An Integrated Approach to Testing and Assessment to Support Grouping and Read-Across of Nanomaterials After Inhalation Exposure

Abstract

Introduction: Here, we describe the generation of hypotheses for grouping nanoforms (NFs) after inhalation exposure and the tailored Integrated Approaches to Testing and Assessment (IATA) with which each specific hypothesis can be tested. This is part of a state-of-the-art framework to support the hypothesis-driven grouping and read-across of NFs, as developed by the EU-funded Horizon 2020 project GRACIOUS. Development of Grouping Hypotheses and IATA: Respirable NFs, depending on their physicochemical properties, may dissolve either in lung lining fluid or in acidic lysosomal fluid after uptake by cells. Alternatively, NFs may also persist in particulate form. Dissolution in the lung is, therefore, a decisive factor for the toxicokinetics of NFs. This has led to the development of four hypotheses, broadly grouping NFs as instantaneous, quickly, gradually, and very slowly dissolving NFs. For instantaneously dissolving NFs, hazard information can be derived by read-across from the ions. For quickly dissolving particles, as accumulation of particles is not expected, ion toxicity will drive the toxic profile. However, the particle aspect influences the location of the ion release. For gradually dissolving and very slowly dissolving NFs, particle-driven toxicity is of concern. These NFs may be grouped by their reactivity and inflammation potency. The hypotheses are substantiated by a tailored IATA, which describes the minimum information and laboratory assessments of NFs under investigation required to justify grouping. Conclusion:The GRACIOUS hypotheses and tailored IATA for respiratory toxicity of inhaled NFs can be used to support decision making regarding Safe(r)-by-Design product development or adoption of precautionary measures to mitigate potential risks. It can also be used to support read-across of adverse effects such as pulmonary inflammation and subsequent downstream effects such as lung fibrosis and lung tumor formation after long-term exposure.

Validation and Demonstration of an Atmosphere-Temperature-pH-Controlled Stirred Batch Reactor System for Determination of (Nano)Material Solubility and Dissolution Kinetics in Physiological Simulant Lung Fluids

“…Physicochemical parameters, such as the solubility and dissolution rate, are critical parameters in different industries, including the pharmaceutical [ 14 , 15 ], food [ 16 ], and cosmetic fields [ 17 ], and plays an important role in risk assessment as well as grouping and read-across [ 18 , 19 ]. Dissolution is a dynamic process fundamentally controlled by the thermodynamic parameter of solubility, which, along with the concentration gradient, acts as the driving force for the dissolution of the material [ 20 ].…”

Experimental and Computational Nanotoxicology—Complementary Approaches for Nanomaterial Hazard Assessment

“…In silico toxicology refers to the use of computational methods to analyze, simulate, visualize, or predict the toxicity of chemicals and nanomaterials [54,144]. To be accurately predictive of nanomaterial toxicity, models should carefully consider the complexity of nanomaterials (requiring a complete physicochemical characterization) and their diverse environments (exposure route) [143,145]. Concretely, the aim of computational approaches is to model the relationships between nanomaterials' structure, properties, and biological effects [143].…”

“…The aim is to predict the effects of an unknown substance (target material) based on the data available from substances classified in the same group because they are considered similar in some way (source material). Similarity is usually based on structural and/or physicochemical properties [13,145,150,152,165,186]. In other words, this approach is based on the assumption that materials that are considered similar may have a comparable toxicological behavior.…”

“…One may wonder if such an approach initially proposed for chemical compounds is suitable for nanomaterials due to their heterogeneity as previously discussed [13]. However, grouping/read-across methods are considered valid analytical tools to enable a more efficient hazard identification and assessment of nanomaterials by bringing together substances with similar hazardous profiles [145,146,186,188]. A major advantage of grouping/readacross methods is that they do not require a large amount of data to identify groups of similar compounds [152].…”

The application of existing genotoxicity methodologies for grouping of nanomaterials: towards an integrated approach to testing and assessment

“…2 ). The strategy is based on and builds upon existing guidance for assessment of NF-induced genotoxicity [ 36 – 38 ] and incorporates OECD guidelines when available [ 39 ]. In addition and importantly, previous EU projects have also worked and contributed to method adaptation of genotoxicity testing methods required for NFs (e.g.…”