Environmental mixtures of nanomaterials and chemicals

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Article history: ..... organisms at all (Farkas et al., 2017; Tedesco et al., 2010; Vale et al.,. 2014). ..... port by cation transporters and this should result in no effect alterations. ..... Chai, M.W., Shi, F.C., Li, R.L., Liu, L.M., Liu, Y., Liu, F.C., 2013.
Science of the Total Environment 635 (2018) 1170–1181

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Science of the Total Environment journal homepage: www.elsevier.com/locate/scitotenv

Review

Environmental mixtures of nanomaterials and chemicals: The Trojan-horse phenomenon and its relevance for ecotoxicity Steffi Naasz, Rolf Altenburger, Dana Kühnel ⁎ Helmholtz Centre for Environmental Research - UFZ, Department Bioanalytical Ecotoxicology, Permoserstr. 15, 04318 Leipzig, Germany

H I G H L I G H T S

G R A P H I C A L

A B S T R A C T

• Studies on nanomaterials (NM)-chemical mixtures in environmental organisms are reviewed. • Combined effects were categorised by modulation in bioaccumulation as well as toxicity. • Processes relevant for the emergence of mixture effects in organisms were identified. • Based on identified processes, NMchemical mixture effects were assigned to 6 groups. • A concise nomenclature for the different mechanisms of interaction is proposed.

a r t i c l e

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Article history: Received 6 March 2018 Received in revised form 13 April 2018 Accepted 13 April 2018 Available online xxxx Editor: D. Barcelo Keywords: Combined effect Mixture toxicity Nanoparticle Co-exposure Pollutants Bioconcentration Trojan horse

a b s t r a c t The usage of engineered nanomaterials (NM) offers many novel products and applications with advanced features, but at the same time raises concerns with regard to potential adverse biological effects. Upon release and emission, NM may interact with chemicals in the environment, potentially leading to a co-exposure of organisms and the occurrence of mixture effects. A prominent idea is that NM may act as carriers of chemicals, facilitating and enhancing the entry of substances into cells or organisms, subsequently leading to an increased toxicity. In the literature, the term ‘Trojan-horse effect’ describes this hypothesis. The relevance of this mechanism for organisms is, however, unclear as yet. Here, a review has been performed to provide a more systematic picture on existing evidence. It includes 151 experimental studies investigating the exposure of various NM and chemical mixtures in ecotoxicological in vitro and in vivo model systems. The papers retrieved comprised studies investigating (i) uptake, (ii) toxicity and (iii) investigations considering both, changes in substance uptake and toxicity upon joint exposure of a chemical with an NM. A closer inspection of the studies demonstrated that the existing evidence for interference of NM-chemical mixture exposure with uptake and toxicity points into different directions compared to the original Trojan-horse hypothesis. We could discriminate at least 7 different categories to capture the evidence ranging from no changes in uptake and toxicity to an increase in uptake and toxicity upon mixture exposure. Concluding recommendations for the consideration of relevant processes are given, including a proposal for a nomenclature to describe NMchemical mixture interactions in consistent terms. © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

⁎ Corresponding author. E-mail address: [email protected]. (D. Kühnel).

https://doi.org/10.1016/j.scitotenv.2018.04.180 0048-9697/© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Modulation of toxicity upon NM – chemical mixture exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Enhancement in toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Reduction in toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. No change in toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. How does co-exposure of chemicals and NM modify uptake and bioconcentration of the respective chemical in biological test systems 2.2.1. Adsorption behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Availability of NM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Linking accumulation and toxicity of NM-chemicals mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Process-oriented approach and development of a reference nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Matching observations from the evaluated studies with the suggested categories . . . . . . . . . . . . . . . . . . . . . . . . . 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In recent years, nanomaterials (NM) of anthropogenic origin have been detected in different environmental compartments, e.g. in the atmosphere and in surface waters (Astefanei et al., 2014; Bäuerlein et al., 2017; Gondikas et al., 2014; Kaegi et al., 2010; Sanchís et al., 2011). Currently, such measurements are very laborious and are hence complemented by estimations from modeling studies (Sun et al., 2014b). For example, predicted environmental concentrations (PEC) reported for Ag-NP and TiO2-NP were 0.66 and 0.53 ng L−1 for surface water in the EU, respectively (Sun et al., 2014b). The occurrence and distribution of NMs in the environment lead to the interaction with chemicals which possibly exerts mixture effects in environmental organisms through acting as carriers for various organic chemicals and heavy metals (Hartmann and Baun, 2010). NM specific properties can result in a high adsorption capacity, which is utilized intentionally in various applications such as nanomedicine, nanotherapeutics and environmental remediation (Davis et al., 2008; Fu et al., 2014; Mackenzie et al., 2012). The interaction between NMs and chemicals depends on the individual properties of the components, environmental conditions, and the biological system considered (Dwivedi and Ma, 2014). Many NM-substance combinations have been experimentally analyzed using a range of different biological models. Limbach et al. (2007) initially coined the term ´Trojan-horse mechanism´ to label an increase or prolongation of the damaging action of a NM compared to the corresponding metal ions, either through catalytic activity of the NM or due to the continuous intracellular release of ions from the NM. The use of this term was further extended to capture the potential carrier function of NM for chemicals leading to a facilitated uptake of chemicals into organisms and resulting in an increased toxicity (Hartmann and Baun, 2010). Despite this inherent linkage of uptake and the occurrence of a damaging effect, many mixture studies can be found that focus on either the modulation in uptake of chemicals or NM, or on alterations in toxicity upon mixture exposure. Accordingly, few studies allow firm conclusions on whether the coexposure of NM and chemicals actually results in the occurrence of Trojan-horse-like effects. As indicated in some recent reviews with focus on nano-TiO2 and carbon based NM, mixtures of NM and chemicals act by several mechanisms beyond the Trojan horse type (Boncel et al., 2015; Canesi et al., 2015; Hartmann and Baun, 2010; Liu et al., 2013). At the same time it was recognized that the influence of NM on uptake and bioconcentration of chemicals may play a role for the occurrence of enhanced or reduced toxicity. Hence, we aimed to explore the relationship between changes in uptake, bioconcentration, and toxicity in more detail. For this purpose, mixture studies involving environmental test organisms were reviewed in order to describe more specifically the interactions that have been

