Regulatory preparedness for multicomponent nanomaterials: Current state, gaps and challenges of REACH.

In 2018 the European Commission adopted revisions to the Annexes of Regulation (EC) No 1907/2006 concerning registration, evaluation, authorisation and restriction of chemicals (REACH) to introduce nanomaterial-specific clarifications and provisions. Multicomponent nanomaterial (MCNM) is a non-regulatory term that has been used in recent EU-funded projects to describe nanomaterials with a complex structure and/or composition and which are expected to be increasingly used in products in the near future. This paper examines the regulatory preparedness of REACH, and its revised Annexes, for MCNMs.

Roadmap towards safe and sustainable advanced and innovative materials. (Outlook for 2024-2030).

The adoption of innovative advanced materials holds vast potential, contingent upon addressing safety and sustainability concerns. The European Commission advocates the integration of Safe and Sustainable by Design (SSbD) principles early in the innovation process to streamline market introduction and mitigate costs. Within this framework, encompassing ecological, social, and economic factors is paramount.

Governance of advanced materials: Shaping a safe and sustainable future.

The past few decades of managing the uncertain risks associated with nanomaterials have provided valuable insights (knowledge gaps, tools, methods, etc.) that are equally important to promote safe and sustainable development and use of advanced materials. Based on these insights, the current paper proposes several actions to optimize the risk and sustainability governance of advanced materials.

Learning from Safe-by-Design for Safe-and-Sustainable-by-Design: Mapping the current landscape of Safe-by-Design reviews, case studies, and frameworks.

With the introduction of the European Commission's "Safe and Sustainable-by-Design" (SSbD) framework, the interest in understanding the implications of safety and sustainability assessments of chemicals, materials, and processes at early-innovation stages has skyrocketed. Our study focuses on the "Safe-by-Design" (SbD) approach from the nanomaterials sector, which predates the SSbD framework. In this assessment, SbD studies have been compiled and categorized into reviews, case studies, and frameworks.

A roadmap to strengthen standardisation efforts in risk governance of nanotechnology.

A roadmap was developed to strengthen standardisation activities for risk governance of nanotechnology. Its baseline is the available standardised and harmonised methods for nanotechnology developed by the International Organization for Standardization (ISO), the European Committee for Standardization (CEN), and the Organisation for Economic Co-operation and Development (OECD). In order to identify improvements and needs for new themes in standardisation work, an analysis of the state-of-the-art concepts and interpretations of risk governance of nanotechnology was performed.

Life cycle thinking and safe-and-sustainable-by-design approaches for the battery innovation landscape.

Developments in battery technology are essential for the energy transition and need to follow the framework for safe-and-sustainable-by-design (SSbD) materials, chemicals, products, and processes as set by the EU. SSbD is a broad approach that ensures that chemicals/advanced materials/products/services are produced and used in a way to avoid harm to humans and the environment. Technical and policy-related literature was surveyed for battery technologies and recommendations were provided for a broad SSbD approach that remains firmly grounded in Life Cycle Thinking principles.

The State of the Art and Challenges of In Vitro Methods for Human Hazard Assessment of Nanomaterials in the Context of Safe-by-Design.

The Safe-by-Design (SbD) concept aims to facilitate the development of safer materials/products, safer production, and safer use and end-of-life by performing timely SbD interventions to reduce hazard, exposure, or both. Early hazard screening is a crucial first step in this process. In this review, for the first time, commonly used in vitro assays are evaluated for their suitability for SbD hazard testing of nanomaterials (NMs).

Challenges in Predicting the Change in the Cumulative Exposure of New Tobacco and Related Products Based on Emissions and Toxicity Dose-Response Data.

Many novel tobacco products have been developed in recent years. Although many may emit lower levels of several toxicants, their risk in the long term remains unclear. We previously published a method for the exposure assessment of mixtures that can be used to compare the changes in cumulative exposure to carcinogens among tobacco products.

Safe-by-Design part II: A strategy for balancing safety and functionality in the different stages of the innovation process.

Manufactured nanomaterials have the potential to impact an exceedingly wide number of industries and markets ranging from energy storage, electronic and optical devices, light-weight construction to innovative medical approaches for diagnostics and therapy. In order to foster the development of safer nanomaterial-containing products, two main aspects are of major interest: their functional performance as well as their safety towards human health and the environment. In this paper a first proposal for a strategy is presented to link the functionality of nanomaterials with safety aspects.

Safe-and-Sustainable-by-Design Framework Based on a Prospective Life Cycle Assessment: Lessons Learned from a Nano-Titanium Dioxide Case Study.

Safe-and-sustainable-by-design (SSbD) is a concept that takes a systems approach by integrating safety, sustainability, and functionality throughout a product's the life cycle. This paper proposes a framework based on a prospective life cycle assessment for early safety and sustainability assessment. The framework's purpose is to identify environmental sustainability and toxicity hotspots early in the innovation process for future SSbD applicability.

Risk assessment of components in tobacco smoke and e-cigarette aerosols: a pragmatic choice of dose metrics.

Background: Risk assessment of individual tobacco smoke components is important for the purpose of prioritization or selecting chemicals for monitoring products. Smoking is characterized by a highly varying, intermittent exposure and the challenge is to choose the most appropriate dose metric.

