Environmental Science: Advances
Environmental Science: Advances
Environmental Science: Advances
Advances
View Article Online
PERSPECTIVE View Journal | View Issue
“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
Received 12th June 2022
Accepted 10th December 2022
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
DOI: 10.1039/d2va00128d
between AdMas based on their properties that might induce specific hazards and facilitate a faster
rsc.li/esadvances pathway to identify the hazards of new AdMas, which is particularly relevant for safe-by-design.
Environmental signicance
Advanced 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 classication of AdMas to facilitate generating toxico-
logical data for risk assessment.
1. Introduction
The technology of Advanced Materials (AdMas) is still maturing
as a discipline, with many new material discoveries expanding
a
Department of Environmental & Biological Sciences, University of Eastern Finland,
its realm. AdMas are more complex than conventional materials
P.O. Box 111, FI-80101 Joensuu, Finland. E-mail: fazel.monikh@uef.; f.a.monikh@
gmail.com
and cover a wide variety of materials, material combinations
b
Department of Chemical Sciences, University of Padua, Via Marzolo 1, 35131 Padova, and material scales (including the nano-scale). They are of
Italy interest due to their novel or enhanced properties1 that poten-
c
Institute of Environmental Sciences (CML), Leiden University, Einsteinweg 2, 2333 CC tially enable applications such as digital innovations and health
Leiden, The Netherlands advancement and aid in increasing energy conversion and
d
National Institute for Public Health and the Environment (RIVM), Center for Safety of storage,2 and advanced environmental remediation potential.
Substances and Products, Bilthoven, The Netherlands
e
For example, some AdMas can function dynamically which
Institute for Biodiversity and Ecosystem Dynamics (IBED), University of Amsterdam,
Amsterdam, The Netherlands
means they have passive and active states, leading to the
f
School of Geography, Earth and Environmental Sciences, University of Birmingham, performance of specic tasks upon activation, e.g., catalytically
Edgbaston, B15 2TT Birmingham, UK active AdMas known as nanozymes. AdMas are evolving to offer
g
Institute of Biological Chemistry, Biophysics and Bioengineering, School of seemingly endless possibilities by elaborating molecular
Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK architectures for different applications ranging from food to
h
Institute for Nanomaterials, Advanced Technologies and Innovation, Technical medicine and electronics.
University of Liberec, Bendlova 1409/7, 460 01, Liberec, Czech Republic
162 | Environ. Sci.: Adv., 2023, 2, 162–170 © 2023 The Author(s). Published by the Royal Society of Chemistry
View Article Online
Assessing the potential risks associated with use of different which can make comparisons between AdMas and other
types of AdMas is critical. This is important not only for tech- substances difficult. Such uncertainties can also lead to a lack of
nological development but also to reach some of the transitions clarity with respect to their consideration in legal frameworks,
and goals of the European Green Deal.3 Indeed, the introduc- e.g., as NMs, substances, or as an article.
tion of new and evolving technologies to the market to benet It is therefore now opportune to develop a perspective on the
society and the economy requires balancing the risks and applicability of existing frameworks for the hazard assessment
benets for humans and the environment. Addressing the of AdMas, to see where it applies, where modications or new
safety and the sustainability of materials, in general, at an early approaches might be needed. Such considerations will high-
stage of their design may benet (risk) governance, but requires light the challenges the toxicology community might face in
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
adequate methods for risk and sustainability assessment.4 optimal adaptation and therefore efficient use of existing
Open Access Article. Published on 21 December 2022. Downloaded on 7/4/2023 6:27:55 AM.
The considerations of balancing risks and benets are frameworks for assessing AdMa hazards. We performed an
therefore an important question to address if AdMas are to analysis of the existing knowledge pertaining to AdMas and
reach their full commercial and societal potential. However, their physicochemical properties to propose some criteria for
such considerations do not start from zero. For example, risk is the classication of AdMas to facilitate generating toxicological
calculated from exposure (the dose delivered) and hazard (how data for risk assessment. We propose potential solutions that
toxic the substance is). The relationships between physico- may be applicable to tackle some of the challenges anticipated
chemical properties and both exposure and hazard have been for AdMas and help to assess the hazard associated with these
widely studied for nanomaterials (NMs), which can provide materials by using some of the knowledge generated on NMs.
