Next generation risk assessment for occupational chemical safety - A real world example with sodium-2-hydroxyethane sulfonate.

Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted to assessments of consumer use of cosmetics and is not currently implemented in occupational safety assessments, e.g. under EU REACH. By contrast, a large proportion of regulatory worker safety assessments are underpinned by toxicological studies using experimental animals. Consequently, occupational safety assessment represents an area that would benefit from increasing application of NGRA to safety decision making. Here, a workflow for conducting NGRA under an occupational safety context was developed, which is illustrated with a case study chemical; sodium 2-hydroxyethane sulphonate (sodium isethionate or SI). Exposures were estimated using a standard occupational exposure model following a comprehensive life cycle assessment of SI and considering factory-specific data. Outputs of this model were then used to estimate internal exposures using a Physiologically Based Kinetic (PBK) model, which was constructed with SI specific Absorption, Distribution, Metabolism and Excretion (ADME) data. PBK modelling indicated a worst-case plasma maximum concentration (Cmax) of 0.8 µM across the SI life cycle. SI bioactivity was assessed in a battery of NAMs relevant to systemic, reproductive, and developmental toxicity; a cell stress panel, high throughput transcriptomics in three cell lines (HepG2, HepaRG and MCF-7 cells), pharmacological profiling and specific assays relating to developmental toxicity (Reprotracker and devTOX quickPredict). Points of Departure (PoDs) for SI ranged from 104 to 5044 µM. Cmax values obtained from PBK modelling of occupational exposures to SI were compared with PoDs from the bioactivity assays to derive Bioactivity Exposure Ratios (BERs) which demonstrated the safety for workers exposed to SI under current levels of factory specific risk management. In summary, the tiered and iterative workflow developed here represents an opportunity for integrating non animal approaches for a large subset of substances for which systemic worker safety assessment is required. Such an approach could be followed to ensure that animal testing is only conducted as a "last resort" e.g. under EU REACH.

A framework for chemical safety assessment incorporating new approach methodologies within REACH.

The long-term investment in new approach methodologies (NAMs) within the EU and other parts of the world is beginning to result in an emerging consensus of how to use information from in silico, in vitro and targeted in vivo sources to assess the safety of chemicals. However, this methodology is being adopted very slowly for regulatory purposes. Here, we have developed a framework incorporating in silico, in vitro and in vivo methods designed to meet the requirements of REACH in which both hazard and exposure can be assessed using a tiered approach. The outputs from each tier are classification categories, safe doses, and risk assessments, and progress through the tiers depends on the output from previous tiers. We have exemplified the use of the framework with three examples. The outputs were the same or more conservative than parallel assessments based on conventional studies. The framework allows a transparent and phased introduction of NAMs in chemical safety assessment and enables science-based safety decisions which provide the same level of public health protection using fewer animals, taking less time, and using less financial and expert resource. Furthermore, it would also allow new methods to be incorporated as they develop through continuous selective evolution rather than periodic revolution.

The use of Bayesian methodology in the development and validation of a tiered assessment approach towards prediction of rat acute oral toxicity.

There exists consensus that the traditional means by which safety of chemicals is assessed-namely through reliance upon apical outcomes obtained following in vivo testing-is increasingly unfit for purpose. Whilst efforts in development of suitable alternatives continue, few have achieved levels of robustness required for regulatory acceptance. An array of "new approach methodologies" (NAM) for determining toxic effect, spanning in vitro and in silico spheres, have by now emerged. It has been suggested, intuitively, that combining data obtained from across these sources might serve to enhance overall confidence in derived judgment. This concept may be formalised in the "tiered assessment" approach, whereby evidence gathered through a sequential NAM testing strategy is exploited so to infer the properties of a compound of interest. Our intention has been to provide an illustration of how such a scheme might be developed and applied within a practical setting-adopting for this purpose the endpoint of rat acute oral lethality. Bayesian statistical inference is drawn upon to enable quantification of degree of confidence that a substance might ultimately belong to one of five LD50-associated toxicity categories. Informing this is evidence acquired both from existing in silico and in vitro resources, alongside a purposely-constructed random forest model and structural alert set. Results indicate that the combination of in silico methodologies provides moderately conservative estimations of hazard, conducive for application in safety assessment, and for which levels of certainty are defined. Accordingly, scope for potential extension of approach to further toxicological endpoints is demonstrated.

