellectual disabilities.