information relevant to AdMas. NMs are dened based on their We identify the knowledge gaps to be further studied and
size (1–100 nm) (EU Commission, 2011), where the size- scrutinized, and we provide some recommendations for future
dependent unique properties distinguish them from their toxicological studies of AdMas.
bulk counterparts. NMs could be considered as AdMas, but not
all AdMas are NMs. For example, some AdMas have a size larger 2. What are AdMas?
than the dimension proposed by the European Commission
(EC) for dening NMs, such as articial bacterial agellum (200 Several denitions or working descriptions have been proposed
nm) and two-armed nanoswimmer (200 nm). Various studies for AdMas (Table 1). Recently, the German Environment Agency
have assessed the human health and environmental risks of has provided a description for AdMas for regulatory purposes.9
NMs, which facilitated some political actions, e.g. in the EU.5 The EC uses a broad denition of “AdMas”, which includes any
Now, similar concerns arise for AdMas, noting that some of material that features a series of exceptional properties
these materials are already used in products with biomedical, (mechanical, electrical, optical, magnetic, etc.) or functional-
cosmetic and electronic applications.6 ities (self-repairing, shape change, decontamination, the
The current risk assessment frameworks for NMs are based transformation of energy, etc.) which can be new or enhanced
on the data generated for the so-called “rst generation” of compared to the conventional materials.10 This denition
NMs,7 where the materials are made of one main substance7 covers almost all materials, including all NMs and their future
(such as TiO2, ZnO, CeO2 and Ag), sometimes with an additional generations. It is worth mentioning that the OECD has
substance coating used to provide surface functionalization or launched a Steering Group on AdMas that addresses the suit-
colloidal stability. The question is whether such frameworks ability of existing safety regulatory systems. The OECD does not
can be utilised (or adapted) for AdMas. This review focuses on aim to develop an exact denition for AdMas, instead
hazards (rather than exposure and risk assessment), for which it a “working description” for AdMas that falls within the scope of
is critical to understand whether the AdMas can be assessed OECD is elaborated. Meanwhile, a technical committee of the
either International Organization for Standardization (ISO) is inde-
on the basis of the known hazards of their constituents, pendently working on a formal denition for AdMas.
on a more complex consideration of the possible toxic The German Environment Agency identied eight clusters of
effects of AdMas resulting from new or enhanced function, or AdMas10 (Fig. 1) based upon their structures that demonstrate
by addressing the potential for different components to their breadth of chemistry and applications, which clearly
interact and exacerbate the toxicological response. indicates the wide variety of AdMas available and under devel-
Toxicological data can serve to provide an early warning of opment. Here we provide some specic examples of AdMas in
risk, while a lack of such toxicological data can cause risk order to exemplify this diversity and furthermore their useful-
governance to lag behind innovation. However, the hazard ness. The rst example includes multi-layered nickel–cobalt
assessment of AdMas might face challenges due to uncertainty organic framework nanosheets (based on the scheme in Fig. 1,
on the adequacy of current test methods. The Organisation for this AdMa can be categorized as a composite), developed as
Economic Cooperation and Development (OECD) has con- electrode materials for energy storage.13 Some of these materials
ducted analyses of a number of guidance documents and test can be switched off and on or controlled remotely, which
guidelines for their relevance to adequately assess the toxicity of denes them as smart AdMas or smart NMs.6 As another
NMs.8 These considerations could be adopted for some AdMas. example, nanoscale bending-sensitive and optically transparent
Such considerations would need to incorporate the complexity pressure sensors have been fabricated using composite nano-
of the materials, their properties, and their dynamic functions, bers.14 Many other NMs, e.g. ionic polymer–metal composites,
© 2023 The Author(s). Published by the Royal Society of Chemistry Environ. Sci.: Adv., 2023, 2, 162–170 | 163
View Article Online
Any material that, through the precise control of its composition and European Commission10
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,
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
164 | Environ. Sci.: Adv., 2023, 2, 162–170 © 2023 The Author(s). Published by the Royal Society of Chemistry
View Article Online
3.1. Chemical composition is not the only inuential factor the particles rather than to the particle itself. For an AdMa
composed of both quickly and slowly dissolving components,
One of the main advantages of AdMas, in general, is the
linking the biological and ecological effects to the physical form
possibility to design them with different physicochemical
during exposure or uptake might be complicated. Azevedo et al.
properties such as size, shape, aspect ratio, hydrophobicity, etc.