Chemical safety: Pesticides

Pesticides are used in public health to kill vectors of disease, such as mosquitoes, and in agriculture to kill pests that damage crops

Inherent Safety Assessment of Industrial-Scale Production of Chitosan Microbeads Modified with TiO2 Nanoparticles.

In this study, the inherent safety analysis of large-scale production of chitosan microbeads modified with TiO2 nanoparticles was developed using the Inherent Safety Index (ISI) methodology. This topology was structured based on two main stages: (i) Green-based synthesis of TiO2 nanoparticles based on lemongrass oil extraction and titanium isopropoxide (TTIP) hydrolysis, and (ii) Chitosan gelation and modification with nanoparticles. Stage (i) is divided into two subprocesses for accomplishing TiO2 synthesis, lemongrass oil extraction and TiO2 production. The plant was designed to produce 2033 t/year of chitosan microbeads, taking crude chitosan, lemongrass, and TTIP as the primary raw materials. The process was evaluated through the ISI methodology to identify improvement opportunity areas based on a diagnosis of process risks. This work used industrial-scale process inventory data of the analyzed production process from mass and energy balances and the process operating conditions. The ISI method comprises the Chemical Inherent Safety Index (CSI) and Process Inherent Safety Index (PSI) to assess a whole chemical process from a holistic perspective, and for this process, it reflected a global score of 28. Specifically, CSI and PSI delivered scores of 16 and 12, respectively. The analysis showed that the most significant risks are related to TTIP handling and its physical-chemical properties due to its toxicity and flammability. Insights about this process's safety performance were obtained, indicating higher risks than those from recommended standards.

Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity.

A group of triazole compounds was selected to investigate the confidence that may be associated with read-across of a complex data gap: repeated dose toxicity. The read-across was evaluated using Assessment Elements (AEs) from the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF), alongside appraisal of associated uncertainties. Following an initial read-across based on chemical structure and properties, uncertainties were reduced by the integration of data streams such as those from New Approach Methodologies (NAM) and other existing data. In addition, addressing the findings of the ECHA RAAF framework, complemented with specific questions concerning uncertainties, increased the confidence that can be placed in read-across. Although a data rich group of compounds with a strong mechanistic basis was analysed, it was clearly demonstrated that NAM data available from publicly available resources could be applied to support read-across. It is acknowledged that most read-across studies will not be so data rich or mechanistically robust, therefore some targeted experimentation may be required to fill the data gaps. In this sense, NAMs should constitute new experimental tests performed with the specific goal of reducing the uncertainties and demonstrating the read-across hypothesis.

ECOLOGICAL DETERMINANTS IN THE FORMATION OF THE POPULATION'S ATTITUDE TO THE DEVELOPMENT OF NUCLEAR ENERGY. / EKOLOGIChNI DETERMINANTY U FORMUVANNI STAVLENNIa NASELENNIa DO ROZVYTKU ATOMNOÏ ENERGETYKY.