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observed. Mixture studies conducted in in vivo or in vitro systems were considered. For the purpose of this review, the term ‘chemicals’ comprises substances classified as polar and nonpolar organic compounds, highly functionalized compounds such as drugs and hormones, organometallic substances, amphiphilic substances, and also heavy metals. By contrast, all studies dealing with mixture effects of NMs and natural organic substances, such as natural organic carbon (NOM) or humic acid (HA) were excluded. The classes of NMs included in this review comprised of carbonaceous materials (SWCNTs, MWCNTs, fullerenes, graphene), metal and metal oxide particles (e.g. AuNPs, TiO2), semi-conductor nanocrystals (e.g. quantum dots), and polymers with the exception of carbon black and related materials. The major aim of this review was to provide a more systematic understanding of observable NM-chemical interactions and their transition into specific biological effects. For the groups identified, a consistent nomenclature is proposed. This will allow a more concise description of evidence and an improved understanding as a basis for assessing potential risks of NM-chemical mixtures for human health and the environment.

2. Methods The original literature search was conducted in Thomson Reuters ISI Web of Science and Elseviers Scopus by using the search terms ‘nanoparticles, combined effects’, ‘nanomaterials and chemicals’, or ‘nanoparticles, mixture toxicity’. The search by these terms resulted in a limited outcome since the reviewed topic relates to diverse research fields and nomenclature is not consistent. For these reasons additional cross-referenced literature from the retrieved studies was identified. Selected for the purpose of this review were studies assessing the effects of joint exposure on environmental in vitro models and organisms, such as cell lines, bacteria, algae, crustaceans, fish, mollusks, nematodes and plants (Fig. 1b). In total, 151 studies (see also Tables in Supplement) (e.g. Al-Subiai et al., 2012; Anjum et al., 2014; Baun et al., 2008; Cui et al., 2011; De La Torre-Roche et al., 2013; Della Torre et al., 2015a, 2015b; Fan et al., 2012; Fayaz et al., 2010; Gajbhiye et al., 2009; Hamdi et al., 2015; Hartmann et al., 2010; Hu et al., 2014b; Hu et al., 2011; Kühnel et al., 2009; Lammel et al., 2015; McShan et al., 2015; Mohmood et al., 2015; Petersen et al., 2009; Qin et al., 2014; Rocco et al., 2015; Sanchis et al., 2016; Santaella et al., 2014; Shahverdi et al., 2007; Shen et al., 2012; Silveira et al., 2015; Tang et al., 2015, 2013; Tian et al., 2014a; Völker et al., 2014; Wang et al., 2014b, 2011a, 2011b; Worms et al., 2012; Yang et al., 2010; Yu and Wang, 2013, 2014; Zhang et al., 2009, 2007) were identified dealing with mixtures of NM and chemicals in ecotoxicological test organisms and model systems. The last search was performed in December 2017.

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Fig. 1. Number of investigations on mixture exposure classified by a) the NM and group of chemical tested, or b) the biological test system. The chemicals used in the mixture exposure were classified as polar and nonpolar organics, metals, organometallic substances or surfactants. Some studies investigated more than one nanomaterial or more than one auxiliary component.

The 151 studies were sorted according to the NMs and chemicals studied as well as for the in vitro or in vivo test model used (Fig. 1). Almost half of the studies dealt with TiO2-NPs followed by the carbonaceous NMs CNT and fullerenes (Fig. 1a). TiO2-NPs were mostly tested together with heavy metals whereas for carbonaceous materials the combination with organic substances was dominating. The selection of these combinations is most likely driven by the anticipated applications of these NMs, e.g. for environmental remediation or nanomedicine (Josko et al., 2013; Patrizia et al., 2016; Saqib et al., 2016; Stark, 2011). Other NMs which are also produced in large quantities, e.g., ZnO- or SiO2-NPs were less studied with regard to mixture effects with chemicals (Falfushynska et al., 2015; Fang et al., 2013; Piccinno et al., 2012). Most of the studies tested binary mixtures with one NM and chemical applied simultaneously, few investigated the influence of contaminant mixtures and one NM on the accumulation and biological outcome (Ferguson et al., 2008; Josko et al., 2013; Pavagadhi et al., 2014) and we found none that applied chemical and NM in temporal sequence. For the evaluation of mixture effects various in vitro and in vivo biological test systems were used with about half of the studies investigating effects in fish and crustaceans (Fig. 1b). A detailed overview on the collected studies can be found in the Supplementary Material. 2.1. Modulation of toxicity upon NM – chemical mixture exposure In a first step, 127 studies dealing with a modulation of toxicity upon mixture exposure were extracted from the retrieved literature (see also Tables in Supplement) (e.g. Banni et al., 2016; Campos-Garcia et al., 2015; Deng et al., 2016; Falconer et al., 2015; Fan et al., 2016a; Glomstad et al., 2016; Hu et al., 2012b; Li et al., 2017; Molins-Delgado et al., 2016; Panáček et al., 2016; Rossi et al., 2014; Wang et al., 2014a, 2015a; Yan et al., 2014, 2010; Zou et al., 2013). In the different organisms, a broad range of acute and subacute endpoints such as mortality, mobility, growth, reproduction, DNA damage, ROS formation, and enzyme expression were observed. The studies were inspected with regard to whether an enhancement, a decrease or no change in toxicity upon exposure to a NM-chemical mixture was observed; and with regard to the mechanisms which were discussed to be causative for any observed modulated toxicity. 2.1.1. Enhancement in toxicity Of the 127 studies evaluated, the majority (66%) reported an enhanced toxicity upon mixture exposure compared to single-substance

