Fazel
Abdolahpur Monikh
*ab,
Willie
Peijnenburg
cd,
Agnes G.
Oomen
de,
Eugenia
Valsami-Jones
f,
Vicki
Stone
g,
Raine
Kortet
a,
Jarkko
Akkanen
a,
Peng
Zhang
e,
Jukka
Kekäläinen
a,
Alena
Sevcu
h and
Jussi V. K.
Kukkonen
a
aDepartment of Environmental & Biological Sciences, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland. E-mail: fazel.monikh@uef.fi; f.a.monikh@gmail.com
bDepartment of Chemical Sciences, University of Padua, Via Marzolo 1, 35131 Padova, Italy
cInstitute of Environmental Sciences (CML), Leiden University, Einsteinweg 2, 2333 CC Leiden, The Netherlands
dNational Institute for Public Health and the Environment (RIVM), Center for Safety of Substances and Products, Bilthoven, The Netherlands
eInstitute for Biodiversity and Ecosystem Dynamics (IBED), University of Amsterdam, Amsterdam, The Netherlands
fSchool of Geography, Earth and Environmental Sciences, University of Birmingham, Edgbaston, B15 2TT Birmingham, UK
gInstitute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
hInstitute for Nanomaterials, Advanced Technologies and Innovation, Technical University of Liberec, Bendlova 1409/7, 460 01, Liberec, Czech Republic
First published on 21st December 2022
“Advanced Materials” (AdMas) represent the next technology frontier. According to the European Union, AdMas are materials that feature a series of exceptional properties or functionalities compared to conventional materials. Considering the progress made in the design and application of AdMas, their adverse effects are still largely unknown whilst this is critical for assessing their environmental and human health risk. In this perspective, we first summarize the available definitions/descriptions and categorizations that cover AdMas and evaluate their adequacy from a toxicological point of view. We further describe the challenges and outlook on the toxicology of AdMas and propose solutions to tackle some of the challenges. Criteria related to which AdMas might induce hazards are discussed and used to propose a starting point of how to address AdMas in legal frameworks that consider human and environmental risks. Finally, we highlight the benefit of classification, e.g., enabling differentiation between AdMas based on their properties that might induce specific hazards and facilitate a faster pathway to identify the hazards of new AdMas, which is particularly relevant for safe-by-design.
Environmental significanceAdvanced materials (AdMas) are evolving to offer new materials for different applications ranging from food to medicine and electronics. Addressing the safety and the sustainability of materials, in general, at an early stage of their design requires adequate methods for risk and sustainability assessment. The current risk assessment framework for chemicals and nanomaterials cannot cover AdMas. In this perspective we highlight the challenges the toxicology community might face in optimal design and efficient use of the frameworks for AdMas and predicting their (environmental) risk. We performed an analysis of the existing knowledge pertaining to AdMas and their physicochemical properties to propose some criteria for the classification of AdMas to facilitate generating toxicological data for risk assessment. |
Assessing the potential risks associated with use of different types of AdMas is critical. This is important not only for technological development but also to reach some of the transitions and goals of the European Green Deal.3 Indeed, the introduction of new and evolving technologies to the market to benefit society and the economy requires balancing the risks and benefits for humans and the environment. Addressing the safety and the sustainability of materials, in general, at an early stage of their design may benefit (risk) governance, but requires adequate methods for risk and sustainability assessment.4
The considerations of balancing risks and benefits are therefore an important question to address if AdMas are to reach their full commercial and societal potential. However, such considerations do not start from zero. For example, risk is calculated from exposure (the dose delivered) and hazard (how toxic the substance is). The relationships between physicochemical properties and both exposure and hazard have been widely studied for nanomaterials (NMs), which can provide information relevant to AdMas. NMs are defined based on their size (1–100 nm) (EU Commission, 2011), where the size-dependent unique properties distinguish them from their bulk counterparts. NMs could be considered as AdMas, but not all AdMas are NMs. For example, some AdMas have a size larger than the dimension proposed by the European Commission (EC) for defining NMs, such as artificial bacterial flagellum (200 nm) and two-armed nanoswimmer (200 nm). Various studies have assessed the human health and environmental risks of NMs, which facilitated some political actions, e.g. in the EU.5 Now, similar concerns arise for AdMas, noting that some of these materials are already used in products with biomedical, cosmetic and electronic applications.6
The current risk assessment frameworks for NMs are based on the data generated for the so-called “first generation” of NMs,7 where the materials are made of one main substance7 (such as TiO2, ZnO, CeO2 and Ag), sometimes with an additional substance coating used to provide surface functionalization or colloidal stability. The question is whether such frameworks can be utilised (or adapted) for AdMas. This review focuses on hazards (rather than exposure and risk assessment), for which it is critical to understand whether the AdMas can be assessed either
• on the basis of the known hazards of their constituents,
• on a more complex consideration of the possible toxic effects of AdMas resulting from new or enhanced function, or
• by addressing the potential for different components to interact and exacerbate the toxicological response.
