How to formulate hypotheses and IATA to support grouping and read-across of nanoforms

Abstract

Manufacturing and functionalizing materials at the nanoscale has led to the generation of a whole array of nanoforms (NFs) of substances varying in size, morphology and surface characteristics. Due to financial, time and ethical considerations, testing every unique NF for adverse effects is virtually impossible. Use of hypothesis-driven grouping and read-across approaches, as supported by the GRACIOUS Framework, represent a promising alternative to case-by-case testing which will make the risk assessment process more efficient. Through application of appropriate grouping hypotheses, the Framework facilitates the assessment of similarity between NFs, thereby supporting grouping and read-across of information, minimizing the need for new testing and aligning with 3R principles of Replacement, Reduction and Refinement of animals in toxicology studies. For each grouping hypothesis an Integrated Approach to Testing and Assessment (IATA) guides the user in data gathering and acquisition to test the hypothesis, following a structured format to facilitate efficient decision-making. Here we present the template used to generate the GRACIOUS grouping hypotheses encompassing information relevant to "Lifecycle, environmental release and human exposure", "What they are: physicochemical characteristics", "Where they go: Environmental fate, uptake and toxicokinetics", and "What they do: human and environmental toxicity". A summary of the template-derived hypotheses focusing on human health is provided, along with an overview of the IATAs generated by the GRACIOUS project. We discuss the application and flexibility of the template, providing the opportunity to expand the application of grouping and read-across, in a logical evidencebased manner, to a wider range of NFs and substances.

How to describe the time-dependent dissolution of engineered nanomaterials?

“…In the context of developing New Generation Risk Assessment (NGRA) methodology, the OECD [33] has recommended further enlarging the concept of Integrated Approaches to Testing and Assessments (IATAs). These employ decision trees that facilitate a systematic inquiry of pertinent information required to evaluate the potential toxicity of chemicals based on a combination of New Approach Methodologies (NAMs), and several IATAs have recently been proposed [30] , [34] , [35] . Particular IATAs underscore the significance of considering relevant factors, such as physicochemical properties, environmental behavior, and exposure, when making informed decisions about grouping nanomaterials.…”

Critical aspects in dissolution testing of nanomaterials in the oro-gastrointestinal tract: the relevance of juice composition for hazard identification and grouping

“…Extrinsic parameters relevant to dissolution kinetics are the physical chemical (PC) properties of the NMs, which can be applied to group NFs of a NM with similar properties. 2,3,10–14…”

“…9 Extrinsic parameters relevant to dissolution kinetics are the physical chemical (PC) properties of the NMs, which can be applied to group NFs of a NM with similar properties. 2,3,[10][11][12][13][14] Currently, different in vitro methods are available to measure dissolution, in static or dynamic mode (e.g., ow-through and continuous ow), as described by the ISO/TR 19057. 5 The molecular composition of the simulated juices usually varies in regard to the extent of prediction of in vivo conditions when a toxicity assessment is required.…”

Similarity of multicomponent nanomaterials in a safer-by-design context: the case of core–shell quantum dots

“…2 The GRACIOUS framework starts by guiding the development of an appropriate grouping hypothesis. 3 The hypothesis proposes similarities in terms of (i) physicochemical characteristics (what they are), (ii) fate or toxicokinetics (where they go) and (iii) hazards (what they do) for each group member. Testing of the hypothesis is achieved via tailored integrated approaches to testing and assessment (IATA), which guide the user to collect existing information, or to generate key relevant information to fill data gaps.…”