exposure. Enhanced toxicity of the chemicals are reported for all combinations: inorganic NM/inorganic chemical (Fan et al., 2011; Han et al., 2011; Miao et al., 2015; Tan et al., 2012; Wang et al., 2015b), inorganic NM/organic chemical (Falfushynska et al., 2015; Krysanov and Demidova, 2012), organic NM/inorganic chemical (Chai et al., 2013; Kim et al., 2009), and organic NM/organic chemical (De La TorreRoche et al., 2012a; Ferreira et al., 2014; Hu et al., 2013). Mainly, the chemical rather than the NM was held responsible for the enhanced toxicity (Dalai et al., 2014), as often no toxicological effects are observed for the NM alone (Cuahtecontzi-Delint et al., 2013; Dalai et al., 2014). In addition, some studies selected non-toxic NM exposure concentrations. Most studies attributed the increase in toxicity to an increased bioavailability and internalization of the chemical due to the presence of the NM. Some studies discussed additional mechanisms for enhancement in toxicity, namely transformation of substances into products exerting a higher toxicity than the parent compound inside the organism/cell. Such transformations may be influenced by the presence of NM. For example, the conversion of tetrahydrofuran to the more toxic degradation product γ-butyrolactone (Henry et al., 2007), as well as the transformation of pentachlorophenol (Fang et al., 2015) in zebrafish larvae in the presence of fullerenes were discussed in this direction. For the transformation of BDE-209 in the presence of TiO2-NPs the impact of the observed transformation products on toxicity remained inconclusive (Wang et al., 2014c).

2.1.2. Reduction in toxicity Of the remaining studies, 26 reported a decrease in toxicity upon mixture exposure. Most studies attribute this observation to a reduction in the bioavailability of the chemical to the organisms, due to the presence of the NM. Mechanistically, it is assumed that the sorption of chemicals to the NM prevents the internalization of the chemical, either because particles are not taken up by the organisms and/or because sorption is irreversible (Martin-de-Lucia et al., 2017; Simon et al., 2015). In some cases, a subsequent sedimentation of particles was observed, leading to a reduced bioavailability of the chemical for the organism and therefore reducing the toxic effect (Chai et al., 2013; Rosenfeldt et al., 2014; Rosenfeldt et al., 2015a, 2015b; Tan et al., 2017; Zhang et al., 2014). This effect was particularly described in studies using CNT and fullerenes (Chai et al., 2013; Josko et al., 2013; Magesky and Pelletier, 2015; Park et al., 2010; Zhang et al., 2014).

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2.1.3. No change in toxicity In 18 studies, the toxicity was not altered by the presence of a NM. In the studies reporting no modulation of toxicity it was commonly assumed that NM and chemicals do not interact and no sorption of the chemical takes place (Dalai et al., 2014; Hartmann et al., 2012; Tourinho et al., 2015; Vale et al., 2014; Vannuccini et al., 2015). Further, for some chemicals it was suspected that they are not taken up by the organisms at all (Farkas et al., 2017; Tedesco et al., 2010; Vale et al., 2014). Hence, the presence of the NM had no modulatory effect on toxicity. For example, a chronic study with D. magna exposed to functionalized C60 and bifenthrin or tribufos, for 21 or 70 days respectively could not detect any effects on the reproduction (Brausch et al., 2010). 2.2. How does co-exposure of chemicals and NM modify uptake and bioconcentration of the respective chemical in biological test systems As most of the studies reporting on changes in toxicity upon mixture exposure consider the influence of the NM on the availability of the chemical as crucial, in a second step studies that focus on uptake and bioconcentrations were inspected in more detail. Of the retrieved studies, 94 quantified the uptake of chemicals upon co-exposure to NM and allowed to evaluate the different ways of interaction in this process. The internal concentration of either the chemical, the NM or both were quantified and single substance and mixture exposure were compared in the respective biological system. Most of these studies (76%) focused on the quantification of the chemical since they expected a direct correlation to the amount of internalized NM, whereas 71% of the studies determined the NM uptake within their mixture experiments. Only some studies (24%) investigated both, the uptake of the NM as well as that of the chemical. The majority of studies (59%) reported an enhanced accumulation of a chemical within the test system (e.g. Hu et al., 2010; Ma and Wang, 2010; Sun et al., 2007; Sun et al., 2014a). On the other end, a third of the studies reported a reduced internalization of chemicals in the presence of a NM compared to single substance exposure (e.g. Ferguson et al., 2008; Kelsey and White, 2013; Xia et al., 2012). For combinations of chemicals with metallic NMs specifically, an unmodified internalization of the chemical has been reported (De La Torre-Roche et al., 2012b; Farkas et al., 2017). As evident by the discussion of results in the reviewed studies, two processes are generally assumed to determine the bioconcentration of a chemical upon mixture exposure: (1) the adsorption behaviour of the respective chemical for the NM and (2) the availability of the NM in the respective test system. 2.2.1. Adsorption behaviour The interaction between NM and chemicals were analyzed in several studies and depending on the type of NM and chemical, different processes were found to determine the interaction. For organic compounds hydrodynamic binding to the NM prevails (Kah et al., 2011; Xia et al., 2012), whereas electrostatic interactions are the major mechanism for inorganic substances and metals. Also, complexation plays a role, as described e.g. for chromium (Balbi et al., 2014; Vale et al., 2014). Both reversible and irreversible adsorption was reported, the latter preventing chemical release from NM after uptake into organisms (Etale et al., 2016; Tao et al., 2013; Yang et al., 2014). In general, the sorption behaviour was found to be influenced by several factors such as NM properties, chemical properties, but also test medium, test environment and test organism. Studies investigating the adsorption capacities of NM for chemicals hence found obvious differences, e.g. for SiO2, TiO2 and Fe3O4 binding waste water pollutants (Martin-de-Lucia et al., 2017); for the capacity of Al2O3 particles to bind Cs and Sr (Asztemborska et al., 2016), and of chromium for Al2O3 and TiO2 particles (Dalai et al., 2014). The sorption capacity was also found to depend on NM surface area (De La Torre-Roche et al., 2012b; Josko et al., 2013). Organic matter has been shown to modulate the