Toxicological data can serve to provide an early warning of risk, while a lack of such toxicological data can cause risk governance to lag behind innovation. However, the hazard assessment of AdMas might face challenges due to uncertainty on the adequacy of current test methods. The Organisation for Economic Cooperation and Development (OECD) has conducted analyses of a number of guidance documents and test guidelines for their relevance to adequately assess the toxicity of NMs.8 These considerations could be adopted for some AdMas. Such considerations would need to incorporate the complexity of the materials, their properties, and their dynamic functions, which can make comparisons between AdMas and other substances difficult. Such uncertainties can also lead to a lack of clarity with respect to their consideration in legal frameworks, e.g., as NMs, substances, or as an article.
It is therefore now opportune to develop a perspective on the applicability of existing frameworks for the hazard assessment of AdMas, to see where it applies, where modifications or new approaches might be needed. Such considerations will highlight the challenges the toxicology community might face in optimal adaptation and therefore efficient use of existing frameworks for assessing AdMa hazards. We performed an analysis of the existing knowledge pertaining to AdMas and their physicochemical properties to propose some criteria for the classification of AdMas to facilitate generating toxicological data for risk assessment. We propose potential solutions that may be applicable to tackle some of the challenges anticipated for AdMas and help to assess the hazard associated with these materials by using some of the knowledge generated on NMs. We identify the knowledge gaps to be further studied and scrutinized, and we provide some recommendations for future toxicological studies of AdMas.
Proposed definition/description of AdMas | References |
---|---|
Any material that, through the precise control of its composition and internal structure, features a series of exceptional properties (mechanical, electric, optic, magnetic, etc.) or functionalities (self-repairing, shape change, decontamination, transformation of energy, etc.) that differentiate it from the rest of the universe of materials, or one that, when transformed through advanced manufacturing techniques, features these properties or functionalities | European Commission10 |
Materials that are rationally designed to have new or enhanced properties, and/or targeted or enhanced structural features with the objective to achieve specific or improved functional performance | OECD11 |
Materials that are rationally designed through the precise control of their composition and internal or external structure in order to fulfil new functional requirements | The German Environment Agency9 |
Materials, and their associated process technologies, with the potential to be exploited in high value-added products | UK Technology Strategy Board1 |
Materials that have been developed to the point that unique functionalities have been identified and these materials now need to be made available in quantities large enough for innovators and manufacturers to test and validate in order to develop new products | 12 |
Materials that are specifically engineered to exhibit novel or enhanced properties that confer superior performance relative to conventional materials | 1 |
The German Environment Agency identified eight clusters of AdMas10 (Fig. 1) based upon their structures that demonstrate their breadth of chemistry and applications, which clearly indicates the wide variety of AdMas available and under development. Here we provide some specific examples of AdMas in order to exemplify this diversity and furthermore their usefulness. The first example includes multi-layered nickel–cobalt organic framework nanosheets (based on the scheme in Fig. 1, this AdMa can be categorized as a composite), developed as electrode materials for energy storage.13 Some of these materials can be switched off and on or controlled remotely, which defines them as smart AdMas or smart NMs.6 As another example, nanoscale bending-sensitive and optically transparent pressure sensors have been fabricated using composite nanofibers.14 Many other NMs, e.g. ionic polymer–metal composites, carbon nanotube composites, deformable polymer-based systems and biological molecular motors, have been fabricated so that these can be activated with a specific stimulus, such as pH, light, or temperature.7,15 Interesting examples are NMs consisting of an elastic polymer network and a molecular switch, which can change their structure from ribbon to a tight coil, then back to a ribbon when activated by light,16 and nanorobots which are currently being extensively researched and developed for medical applications.4 Using advanced polymers or hybrid advanced materials, we might also encounter advanced plastics in the future that can release smart microplastics and nanoplastics into the environment.