OBJECTIVE: Evaluation of the key environmental determinants that shape the response of the social environment tothe activities of nuclear power plants. MATERIALS AND METHODS: The poll was conducted in the observation zone (OZ) of the South-Ukrainian NPP (SUNPP).A repetition-free probabilistic selection was used in the population survey. The sample of respondents from the population of the SUNPP OZ was 322 people with the sampling error of 5.4 % and confidence interval of 95.0%. An ordinal 5-point measurement scale was used to assess the quality of life and anxiety, and nominal measurement scaleswere used for other issues. All the age groups of population from 20 to 65 years were taken into account. The sociohygienic, sociological, statistical and mathematical research methods were applied in the process of work (relativevalues, averages, reliability of paired differences according to Student's t test). RESULTS: The level of perception of radiation risk by the population of the NPP OZ was the lowest among respondentsof satellite cities of Rivne NPP (RNPP) and SUNPP compared to the population of rural settlements and cities of theOZ. Storage and shipment of radioactive waste are the determinant among the factors that form an environmentalthreat to the population of OZ as a result of NPP activities. Social factors that determine the assessment of environmental safety of NPP activities are employment at the NPP, place of residence, gender, age, level of education of thepopulation, etc. The «Ch-image¼ of the ecological catastrophe formed in the population of Ukraine as a result of theChNPP accident , regardless of the place of residence on the territory of Ukraine, influences behavior, formation ofplans and assessments, especially in population living near the ionizing radiation sources. CONCLUSION: The current legislation governing the relationship between functioning NPPs and the communities inwhich they are located needs to be improved, guided by the basic principle of environmental public health - socialjustice, i.e. the human right to a healthy environment. It means that the settlements of the OZ (communities)receive funds to compensate for risk living in compliance with certain safety rules to maintain health. Legal regulation and constant awareness of population are the main directions for the formation of adequate assessments.

Optimising testing strategies for classification of human health and environmental hazards - A proof-of-concept study.

This paper outlines a new concept to optimise testing strategies for improving the efficiency of chemical testing for hazard-based risk management. While chemical classification based on standard checklists of information triggers risk management measures, the link is not one-to-one. Toxicity testing may be performed with no impact on the safe use of chemicals . Each hazard class and category is not assigned a unique pictogram and for the purpose of this proof-of-concept study, the level of concern for a chemical for the population and the environment is simplistically considered to be reflected by the hazard pictograms. Using active substances in biocides and plant protection products as a dataset, three testing strategies were built with the boundary condition that an optimal approach must indicate a given level of concern while requiring less testing (strategy B), prioritising new approach methodologies (strategy C) or combining the two considerations (strategy D). The implementation of the strategies B and D reduced the number of tests performed by 6.0% and 8.8%, respectively, while strategy C relied the least on in vivo methods. The intentionally simplistic approach to optimised testing strategies presented here could be used beyond the assessment of biocides and plant protection products to gain efficiencies in the safety assessment of other chemical groups, saving animals and making regulatory testing more time- and cost-efficient.

The ChemSM-Hub project in the light of a new paradigm for chemical safety management.

OBJECTIVES: The work is aimed to present and promote the Chemical Safety Management Training Hub for Chemicals Users (ChemSM-Hub) project implemented by the Nofer Institute of Occupational Medicine in cooperation with the Lodz University of Technology, Poland, and other partners from Germany (Oekopol GmbH), Greece (Prolipsis) and Romania (Romtens). The project is co-funded by the European Commission under the Erasmus+ program, whose aim is to support downstream users (DUs) and distributors (Ds) of chemicals in complying with the REACH and CLP Regulations by developing an innovative training program in chemical safety management (CSM), available via the online project platform, adapted to the real needs of the target groups. MATERIAL AND METHODS: The methodology for implementing the ChemSM-Hub project includes: 1) conducting survey research among the target groups, 2) conducting a state-of-the-art review of literature and websites, 3) developing the Dissemination and Promotion Plan, 4) developing the Monitoring and Evaluation Procedure, 5) developing the CSM training curriculum, 6) designing the project e-learning platform and mobile app, 7) developing the "Training pattern for trainers" guidance, and 8) organizing training events. RESULTS: The project is being implemented in response to the changing EU legislation on chemicals. As a result of the project, a CSM training program has been established consisting of 3 modules (introductory, basic and advanced) with varying degrees of complexity. In addition, a pocket guide has been developed that contains basic information for DUs and Ds regarding the REACH and CLP Regulations, as well as the "Training pattern for trainers" guidance containing a CSM training session plan for trainers. All these materials will be available via the project platform, and their selected elements also via a mobile app. CONCLUSIONS: The publication is aimed to familiarize the potential users of the ChemSM-Hub training program with its thematic scope, the structure of the training and the expected results. It is also a way to promote online training adapted to the needs of its target groups. Int J Occup Med Environ Health. 2020;33(3):247-61.