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adsorption of metals to NMs, thereby also modulating bioaccumulation (Fan et al., 2016b; Ma et al., 2017). Conversely, the binding of the contaminant to the particle may also change the NM behavior, e.g. by changing the zeta potential with subsequent consequences for agglomeration and sedimentation (e.g. Rosenfeldt et al., 2015a). Little is known on the fate of adsorbed chemicals upon incorporation into organisms. Some studies indicated that incorporated NM-bound chemicals may not become available to daphnids and zebrafish, as they are not released from the particles (Naqvi et al., 2013; Park et al., 2011; Park et al., 2010). But also a facilitated release of NM-bound chemicals from the particle surface due to changes of pH inside the gut of mussels was reported (Tian et al., 2014b). Interestingly, also facilitated uptake of pollutants in the presence of NM independent of the adsorbed fraction was observed in D. magna (Hartmann et al., 2012). For some NM-chemical mixtures transformation of the chemical due to the reactive or catalytic properties of NM has been reported, with potential consequences for bioconcentration (De La Torre-Roche et al., 2012b; Fang et al., 2015; Farkas et al., 2015; Seitz et al., 2012; Sun et al., 2009). With regard to test species-specific differences, opposite trends in chemical uptake were reported (Ferguson et al., 2008; Hartmann et al., 2012), for example an increase in uptake in copepods and a decrease in the polychaete S. benedicti (Ferguson et al., 2008). Some uncertainty arises from different methodologies being used. Several different approaches for dosing the mixtures were reported, with some studies choosing a direct dosing approach by combining the components of the mixture just before the onset of organism exposure (Brausch et al., 2010; Fang et al., 2016; Rosenfeldt et al., 2014; Srikanth et al., 2014; Xia et al., 2010). By this approach, three processes run in parallel, namely the adsorption of chemical to the NM, the uptake of the chemical by the organism and a potential NM uptake. On the other hand, mixtures of NM and chemicals were allowed to reach the adsorption equilibrium before exposure by pre-incubation for a certain amount of time (Binelli et al., 2017; Henry et al., 2013; Hu et al., 2015; Park et al., 2010; Qiang et al., 2016, 2015; Su et al., 2013, 2007; Sun et al., 2009; Tian et al., 2014b). 2.2.2. Availability of NM A mechanism described as crucial in several studies is the NM behavior in media, especially agglomeration and subsequent sedimentation. By this media-dependent process, chemicals bound to NM will become unavailable to the organisms (Dalai et al., 2014; Rosenfeldt et al., 2014). This is especially relevant for studies involving marine organisms, because the high ionic strength of test media is fostering NM agglomeration and sedimentation (Farkas et al., 2015; Zhu et al., 2011). The relevance of this process is supported by a study comparing cadmium accumulation in Daphnia magna upon exposure to agglomerated and non-agglomerated TiO2 particles (Tan et al., 2017). An additional secondary effect may facilitate the uptake of chemicals even when no sorption to the NM surface takes place. Here the NM (specifically fibres such as CNTs) is damaging plant and algae cells due to piercing, resulting in a facilitated uptake of the chemical (Ma and Wang, 2010; Schwab et al., 2013; Wild and Jones, 2009). Studies dealing with soil and sediment organisms such as worms and plants need to additionally consider the complex interaction between NMs, soil and sediment particles and organic matter. Chemicals will adsorb not only to NMs but likewise to soil and sediment, which may again alter the availability of NM and chemicals to organisms (Tourinho et al., 2015). For example, higher adsorption capacities of chemicals for NM than for soil particles resulted in an increase of contaminant uptake in sediment-dwelling Chironomus plumosus larvae in the presence of NM (Shen et al., 2014). Moreover, the availability and internalization of the NM by test organisms was described as crucial for the modulation of the uptake of chemicals. First, some test organisms actively incorporate NM, while others do not. Here, the external barrier, the feeding behaviour, but also avoidance behaviour was found to play a role. For example, several