(2017)28 investigated the toxicity of a nanostructure composed
Systematic studies have to some extent been performed to test
of ZnO with Ag NMs on its surface (designated as the ZnO/Ag
the inuence of the physicochemical properties of NMs on their
nanostructure) to Daphnia magna. The toxicity of ZnO and Ag
toxicity.17,18 The ndings have clearly conrmed that chemical
composition is not the only factor inuencing the toxicity of NMs as single components, along with their nanostructure
(ZnO/Ag) was tested. The authors concluded that neither the
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
© 2023 The Author(s). Published by the Royal Society of Chemistry Environ. Sci.: Adv., 2023, 2, 162–170 | 165
View Article Online
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)).
NOM corona is dictated by the physicochemical properties of For AdMas, the formation and evolution of a protein or NOM
NMs such as size, aspect ratio, surface charge and chemical corona is probably also controlled by the physicochemical
composition,33 as well as by the presence of the NOM or proteins properties of the materials. We describe our expectation of
in the surroundings and other conditions of the surroundings protein corona formation on AdMas by using smart NMs as
(pH, temperature, etc.). a model of AdMas in a hypothetical example of a polymeric
particle with an iron NM core and a QD doped surface (Fig. 3).
166 | Environ. Sci.: Adv., 2023, 2, 162–170 © 2023 The Author(s). Published by the Royal Society of Chemistry
View Article Online
Fig. 3 A hypothetical example of a polymeric NM with a core iron NM and surface doped QDs. In the bloodstream, the particles are coated with
protein to form a protein corona. The composition of the protein corona on the surface of the QD is different than the composition of the protein
corona on the surface of the polymeric particles. When the particle is activated by a magnetic field, the iron particle in the core creates heat. We
expect this heat to influence the composition of the protein corona on the surface of the polymeric particle.
In this illustration, we expect that different proteins adsorbed to feasible for many laboratories due to the extensive instrumen-
the surface of the QD NM compare to the case of exposure of tation and the skills required to perform the comprehensive
solely the polymeric NM in the same medium. It is also likely characterization. These challenges have already been recog-
that activation of the iron NM with a magnetic eld would nized for rst generation of NMs, which apply to AdMas. Any
generate heat34 that can inuence the formation of the protein characterisation should be attempted in a media that best
corona (Fig. 3). represents the biological or environmental compartment rele-
Understanding the formation and evolution of protein or vant to the life cycle stage under consideration. There are some
NOM corona is useful for hazard assessment. Sorption of limitations that can further challenge the characterization of
biomolecules on the surface of AdMas confers a new biological AdMas (including smart NMs). For example, the characteriza-
identity to the materials, which inuences the biological fate tion of a multi-element AdMa consisting of inorganic and
and biodistribution of the particles in various organs, tissues, organic components requires combinations of techniques
and cells in organisms. For example, it is known that adsorption suitable for the characterization of each component (by
of proteins facilitates the recognition and uptake of particles by assuming that the sample preparation for the target component
immune cells, which are involved in the uptake and metabolism does not inuence the other component of the AdMa). More-
of foreign particulates.35 We believe that while the existing data over, it is yet unknown how to characterize the activity of smart
on protein corona formation on NMs can help to understand AdMas upon stimulation for toxicological purposes, e.g., in
the corona formation on AdMas, alone it will not be sufficient. nontarget organisms.