A review and critique of academic lab safety research.

Over the past ten years, there have been several high-profile accidents in academic laboratories around the world, resulting in significant injuries and fatalities. The aftermath of these incidents is often characterized by calls for reflection and re-examination of the academic discipline's approach to safety research and policy. However, the study of academic lab safety is still underdeveloped and necessary data about changes in safety attitudes and behaviours has not been gathered. This Review article critically examines the state of academic chemical safety research from a multifactorial stance, including research on the occurrence of lab accidents, contributors to lab accidents, the state of safety training research and the cultural barriers to conducting safety research and implementing safer lab practices. The Review concludes by delineating research questions that must be addressed to minimize future serious academic laboratory incidents as well as stressing the need for committed leadership from our research institutions.

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures.

Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.

The implementation of RAAF in the OECD QSAR Toolbox.

The Read-Across Assessment Framework (RAAF) was developed by the European Chemicals Agency (ECHA) as an internal tool providing a framework for a consistent, structured and transparent assessment of grouping of chemicals and read-across. Following a RAAF-based evaluation, also developers and users of read-across predictions outside ECHA can judge whether their read-across rationale is sufficiently robust from a regulatory perspective. The aim of this paper is to describe the implementation of RAAF functionalities in the OECD QSAR Toolbox report. These can be activated in the prediction report after performing a readacross prediction. Once the user manually selects the appropriate scenario, the RAAF assessment elements appear and are automatically aligned with the suitable category elements of the Toolbox report. Subsequently, these are evaluated as part of the category consistency assessment functionality. The implementation of the RAAF functionality is illustrated in practice with two examples.

Using a hybrid read-across method to evaluate chemical toxicity based on chemical structure and biological data.

Read-across has become a primary approach to fill data gaps for chemical safety assessments. Chemical similarity based on structure, reactivity, and physic-chemical property information is a traditional approach applied for read-across toxicity studies. However, toxicity mechanisms are usually complicated in a biological system, so only using chemical similarity to perform the read-across for new compounds was not satisfactory for most toxicity endpoints, especially when the chemically similar compounds show dissimilar toxicities. This study aims to develop an enhanced read-across method for chemical toxicity predictions. To this end, we used two large toxicity datasets for read-across purposes. One consists of 3979 compounds with Ames mutagenicity data, and the other contains 7332 compounds with rat acute oral toxicity data. First, biological data for all compounds in these two datasets were obtained by querying thousands of PubChem bioassays. The PubChem bioassays with at least five compounds from either of these two datasets showing active responses were selected to generate comprehensive bioprofiles. The read-across studies were performed by using chemical similarity search only and also by using a hybrid similarity search based on both chemical descriptors and bioprofiles. Compared to traditional read-across based on chemical similarity, the hybrid read-across approach showed improved accuracy of predictions for both Ames mutagenicity and acute oral toxicity. Furthermore, we could illustrate potential toxicity mechanisms by analyzing the bioprofiles used for this hybrid read-across study. The results of this study indicate that the new hybrid read-across approach could be an applicable computational tool for chemical toxicity predictions. In this way, the bottleneck of traditional read-across studies can be overcome by introducing public biological data into the traditional process. The incorporation of bioprofiles generated from the additional biological data for compounds can partially solve the "activity cliff" issue and reveal their potential toxicity mechanisms. This study leads to a promising direction to utilize data-driven approaches for computational toxicology studies in the big data era.