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algae species were found not to incorporate NM, possibly due to their rigid cell wall structures (Schwab et al., 2013). By contrast, most bacteria, primary cells and cell lines are able to actively incorporate particles (Busch et al., 2011; Li et al., 2005; Naqvi et al., 2013). The same is true for filter feeders such as daphnids who actively incorporate NM into their gut, facilitating the uptake of bound chemicals (Naqvi et al., 2013). An interesting observation was that the quantity of internalized NM may differ between particle types, e.g. the uptake of TiO2-NPs was 10-fold higher than that of Al2O3-NPs in the freshwater microalgae S. obliquus. Subsequently, enhanced chromium concentrations were found within the algae for the exposure with TiO2-NPs (Dalai et al., 2014). In addition, organism specific protection mechanisms may prevent the uptake of NMs and NM-bound chemicals, e.g. mussels closing their valves (Tedesco et al., 2010) or the avoidance behavior of worms (Hu et al., 2014a) have been studied in this line of thought. 2.3. Linking accumulation and toxicity of NM-chemicals mixtures From the separate inspection of mixture toxicity and bioaccumulation studies, crucial mechanisms and processes that play a role in NMchemical mixture toxicity were recognized. However, it is not possible to draw systematic conclusions on the link between the modulation in bioconcentration and subsequent toxicity of a mixture. In order to gain more knowledge on this linkage, a subset of 42 studies investigating the accumulation in parallel to the toxicological outcome in a quantitative manner were inspected in more detail (Azevedo Costa et al.,

2012; Balbi et al., 2014; Canesi et al., 2014; Dalai et al., 2014; Della Torre et al., 2017; Fan et al., 2011, 2016b; Fang et al., 2011, 2015; Farkas et al., 2015, 2017; Ferreira et al., 2014; Han et al., 2011, 2012; Hartmann et al., 2012; Hu et al., 2012a; Kim et al., 2010; Lee et al., 2016; Li et al., 2016a, 2016b; Liu and Wang, 2015; Liu et al., 2015; Ma et al., 2017; Miao et al., 2015; Nigro et al., 2015; Qu et al., 2014; Rosenfeldt et al., 2014, 2015a; Seitz et al., 2012; Tan and Wang, 2014; Tan et al., 2017; Tao et al., 2013; Vale et al., 2014; Wang et al., 2014a, 2014c, 2016; Yan et al., 2017; Yang et al., 2012a; Zhang et al., 2013, 2012; Zhu et al., 2011). The quantitative information provided in these studies was transformed into % change in accumulation and toxicity for a mixture in comparison to the single substance, respectively. Fig. 2 is summarizing the quantitative observations from these studies, allowing the differentiation of 7 categories describing NM-chemical mixture effects: (1) an increase in accumulation and toxicity (2) an increase in accumulation and no change in toxicity (3) an increase in accumulation and a decrease in toxicity (4) no change in accumulation and toxicity (5) no change in accumulation and a decrease in toxicity (6) a decrease in accumulation and toxicity (7) a decrease in accumulation and an increase in toxicity According to this categorization, more than half of the studies considered fall into the first category. This is a clear indication that an increase in bioaccumulation in the majority of studies was accompanied by the increase in biological effects. However, the degree to which an

Fig. 2. Observed changes of accumulation (upper panel) and toxicity (lower panel) in quantitative studies on NM-chemical mixtures in % compared to results obtained by a single chemical exposure. The studies were assigned to 7 categories: Increased accumulation and toxicity (category 1), increased accumulation and no change in toxicity (category 2), increased accumulation and decrease of toxicity (category 3), no change of accumulation and toxicity (category 4), no change in accumulation and a decrease in toxicity (category 5), decrease in accumulation and toxicity (category 6), and decrease in accumulation and increase in toxicity (category 7) of the chemical by a NM mixture exposure.