Some physicochemical properties of AdMas such as the multi-
elemental composition and implementation of switchable
3.3. Being smart further challenges the toxicity testing of
properties in some AdMas, which imparts dynamic properties
smart AdMas
to the NMs, may add another dimension to the biological fate of
AdMas, consequently complicating the prediction of their bio- Some AdMas are designed to undergo changes in their physi-
distribution and hazard. cochemical properties in response to a specic stimulus. These
Most of the available information on the elimination of NMs are referred to as smart AdMas or smart NMs (although most of
from the body is medically oriented and it is indicated that them have size larger than 100 nm). Examples of such AdMas
>6 nm particles cannot be eliminated via renal excretion.36 Few include light-driven molecular motors and smart nano-
(eco)toxicological studies on sh showed that NMs might be pesticides. For example, it is possible to design nano-
excreted from the gills.37,38 Many promising AdMas have a size pesticides (Fig. 2b) that minimize biocidal leaching. They thus
large than 6 nm.39 More studies are still needed to understand reduce bioaccumulation in non-targeted organisms,40 which is
the uptake and elimination pathway of AdMas from different a drawback of traditional pesticides. The nano-pesticides can be
model organisms with (eco)toxicological purposes. designed to target specic tissues in plants and remain passive
However, extensive characterization of pristine materials, in (Fig. 2c and d). They could be activated by stimuli such as pH or
products or in various life cycle stages is not always practically a specic enzyme,15 leading to, e.g., triggered and controlled
cargo release in the target organisms. Similar AdMas have been
© 2023 The Author(s). Published by the Royal Society of Chemistry Environ. Sci.: Adv., 2023, 2, 162–170 | 167
View Article Online
developed for medical applications and for environmental critical for current risk assessment procedures and support the
remediation. These smart NMs might nd their way to the international acceptance of data as well as harmonization
market within a few years. Regardless of their terminologies, across different labs and the generation of reliable data.48
e.g., nanomachines, nanobiodevices, actuators, nanomotors Examples of published TGs for NMs include TG 125 on particle
and nanostructures, from a toxicological perspective they are size and particle size distribution, TG 413 of subchronic inha-
AdMas interacting with cells and biomolecules in organisms.41 lation tests, and GD 317 on aquatic and sediment toxicological
The question is what drives these interactions and what are the testing. These TGs or GDs have been newly developed for NMs
consequences for risk assessment. or adapted from existing ones for chemicals.49,50 Further work is
There are few toxicological studies in which the effect of ongoing for a number of other TGs and GDs. The increased
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
activated smart NMs has been investigated, although such tests complexity of AdMas, such as for the smart and multi-elemental
Open Access Article. Published on 21 December 2022. Downloaded on 7/4/2023 6:27:55 AM.
are currently uncommon.42,43 The question is whether and to AdMas, might further challenge the adequateness and t-for-
what extent the smart or enhanced properties must be consid- purpose of the TGs and GDs for NMs, which have been devel-
ered in toxicological studies. Hazard assessment based on the oped for mono-element NMs.
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 4. Recommendation for classification
AdMas. Testing of the different forms of a material – passive of AdMas for toxicological and risk
and active – can be considered, but could be difficult to assessment purposes
generate. It will also be difficult to assess and simulate the
location of the bioavailability of active forms within the body or Given the anticipated developments of AdMas in the near
within cells. Also, assessing the hazards of different forms future, it is important to consider how to address AdMas in legal
would lead to higher costs for toxicity testing as well as a greater frameworks, and if and what adaptations are needed to
animal use. While guidelines and protocols exist for assessing adequately gather information on safety to accommodate
hazards of dissolved chemicals, and in some cases for NMs, AdMas. Some AdMas will fall under the denition of NMs
further work will be required to determine their suitability for whereas others will not. Due to the large diversity in AdMas, it is
the assessment of smart AdMa-induced toxicity, and to make useful to streamline assessing potential consequences of AdMas
modications if required. for physicochemical and (eco)toxicity testing by classication of
AdMas into different groups. These groups should be based on
3.4. Not all AdMas are NMs their physicochemical properties that may involve similar
mode-of-action of toxicity, e.g., the mode-of-action could
For regulatory purposes, the EC recommended a denition for
include release of ions and particles of different types, surface
NMs in 2011 and the revision will be released soon.44 To enable
area, etc. For example, in the clusters proposed by the German
safety assessment and management and implementation of
Environment Agency, advanced alloys and QDs are classied
regulation, the size range of 1–100 nm was proposed and
into two different clusters. From a toxicological perspective,
adopted. Toxicity of materials is however not limited to
advanced alloys and QDs could be particles consisting of more
a specic size, e.g. <100 nm, and each organism and cell might
than one metal, where each metal within one particle might
respond differently to different sizes.45 It has for instance been
induce toxicity through similar pathways, e.g., generating
shown that a particle with size larger than 100 nm might be
oxidative stress or cell apoptosis. The benets of classication
more toxic than smaller counterparts of the same material.46
are that it: (1) enables differentiation between AdMas based on
AdMas oen exceed the threshold limit of 100 nm.7 For
their properties that might induce specic hazards, (2) provides
example, many AdMas such as nanomotors and nano-
measurable criteria that can be integrated into toxicological
composites have sizes larger than 100 nm. This excludes them
concepts, (3) provides clearer insight into what is needed to
from being NMs according to the EC recommended denition
address AdMas in legal frameworks and (4) facilitates a faster
despite having the term “nano” in their terminologies. It is also
pathway to identify the hazards of new AdMas.