Evaluación del nivel de seguridad en la comunidad de Pogolotti-Finlay-Belén debido a la manipulación de productos químicos peligrosos / Evaluation of the level of security in the community of Pogolotti-Finlay-Belén due to the handling of dangerous chemicals

Introducción: El manejo de los productos químicos peligrosos en la comunidad no se realiza de manera segura y responsable. Objetivo: Evaluar el nivel de seguridad de la comunidad en el manejo de los productos químicos peligros. Métodos: Investigación exploratoria-descriptiva realizada en el consejo popular Pogolotti-Finlay-Belén perteneciente al municipio Marianao, comprendida entre los años 2013-2015. Se contó con una población de 1142 practicantes sistemáticos en el manejo de los productos químicos peligrosos. La muestra fue de 177 personas, se obtuvo de forma no probabilista y seleccionada de forma intencional. Se confeccionó una lista de verificación para aplicar el método de evaluación del nivel de seguridad con objetivos específicos y contenidos de cada escalón de defensa, para la comunidad seleccionada: Escalón 0: diseño de la defensa en profundidad; Escalón 1: Prevención de Sucesos Anormales; Escalón 2: Liquidación de sucesos anormales y Escalón 3: Mitigación de accidentes. Resultados: Los conjuntos definidos como aspectos de seguridad dominantes se calificaron de inaceptable-crítico o inaceptable-extremo en esta localidad; lo que implica la toma de medidas urgentes por los bajos valores del nivel de seguridad existente. Discusión: En el grupo de estudio se identificaron dificultades en la evaluación del riesgo en el contexto comunitario que muestran, luego del análisis de sensibilidad exhaustivo, que las acciones a emprender para revertir la situación inicial no requieren en su mayoría de recursos materiales, con un costo significativo para llegar al estado deseado; sin embargo, este estado puede alcanzarse con la aplicación de un grupo de medidas de orden organizativo y de gestión(AU)

Introduction: the management of hazardous chemicals in the community is not carry on a safe and responsible ways. Objective: to assess the safety level of the selected community in the management of chemicals hazards. Methods: exploratory-descriptive research conducted in the popular council Pogolotti-Finlay-Belen in the municipality of Marianao, between the years 2013-2015. There was a population of 1142 systematic practitioners in the handling of hazardous chemicals. The sample was 177 people; was obtained non-probabilistically and was intentionally selected. An exhaustive checklist was prepared for applying the safety level assessment method (ENS), with specific objectives and contents of each defense echelon: Echelon 0: Design of the Defense in Depth; Echelon 1: Prevention of Abnormal Events; Echelon 2: Control of Abnormal Events and Echelon 3: Accidents mitigation. Results: The sets defined as safety dominant aspects are classified as Unacceptable-Critical (I-C) or Unacceptable-Extreme (I-E) in this neighborhood; what implies the taking of urgent measures by the low values of the existing safety level. Conclusions: In the group of study, difficulties were identified in the evaluation of the risk in the community context that show, after the analysis of exhaustive sensitivity, that the actions to be taken to revert the initial situation, do not require of material resources with a significant cost to reach the desired state; however, this state can be achieved through the application of a group of organizational and management measures(AU)

Evaluación del nivel de seguridad en la comunidad de Pogolotti-Finlay-Belén debido a la manipulación de productos químicos peligrosos / Evaluation of the level of security in the community of Pogolotti-Finlay-Belén due to the handling of dangerous chemicals