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increase in accumulation leads to an increase in toxicity differs and does not directly correlate with the change in accumulation. For example, Qu et al. (2014) showed a 350% increase in chemical uptake resulting in 20% increase in toxicity, whereas Zhang et al. (2012) found a 20% increase in accumulation to result in a N100% enhancement of toxicity. This illustrates that the internalized dose and effects are typically not linearly related. Moreover, an enhanced accumulation of the chemical in the presence of a NM does not always lead to increased toxicity. The studies describing no change in toxicity but enhanced accumulation (category 2) claimed various reasons for this observation. For example, increased antioxidant capacities of cells in the presence of C60 were held responsible, leading to a mitigation of toxicity exerted by increased internal dose of the chemical (Azevedo Costa et al., 2012). Also, the NM was suspected to facilitate biotransformation of the chemical BDE, hence reducing the concentration of the active compound and its toxicity accordingly (Wang et al., 2014c). A reduced toxic effect in spite of an increased accumulation (category 3) of the NM-bound chemical was described by Fang et al. (2011) and Rosenfeldt et al. (2014). Both studies determined an increased accumulation (2 to 6-fold) of the chemical inside the D. magna. However, the toxicity was reduced up to 100%, probably due to the high sorption strength between the NM and the chemical. In addition, the possibility of a modification or encapsulation of the chemical within the gastrointestinal tract was discussed (Rosenfeldt et al., 2014). In the study of Fang et al. (2011), 75% of the total mass of the chemical was sorbed to the NM and was shown to be unavailable for the organism in its free form. Both studies determined the sorption behavior and clearly showed an enhanced bioaccumulation, but at the same time a reduced bioavailability of the free chemical. Under category 4 studies are summarized that showed neither a change in accumulation nor in toxicity. Little to substantial sorption of chemical to the NM studied were reported (10–40% according to (Balbi et al., 2014; Vale et al., 2014)), and the effects corresponded to those of an exposure to the individual substances (Balbi et al., 2014; Farkas et al., 2017; Hartmann et al., 2012; Vale et al., 2014). It is speculated that the reduced bioavailability due to sorption of chemical to NM is outweighed by an increased bioavailability coming from a facilitated uptake of the NM (Hartmann et al., 2012). No change in accumulation but a decrease in toxicity (category 5) was described in only one study (Nigro et al., 2015). The combination of TiO2-NPs and Cd led to a smaller reduction of the genome template stability of marine fish compared to single substance exposure. A reduced accumulation as well as a decrease in the toxicity was observed for several metals in co-exposure with TiO2-NPs (category 6) (Li et al., 2016a; Rosenfeldt et al., 2014, 2015a; Seitz et al., 2012; Yang et al., 2012b); and for CNTs in combination with metals (Lee et al., 2016; Liu and Wang, 2015). Different metals (Cu, As, Ag) were observed to act differently with regard to uptake and toxicity in presence of TiO2-NPs towards D. magna (Rosenfeldt et al., 2014). Only the mixture with copper led to a reduced accumulation (14-fold) and toxicity (27%). The rapid sedimentation of the TiO2-NPs together with the associated Cu was thought to cause reduced exposure. The reduced bioavailability of cadmium due to sorption to TiO2 particles was clearly demonstrated to reduce the toxicity of the mixture (Yang et al., 2012b). Category 7 contains studies showing a decreased uptake of the chemical, but an increased toxicity by a co-exposure with a NM (Fang et al., 2015; Farkas et al., 2015; Liu et al., 2015). In the blue mussel M. edulis, the benzo[a]pyrene availability was reduced by the simultaneous presence of TiO2-NPs. However, the biological outcome for the enzymatic and chromosomal observations was enhanced leading to the assumption that the NPs acted as an additional stressor (Farkas et al., 2015). In zebrafish embryo (D. rerio), decreased internal PCP concentrations and increased toxicity in the presence of TiO2 were explained by the formation of the reactive transformation product tetrachlorohydroquinone (Fang et al., 2015).

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This overview of observations provides a structured collection of ideas how combinations of NM and chemicals may affect bioconcentration and toxicity in environmental organisms. The bioavailability of chemicals may be influenced by the presence of NM in various ways and the observed changes in bioconcentration as well as toxicity show a diverse picture for the different NM, chemicals and their combinations. However, the numbers of studies in the categories 2–7 are low and as evident from the evaluation of the studies included in each category, several underlying processes and mechanisms for the observations are possible. Further, variations in NM properties as well as experimental procedures may influence the accumulation and toxicity. Hence the assignment of specific NM-chemical combinations into the categories does not allow unambiguous conclusions on the underlying mechanisms of interaction. For example, TiO2-NP combined with metals and organic compounds appear throughout the categories 1–7. Therefore, we decided not to further pursue the idea that the link between changes in bioaccumulation and toxicity will allow to predict mixture effects of NM and chemicals, but to develop an alternative, more unambiguous approach that is based on the processes and mechanisms recognized as important for the elucidation of NM-chemical mixture effects.

2.4. Process-oriented approach and development of a reference nomenclature To obtain more coherence from the results of the literature evaluation, the anticipated dominating processes and mechanisms determining the toxicological effects of a NM-chemical mixture were put forward, namely the (1) type of interaction between NM and chemical, (2) the internalization of NM by test organisms, and (3) desorption of chemical from NM upon contact to organisms. The hypothesis is that ultimately, the interplay between these processes will determine the bioavailability of the chemical for the organisms, and hence the mixture toxicity. This organization of the processes allows suggesting a nomenclature that may serve as a reference and hopefully provides a more consistent picture (see Fig. 3 and Table 1; Suppl Table 8). The first process deals with the adsorption of chemicals to NM. In extreme, it results in two options, either adsorption or no adsorption of the chemical to the NM. However, three exposure scenarios result for test organisms, namely (1) exposure to NM-sorbed chemical, (2) exposure to NM-sorbed chemical and free chemical, (3) exposure to NM and free, unbound chemical. In most cases exposure scenario 2 seems to occur, which typically poses some uncertainty to estimate the relevance of the fractions, as the proportion of free chemical entering the organism is difficult to separate from the proportion of NM bound chemical. Likewise, the second process puts in focus the internalization of the NM by organisms. It results in two options in their extremes that the NM may be internalized by organisms or not. If compared to the internalization after exposure to the chemical alone, an enhanced uptake of the chemical may be expected in case the NM sorbs the chemical and is taken up by the organism. A constant or reduced uptake may occur when the chemical sorbs in sufficient quantity to the NM but the latter is not internalized. If no sorption to the NM occurs, chemical uptake is typically restricted to diffusion or in the case of metal ions active transport by cation transporters and this should result in no effect alterations. In case the NM is taken up by the organism, a co-uptake of the chemical with the NM may occur, resulting in an increased uptake. The third process to be considered relates to the potential of desorption of the chemical from the NM inside the organism or cell. This results in several options: A chemical may substantially desorb from the NM upon internalization by the organism, the internal concentration of free chemical is thus expected to increase. Also, the chemical may not desorb and remains attached to the NM upon internalization by the organism, resulting in a constant or even decreased concentration of free chemical due to additional sorption of intracellular substance. Third, the NM with adsorbed chemical is not taken up by the organism, but able to attach to its outside. A desorption of the chemical could result

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Fig. 3. Process-oriented approach for the classification of NM-chemical mixtures with regard to effects arising from mixture exposure. The last column lists the references supporting a role of the respective process. Arrows indicate: ↑ enhanced toxicity expected, ↓ decreased toxicity expected, → unmodified toxicity expected.