Methods: Generally, average daily exposure estimates are used as dose metric, without considering temporal determinants.

Modernizing innovation governance to meet policy ambitions through trusted environments.

A vision for modernization of nanotechnology innovation governance is a Safe Innovation Approach (SIA). SIA combines two concepts: Safe-by-Design (SbD) and Regulatory Preparedness (RP). SbD aims to motivate industry to integrate safety considerations early in the innovation process and onwards.

A Method for Comparing the Impact on Carcinogenicity of Tobacco Products: A Case Study on Heated Tobacco Versus Cigarettes.

Comparing the harmful health effects related to two different tobacco products by applying common risk assessment methods to each individual compound is problematic. We developed a method that circumvents some of these problems by focusing on the change in cumulative exposure (CCE) of the compounds emitted by the two products considered. The method consists of six steps.

A Methodological Safe-by-Design Approach for the Development of Nanomedicines.

Safe-by-Design (SbD) concepts foresee the risk identification and reduction as well as uncertainties regarding human health and environmental safety in early stages of product development. The EU's NANoREG project and further on the H2020 ProSafe initiative, NanoReg2, and CALIBRATE projects have developed a general SbD approach for nanotechnologies (e.g.

A test strategy for the assessment of additive attributed toxicity of tobacco products.

The new EU Tobacco Product Directive (TPD) prohibits tobacco products containing additives that are toxic in unburnt form or that increase overall toxicity of the product. This paper proposes a strategy to assess additive attributed toxicity in the context of the TPD. Literature was searched on toxicity testing strategies for regulatory purposes from tobacco industry and governmental institutes.

Empirical analysis of BMD metrics in genetic toxicology part I: in vitro analyses to provide robust potency rankings and support MOA determinations.

Genetic toxicity testing has traditionally been used for hazard identification, with dichotomous classification of test results serving to identify genotoxic agents. However, the utility of genotoxicity data can be augmented by employing dose-response analysis and point of departure determination. Via interpolation from a fitted dose-response model, the benchmark dose (BMD) approach estimates the dose that elicits a specified (small) effect size.

Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study.

In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9.

Estimating the carcinogenic potency of chemicals from the in vivo micronucleus test.

In this study, we investigated the applicability of using in vivo mouse micronucleus (MN) data to derive cancer potency information. We also present a new statistical methodology for correlating estimated potencies between in vivo MN tests and cancer studies, which could similarly be used for other systems (e.g.

Potential harmful health effects of inhaling nicotine-free shisha-pen vapor: a chemical risk assessment of the main components propylene glycol and glycerol.

Background: A shisha-pen is an electronic cigarette variant that is advertised to mimic the taste of a water pipe, or shisha. The aim of this study was to assess the potential harmful health effects caused by inhaling the vapor of a nicotine-free shisha-pen.

Methods: Gas chromatography analysis was performed to determine the major components in shisha-pen vapor.

IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk.

This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species.

IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure-response relationships and points of departure (PoDs).

This report summarizes the discussion, conclusions, and points of consensus of the IWGT Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (QWG) based on a meeting in Foz do Iguaçu, Brazil October 31-November 2, 2013. Topics addressed included (1) the need for quantitative dose-response analysis, (2) methods to analyze exposure-response relationships & derive point of departure (PoD) metrics, (3) points of departure (PoD) and mechanistic threshold considerations, (4) approaches to define exposure-related risks, (5) empirical relationships between genetic damage (mutation) and cancer, and (6) extrapolations across test systems and species. This report discusses the first three of these topics and a companion report discusses the latter three.

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data.

Allergic contact dermatitis (ACD) is a hypersensitivity immune response induced by small protein-reactive chemicals. Currently, the murine local lymph node assay (LLNA) provides hazard identification and quantitative estimation of sensitizing potency. Given the complexity of ACD, a single alternative method cannot replace the LLNA, but it is necessary to combine methods through an integrated testing strategy (ITS).

Quantitative dose-response analysis of ethyl methanesulfonate genotoxicity in adult gpt-delta transgenic mice.

The assumption that mutagens have linear dose-responses recently has been challenged. In particular, ethyl methanesulfonate (EMS), a DNA-reactive mutagen and carcinogen, exhibited sublinear or thresholded dose-responses for LacZ mutation in transgenic Muta™Mouse and for micronucleus (MN) frequency in CD1 mice (Gocke E and Müller L [2009]: Mutat Res 678:101-107). In order to explore variables in establishing genotoxicity dose-responses, we characterized the genotoxicity of EMS using gene mutation assays anticipated to have lower spontaneous mutant frequencies (MFs) than Muta™Mouse.

Tobacco smoke-related health effects induced by 1,3-butadiene and strategies for risk reduction.

1,3-Butadiene (BD) is a smoke component selected by the World Health Organization (WHO) study group on Tobacco Product Regulation (TobReg) for mandated lowering. We examined the tobacco smoke-related health effects induced by BD and possible health impacts of risk reduction strategies. BD levels in mainstream smoke (MSS) from international and Canadian cigarettes and environmental tobacco smoke (ETS) were derived from scientific journals and international government reports.