Introducción: El manejo de los productos químicos peligrosos en la comunidad no se realiza de manera segura y responsable. Objetivo: Evaluar el nivel de seguridad de la comunidad en el manejo de los productos químicos peligros. Métodos: Investigación exploratoria-descriptiva realizada en el consejo popular Pogolotti-Finlay-Belén perteneciente al municipio Marianao, comprendida entre los años 2013-2015. Se contó con una población de 1142 practicantes sistemáticos en el manejo de los productos químicos peligrosos. La muestra fue de 177 personas, se obtuvo de forma no probabilista y seleccionada de forma intencional. Se confeccionó una lista de verificación para aplicar el método de evaluación del nivel de seguridad con objetivos específicos y contenidos de cada escalón de defensa, para la comunidad seleccionada: Escalón 0: diseño de la defensa en profundidad; Escalón 1: Prevención de Sucesos Anormales; Escalón 2: Liquidación de sucesos anormales y Escalón 3: Mitigación de accidentes. Resultados: Los conjuntos definidos como aspectos de seguridad dominantes se calificaron de inaceptable-crítico o inaceptable-extremo en esta localidad; lo que implica la toma de medidas urgentes por los bajos valores del nivel de seguridad existente. Discusión: En el grupo de estudio se identificaron dificultades en la evaluación del riesgo en el contexto comunitario que muestran, luego del análisis de sensibilidad exhaustivo, que las acciones a emprender para revertir la situación inicial no requieren en su mayoría de recursos materiales, con un costo significativo para llegar al estado deseado; sin embargo, este estado puede alcanzarse con la aplicación de un grupo de medidas de orden organizativo y de gestión(AU)

Introduction: the management of hazardous chemicals in the community is not carry on a safe and responsible ways. Objective: to assess the safety level of the selected community in the management of chemicals hazards. Methods: exploratory-descriptive research conducted in the popular council Pogolotti-Finlay-Belen in the municipality of Marianao, between the years 2013-2015. There was a population of 1142 systematic practitioners in the handling of hazardous chemicals. The sample was 177 people; was obtained non-probabilistically and was intentionally selected. An exhaustive checklist was prepared for applying the safety level assessment method (ENS), with specific objectives and contents of each defense echelon: Echelon 0: Design of the Defense in Depth; Echelon 1: Prevention of Abnormal Events; Echelon 2: Control of Abnormal Events and Echelon 3: Accidents mitigation. Results: The sets defined as safety dominant aspects are classified as Unacceptable-Critical (I-C) or Unacceptable-Extreme (I-E) in this neighborhood; what implies the taking of urgent measures by the low values of the existing safety level. Conclusions: In the group of study, difficulties were identified in the evaluation of the risk in the community context that show, after the analysis of exhaustive sensitivity, that the actions to be taken to revert the initial situation, do not require of material resources with a significant cost to reach the desired state; however, this state can be achieved through the application of a group of organizational and management measures(AU)

Outcomes of Community-Based Suicide Prevention Approaches That Involve Reducing Access to Pesticides: A Systematic Literature Review.

OBJECTIVE: Pesticide ingestion is among the most commonly utilized means of suicide worldwide. Restricting access to pesticides at a local level is one strategy to address this major public health problem, but little is known about its effectiveness. We therefore conducted a systematic literature review to identify effective community-based suicide prevention approaches that involve restricting access to pesticides. METHOD: We searched Embase, Scopus, PsycINFO, Cochrane Library, CINAHL, and PubMed for well-designed studies that reported on suicide-related outcomes (i.e., attempted or completed suicide). RESULTS: We identified only five studies that met our eligibility criteria (two randomized controlled trials, two studies with quasi-experimental designs, and one study with a before-and-after design). These studies tested different interventions: the introduction of nonpesticide agricultural management, providing central storage facilities for pesticides, distributing locked storage containers to households, and local insecticide bans. The only sufficiently powered study produced no evidence of the effectiveness of providing household storage containers. Three interventions showed some promise in reducing pesticide suicides or attempts, with certain caveats. CONCLUSIONS: Our review identified three community interventions that show some promise for reducing pesticide suicides by restricting access to means, which will require replication in large, well-designed trials before they can be recommended.

Computer-assisted UHPLC-MS method development and optimization for the determination of 24 antineoplastic drugs used in hospital pharmacy.