in this case in a locally increased concentration of chemical and in consequence in an enhanced uptake. As depicted in Fig. 3 and Table 1, the organization of these 3 processes results in 6 distinct groups. In general, it is expected that the changes of the internal concentration of the chemical determines the alteration of toxicity upon mixture exposure. The underlying assumption is that the prediction of increase, decrease, or non-modified internal concentrations of the chemical directly translates into enhanced, reduced, or unaltered toxicity, respectively. An unambiguous terminology is proposed by choosing distinct terms, named ´assessment term´ for each group: (1) Trojan horse (+): the increase in chemical uptake results in an enhanced toxicity. (2) Trojan horse (−): increase in chemical uptake, but the chemical is not becoming bioavailable, resulting in reduced toxicity. (3) Surface enrichment (Modification of availability): An enhancement in toxicity may occur, when a NM leads to a local enrichment of chemical concentration in the vicinity to the organism. (4) Retention: The toxicity will be reduced due to a decreased availability of the chemical. (5) Inertism/Passive interaction: An enhancement in toxicity may only occur when the chemical is co-transported with the NM. (6) Coalism/Physical interaction. An enhancement in toxicity will only occur if the uptake of a chemical is facilitated by physical damage to organisms induced by the NM. Note that this terminology is mainly thought to provide a reference for an expected combined effect outcome if adequate knowledge on the three underlying processes is available. It should thus allow a more precise discussion of observed mixture effects and hypothesis-driven experiments in the future. 2.5. Matching observations from the evaluated studies with the suggested categories In a next step, we aimed at assigning the individual studies included in categories 1–7 (Fig. 2) to the 6 groups defined in Fig. 3. As we assume that the observations may be caused by different underlying mechanisms and processes the individual datasets from the studies were assigned to the groups 1–6 according to the tiered description of processes (Fig. 3, last column). For all the 6 proposed groups, evidence

could be found in the literature in at least one study. However, not all datasets included in Fig. 2 could be assigned to the groups in Fig. 3. For 29 datasets we felt confident to assign the experiments to a specific group (detailed in Table 8 in Suppl.). It becomes apparent that the observations from the studies do not directly translate into one of the predefined groups, as the datasets from one category may be assigned to more than one group. For example, while most of the studies from Category 1 were assigned to the assessment term Trojan-horse (+), the study by Zhu et al. (2011) was assigned to the assessment term Surface enrichment. Thus, additional information and interpretations from the papers needed to be included in this exercise. For 18 datasets essential information for the assignment to a specific group was missing. However, for some data sets the potential groups could be narrowed down. For example, missing information on the desorption of the chemical from the NM does not allow differentiation between the assessment term Trojan-horse (+) and Trojan-horse (−) (Seitz et al., 2012), but assignment to group 3–6 is excluded. When further information e.g. on particle uptake is not available, then the assignment to a group gets even more uncertain (Han et al., 2011; Hartmann et al., 2012; Kim et al., 2010; Miao et al., 2015; Rosenfeldt et al., 2014; Vale et al., 2014; Wang et al., 2016). For 6 studies, information on the adsorption/interaction of the chemical to the NM was not provided (Azevedo Costa et al., 2012; Canesi et al., 2014; Farkas et al., 2015; Ferreira et al., 2014; Zhang et al., 2013, 2012). In addition, information on the uptake of the NM into the organisms was not available (Azevedo Costa et al., 2012; Ferreira et al., 2014; Zhang et al., 2013, 2012). Therefore, based on the results the assignment to a specific group was not possible for those studies, for some it can be restricted to some groups based on indirect information (see Table 1). For the 29 datasets that provided sufficient information, most of the datasets (14 out of 27) were found to belong to group Trojan-horse (+) (Fan et al., 2011; Fang et al., 2015; Han et al., 2012, 2012a; Qu et al., 2014; Rosenfeldt et al., 2014; Tan and Wang, 2014; Tao et al., 2013; Wang et al., 2014a, 2014c, 2016), and 5 to group Trojan-horse (−) (Fang et al., 2011; Rosenfeldt et al., 2014; Yang et al., 2012a), (Dalai

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et al., 2014; Rosenfeldt et al., 2015a). Despite the studies providing information on NM-chemical interaction, uptake of NM and chemical as well as toxicity, none of the studies actually demonstrated desorption of the

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chemical from the NM in a relevant system setting. To analyze this process thus poses a specific future analytical challenge, as the studies provide only indirect evidence for this process.

Table 1 Processes, experimental steps, and potential consequences for mixture experiment involving NM, and references supporting a role of the respective process. ↑ - increase, → - no alteration, ↓ - decrease. Experimental

Assessment in the test medium used for subsequent tests

(1) Adsorption/Interaction between NM and chemicals

YES

Experimental

Kinetics: How much chemical is bound to the NM and if so, how fast?