When considering the hazards of AdMas, the mode of action through which AdMas induce toxicity is not yet understood. Furthermore, we cannot assume that the hazards of AdMas across different clusters or within each cluster (of Fig. 1) will be the same. Therefore, the clustering based on the hazard might look different to what is proposed in Fig. 1. This Perspective briefly describes the possible challenges associated with the hazard investigation of AdMas before considering possible categorisation strategies.
Comprehensive characterization of NMs has therefore been required both for research publications and for legislative frameworks. Such characterisation includes size distributions, surface charge, shape, surface area, impurities, etc. Such requirements are likely to be required for AdMas. This information will be useful to understand the toxicity of AdMas and link their properties to the hazards. Although publications are improving, many toxicological studies still do not report a detailed characterization of the tested material, even for single element NMs, partly due to the limitations in analytical capability and availability. Without this information, accurate comparisons between datasets from different toxicological studies, laboratories, or even comparisons between species exposed to the same materials would be impossible. Hence, the scientific community is urged to include information on these characteristics both for NMs and AdMas.
To facilitate the description or understanding of which components of an AdMa drive the hazards, we use Ag NMs which are coated with graphene-sheets containing Quantum Dots (QDs) as an existing example of a multi-elemental AdMa used as an antibacterial material29 (Fig. 2a). These AdMas consist of stable NMs (graphene) as well as quickly soluble (Ag NMs) and slowly soluble (QDs) fractions. From a toxicological perspective, the challenge is to use existing information on the single components as much as possible and complement this with additional issues, e.g., related to the multicomponent nature or new or enhanced functionalities (synergistic or antagonistic between any possible combinations: Fig. 2a).
Fig. 2 (a) Examples of AdMas that are released in the environment. The illustration shows Ag NMs stabilized with graphene-QD NMs. In the environment, the Ag NMs and some elements of the QDs will dissolve (at different rates), leading to the release of Ag ions and QD-related metals, whereas the graphene is stable. (b–e) Smart nano-pesticides. (b) Particle attachment to the surface of the plant. (c) The uptake of the NMs is influenced by the physicochemical properties of the NMs. (d) The NMs translocate in different tissues in the plant. (e) After targeting a specific tissue, the NMs respond to specific stimuli, such as pH, light, enzymes, ionic strength, and temperature (modified after Grillo et al. 2021 (ref. 15)). |
The considerations of dissolution are further complicated by the fact that AdMas may undergo homoaggregation and heteroaggregation in the environment. There is a wealth of knowledge on NMs showing that particles might immediately homoaggregate with themselves or heteroaggregate with background colloids in the environment.30 This could dramatically influence the behavior and fate of AdMas in nature. For example, upon heteroaggregation with naturally occurring iron oxide, AdMas can sediment and be removed from the aquatic phase. Moreover, aggregation might change the solubility of AdMas as was reported for NMs.22
Transformation of materials in the environment or the human body goes beyond dissolution and agglomeration, to include (but not limited to) processes such as accumulation of other molecules onto the surface, modification of the surface chemistry and dissociation of components. All of these considerations are relevant to both NMs and AdMas.
For example, it is well known that when NMs enter the body of an organism, the surfaces of the particles are rapidly covered by biomolecules such as proteins, forming the so-called “protein corona”.31 The same phenomenon can happen when NMs enter the environment, where they can be covered by natural organic matter (NOM). Little information is available on the formation of a NOM corona and the composition of the NOM corona on NMs in the environment due to limitations in analytical techniques. The protein corona consists of proteins which get absorbed to the NM during a time span of a few minutes up to several hours.32 The formation of a protein or NOM corona is dictated by the physicochemical properties of NMs such as size, aspect ratio, surface charge and chemical composition,33 as well as by the presence of the NOM or proteins in the surroundings and other conditions of the surroundings (pH, temperature, etc.).
For AdMas, the formation and evolution of a protein or NOM corona is probably also controlled by the physicochemical properties of the materials. We describe our expectation of protein corona formation on AdMas by using smart NMs as a model of AdMas in a hypothetical example of a polymeric particle with an iron NM core and a QD doped surface (Fig. 3). In this illustration, we expect that different proteins adsorbed to the surface of the QD NM compare to the case of exposure of solely the polymeric NM in the same medium. It is also likely that activation of the iron NM with a magnetic field would generate heat34 that can influence the formation of the protein corona (Fig. 3).