likely that AdMas with sizes larger than 100 nm will be made of
Further renements required to address the safety assess-
NMs with sizes smaller than 100 nm. Since not all AdMas are
ment of AdMas include:
considered to be NMs and, thus, the nano-specic requirements
– Investigate mode-of-action for each class of AdMas.
are not applicable to all AdMas, these materials will not be
– Consider when and how the existing information for single
regulated as NMs whereas physicochemical properties rather
components can be used.
than chemical properties alone determine their fate/
– Consider how information on new or enhanced function-
toxicokinetics and hazards. This may require new adaptations
ality can be used.
in regulations.
– Consider how to address mixture effects of multicompo-
nent AdMas.
3.5. Can current (eco)toxicological guidelines cover AdMas? Currently, the Horizon Europe project SUNSHINE is devel-
The OECD and the ISO are working extensively on developing oping approaches to address the toxicity of some AdMas and
toxicological test guidelines (TGs) or Guidance Documents how existing information on single components or similar
(GDs).47 From a regulatory perspective, these TGs and GDs are AdMas can be used in safety assessment (https://
168 | Environ. Sci.: Adv., 2023, 2, 162–170 © 2023 The Author(s). Published by the Royal Society of Chemistry
View Article Online
308485).
Open Access Article. Published on 21 December 2022. Downloaded on 7/4/2023 6:27:55 AM.
© 2023 The Author(s). Published by the Royal Society of Chemistry Environ. Sci.: Adv., 2023, 2, 162–170 | 169
View Article Online
17 F. Abdolahpur Monikh, D. Arenas-lago, P. Porcal, R. Grillo, 34 R. R. Shah, T. P. Davis, A. L. Glover, D. E. Nikles and
P. Zhang, Z. Guo, M. G. Vijver, W. J. G. M. Peijnenburg, C. S. Brazel, J. Magn. Magn. Mater., 2015, 387, 96–106.
F. Abdolahpur, D. Arenas-lago, P. Porcal and R. Grillo, 35 R. Cai, J. Ren, Y. Ji, Y. Wang, Y. Liu, Z. Chen, Z. Farhadi
Nanotoxicology, 2019, 1–16. Sabet, X. Wu, I. Lynch and C. Chen, ACS Appl. Mater.
18 F. Abdolahpur Monikh, L. Chupani, Z. Guo, P. Zhang, Interfaces, 2020, 12, 1997–2008.
G. K. Darbha, M. G. Vijver, E. Valsami-Jones and 36 W. Poon, Y. N. Zhang, B. Ouyang, B. R. Kingston, J. L. Y. Wu,
W. J. G. M. Peijnenburg, Ecotoxicol. Environ. Saf., 2021, S. Wilhelm and W. C. W. Chan, ACS Nano, 2019, 13(5), 5785–
218, 112280. 5798.
19 X. Li, W. Liu, L. Sun, K. E. Aifantis, B. Yu, Y. Fan, Q. Feng, 37 F. Abdolahpur Monikh, L. Chupani, D. Arenas-Lago, Z. Guo,
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
F. Cui and F. Watari, J. Biomed. Mater. Res., Part A, 2015, P. Zhang, G. K. Darbha, E. Valsami-Jones, I. Lynch,
Open Access Article. Published on 21 December 2022. Downloaded on 7/4/2023 6:27:55 AM.
170 | Environ. Sci.: Adv., 2023, 2, 162–170 © 2023 The Author(s). Published by the Royal Society of Chemistry