This study reports the use of retention modeling software for the successful method development of 24 injectable antineoplastic agents. Firstly, a generic screening of several stationary and mobile phases (using various organic modifiers and pH) was achieved. Then, an optimization procedure of mobile phase temperature, gradient profile and mobile phase binary composition was conducted through only 28 real experiments using retention modeling software for data treatment. Finally, the optimized separation was achieved with a mobile phase consisting in 10 mM acetic acid at pH 5.1 (A) and acetonitrile (B). A Waters CORTECS® T3 column (100 × 2.1 mm, 1.6 µm) operated at 25 °C with a gradient time of 17.5 min (0-51%B) at a flow rate of 0.4 mL/min was used. The prediction offered by the retention model was found to be highly reliable, with an average error lower than 1%. A robustness testing step was also assessed from a virtual experimental design. Success rate and regression coefficient were evaluated without the need to perform any real experiment. The developed LC-MS method was successfully applied to the analysis of pharmaceutical formulations and wiping samples from working environment.

Grouping of nanomaterials to read-across hazard endpoints: from data collection to assessment of the grouping hypothesis by application of chemoinformatic techniques.

BACKGROUND: An increasing number of manufactured nanomaterials (NMs) are being used in industrial products and need to be registered under the REACH legislation. The hazard characterisation of all these forms is not only technically challenging but resource and time demanding. The use of non-testing strategies like read-across is deemed essential to assure the assessment of all NMs in due time and at lower cost. The fact that read-across is based on the structural similarity of substances represents an additional difficulty for NMs as in general their structure is not unequivocally defined. In such a scenario, the identification of physicochemical properties affecting the hazard potential of NMs is crucial to define a grouping hypothesis and predict the toxicological hazards of similar NMs. In order to promote the read-across of NMs, ECHA has recently published "Recommendations for nanomaterials applicable to the guidance on QSARs and Grouping", but no practical examples were provided in the document. Due to the lack of publicly available data and the inherent difficulties of reading-across NMs, only a few examples of read-across of NMs can be found in the literature. This manuscript presents the first case study of the practical process of grouping and read-across of NMs following the workflow proposed by ECHA. METHODS: The workflow proposed by ECHA was used and slightly modified to present the read-across case study. The Read-Across Assessment Framework (RAAF) was used to evaluate the uncertainties of a read-across within NMs. Chemoinformatic techniques were used to support the grouping hypothesis and identify key physicochemical properties. RESULTS: A dataset of 6 nanoforms of TiO2 with more than 100 physicochemical properties each was collected. In vitro comet assay result was selected as the endpoint to read-across due to data availability. A correlation between the presence of coating or large amounts of impurities and negative comet assay results was observed. CONCLUSION: The workflow proposed by ECHA to read-across NMs was applied successfully. Chemoinformatic techniques were shown to provide key evidence for the assessment of the grouping hypothesis and the definition of similar NMs. The RAAF was found to be applicable to NMs.

Development of a systematic method to assess similarity between nanomaterials for human hazard evaluation purposes - lessons learnt.

Within the EU FP-7 GUIDEnano project, a methodology was developed to systematically quantify the similarity between a nanomaterial (NM) that has been tested in toxicity studies and the NM for which risk needs to be evaluated, for the purpose of extrapolating toxicity data between the two materials. The methodology is a first attempt to use current knowledge on NM property-hazard relationships to develop a series of pragmatic and systematic rules for assessing NM similarity. Moreover, the methodology takes into account the practical feasibility, in that it is based on generally available NM characterization information. In addition to presenting this methodology, the lessons learnt and the challenges faced during its development are reported here. We conclude that there is a large gap between the information that is ideally needed and its application to real cases. The current database on property-hazard relationships is still very limited, which hinders the agreement on the key NM properties constituting the basis of the similarity assessment and the development of associated science-based and unequivocal rules. Currently, one of the most challenging NM properties to systematically assess in terms of similarity between two NMs is surface coating and functionalization, which lacks standardized parameters for description and characterization methodology. Standardization of characterization methods that lead to quantitative, unambiguous, and measurable parameters describing NM properties are necessary in order to build a sufficiently robust property-hazard database that allows for evidence-based refinement of our methodology, or any other attempt to systematically assess the similarity of NMs.

Closed-system drug-transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff.

BACKGROUND: Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone. OBJECTIVES: To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017. SELECTION CRITERIA: We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818). AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.