Understanding the formation and evolution of protein or NOM corona is useful for hazard assessment. Sorption of biomolecules on the surface of AdMas confers a new biological identity to the materials, which influences the biological fate and biodistribution of the particles in various organs, tissues, and cells in organisms. For example, it is known that adsorption of proteins facilitates the recognition and uptake of particles by immune cells, which are involved in the uptake and metabolism of foreign particulates.35 We believe that while the existing data on protein corona formation on NMs can help to understand the corona formation on AdMas, alone it will not be sufficient. Some physicochemical properties of AdMas such as the multi-elemental composition and implementation of switchable properties in some AdMas, which imparts dynamic properties to the NMs, may add another dimension to the biological fate of AdMas, consequently complicating the prediction of their biodistribution and hazard.
Most of the available information on the elimination of NMs from the body is medically oriented and it is indicated that >6 nm particles cannot be eliminated via renal excretion.36 Few (eco)toxicological studies on fish showed that NMs might be excreted from the gills.37,38 Many promising AdMas have a size large than 6 nm.39 More studies are still needed to understand the uptake and elimination pathway of AdMas from different model organisms with (eco)toxicological purposes.
However, extensive characterization of pristine materials, in products or in various life cycle stages is not always practically feasible for many laboratories due to the extensive instrumentation and the skills required to perform the comprehensive characterization. These challenges have already been recognized for first generation of NMs, which apply to AdMas. Any characterisation should be attempted in a media that best represents the biological or environmental compartment relevant to the life cycle stage under consideration. There are some limitations that can further challenge the characterization of AdMas (including smart NMs). For example, the characterization of a multi-element AdMa consisting of inorganic and organic components requires combinations of techniques suitable for the characterization of each component (by assuming that the sample preparation for the target component does not influence the other component of the AdMa). Moreover, it is yet unknown how to characterize the activity of smart AdMas upon stimulation for toxicological purposes, e.g., in nontarget organisms.
There are few toxicological studies in which the effect of activated smart NMs has been investigated, although such tests are currently uncommon.42,43 The question is whether and to what extent the smart or enhanced properties must be considered in toxicological studies. Hazard assessment based on the passive form of smart NMs is unlikely to be sufficient to assess their risk. The controlled functionality of smart NMs, therefore, adds another level of complexity to the toxicological studies of AdMas. Testing of the different forms of a material – passive and active – can be considered, but could be difficult to generate. It will also be difficult to assess and simulate the location of the bioavailability of active forms within the body or within cells. Also, assessing the hazards of different forms would lead to higher costs for toxicity testing as well as a greater animal use. While guidelines and protocols exist for assessing hazards of dissolved chemicals, and in some cases for NMs, further work will be required to determine their suitability for the assessment of smart AdMa-induced toxicity, and to make modifications if required.
Further refinements required to address the safety assessment of AdMas include:
– Investigate mode-of-action for each class of AdMas.
– Consider when and how the existing information for single components can be used.
– Consider how information on new or enhanced functionality can be used.
– Consider how to address mixture effects of multicomponent AdMas.
Currently, the Horizon Europe project SUNSHINE is developing approaches to address the toxicity of some AdMas and how existing information on single components or similar AdMas can be used in safety assessment (https://www.h2020sunshine.eu/). Unlike NMs, where strict adherence to a 100 nm size threshold has been proposed, we recommend not to limit the investigations on the toxicity of AdMas to particle sizes smaller than 100 nm. As we described earlier, it is highly likely that the size of AdMas will not be limited to the 100 nm threshold, some components of an AdMa may be smaller than 100 nm whereas the entire structure is not, and there is no scientific rationale related to safety for a strict cut-off at 100 nm.51
It is critical now to support (eco)toxicological studies of AdMas and to advance toxicology to tackle the challenges associated with the development of innovative AdMas. The generated data are important in order to be able to assess the risk of AdMas and to gather information to support the early warning systems, grouping and SSbD. The hazard assessment of a variety of AdMas may need to expand because new toxicological phenomena, which are not covered by the classical (apical) endpoints, might be induced by AdMas. We finally recommend the development of an efficient network between innovators, researchers and policy-makers, where up-to-date findings are transferred to facilitate the development of regulations for AdMas.
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