(2) Uptake of NM by organisms

YES

NO

NO

YES

NO

Internal concentration of chemical →↓ Uptake of unbound chemical

Internal concentration of chemical ↑ → Passive uptake of chemical with NM and uptake of unbound chemical

Internal concentration of chemical ↑ → Indirect influence on uptake e.g. when NM causes cell injury

YES





Experimental

Determination of internal concentrations NM and/or chemical, and uptake kinetics

Consequence of co-exposure compared to exposure to chemical only - uptake

Internal concentration of chemical ↑ → Uptake of chemical bound to NM parallel to uptake of unbound chemical, if sorption b100%

YES (3) Desorption of chemical inside/outside the organism

NO

NO

Physical effects of NM on cell/organism

Experimental

Determination of chemical released from NM

Local enrichment of chemical outside cell/organism

Consequence of co-exposure compared to exposure to chemical only - bioconcentration

Bioconcentration of free chemical

Uptake of Chemical internalized, but still increased amounts of bound chemical may lead to bioconcentration

Bioconcentration possible Availability of chemical reduced, no bioconcentration

Bioconcentration possible in case NM damages cells/organisms

(4) Toxicity Effect expectation

Enhanced effect

Reduced effect

Modified effects

Reduced effects

Unaltered effect

Unaltered effect

Consequence of co-exposure compared to exposure to chemical only - toxicity

Depending on kinetics enhanced or unaltered toxicity

If no desorption of chemical from internalized NM occurs, toxicity is reduced

Local increase of chemical on the outside of organisms possible, modification of availability

“Passive interaction”: in case of passive uptake of chemical with the NM increased internal chemical concentrations may result in enhanced toxicity

“Physical interaction”. in case NM does not interact with cells/organisms, no alteration in toxicity If NM induced damage, toxicity may increase

(Group) Assessment term (1) Trojan-horse (+)

(2) Trojan-horse (−)

(3) Surface enrichment

(4) Retention

(5) Inertism

(6) Coalism

Category according to Fig. 2

1, (2), 4

2, 3, 4, 5

1, 2, 4, 6, 7

4, 5, 6

1, 2, 4

1, 2, 4

Reference to observations from individual studies from Fig. 2

(Della Torre et al., 2017; Fan et al., 2011; Fang et al., 2015; Han et al., 2012; Hu et al., 2012a; Li et al., 2016b; Ma et al., 2017; Qu et al., 2014; Rosenfeldt et al., 2014; Tan and Wang, 2014; Tao et al., 2013; Wang et al., 2014a, 2014c, 2016)

(Dalai et al., 2014; Fang et al., 2011; Rosenfeldt et al., 2014, 2015a; Tan et al., 2017; Yan et al., 2017, 2012a)

(Zhu et al., 2011) (Lee et al., 2016; Li et al., 2016a; Martin-de-Lucia et al., 2017; Yang et al., 2012b)

(Balbi et al., 2014; Liu and Wang, 2015)

(Dalai et al., 2014)

(Liu et al., 2015; Seitz et al., 2012) Unclassified references (Farkas et al., 2017; Nigro et al., 2015) (Han et al., 2011; Hartmann et al., 2012; Kim et al., 2010; Miao et al., 2015; Rosenfeldt et al., (information provided not 2014; Vale et al., 2014; Wang et al., 2016) sufficient to assign to a (Azevedo Costa et al., 2012; Canesi et al., 2014; Farkas et al., 2015; Ferreira et al., 2014; Zhang et al., 2013; Zhang et al., 2012) group or mechanism is not represented in the table) General: Release of ions from NM was not taken into consideration, NM were assumed to be non-toxic or applied in non-toxic concentrations, metabolic processes in cells/organisms as well as catalytic processes induced by the NM may exert additional influences on chemical concentration. Qualitative statements are made, although the processes may also be judged from a quantitative perspective.

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Potentially, some groups may only be relevant for specific organisms, e.g. group Surface retention may be most relevant for single cells such as algae and bacteria, or immobile test organisms or life stages such as fish embryos. This would also bring the role of cell walls and other protective tissues such as chorion into focus (e.g. Böhme et al., 2017). All in all, the results from an in-depth analysis of mixture exposure datasets show that despite the Trojan-horse mechanism seems to be quite prevalent, there are various other processes through which NMchemical mixtures may act on environmental organisms. This underlines the importance of the consideration of the various processes in more details, such as ad- and desorption, bioavailability and internalization by organisms to ultimately understand alterations in toxic response. To be able to account for the broad range of mixture effects that may occur in the environment, we suggest a tiered approach based on the different processes and propose a related, consistent terminology to unambiguously cover the different mechanisms of mixture effects that may occur. 3. Conclusion Nanomaterials and other substances such as organic chemicals or heavy metals can be released into the environment and co-occur in aquatic and terrestrial compartments. We aimed in this review to unravel the role on NM as a potential Trojan horse and the implications of a mixture exposure for environmental organisms. The evaluation of 151 papers studying mixture exposure of NMs and chemicals revealed that NMs may modify the effects of chemicals on organisms in various ways. Many studies confirmed the occurrence of the Trojan horse effect, leading to an increase bioconcentration of the chemical in the presence of a NM, which translates into enhanced toxicity in environmental organisms in many cases. However, the diversity of effects NM-chemical combinations exert in environmental organisms showed that the picture is more diverse. This review specifies the processes on the level of NM-chemical interaction as well as NM-organism interaction that need consideration. In order to make a step towards a systematic consideration of mixture effects, we propose a process oriented interpretation and suggest a terminology that would allow sufficient discrimination: Trojan-horse(+), Trojan-horse(−), Surface enrichment, Retention, Inertism, Coalism. This approach allows capturing and organizing the different processes we identified to be of importance for understanding the impact of NM-chemicals mixtures. It is also applicable to guide the design of future mixture studies. As evidenced by our literature analysis, an important field for future research is the elucidation of the fate of NM-chemical complexes inside of biological systems. Acknowledgement This research was funded by the EU FP7 project NanoValid (Development of reference methods for hazard identification, risk assessment and LCA of engineered nanomaterials; grant no 263147) and by the German Federal Ministry for Education and Research (BMBF) project DaNa2.0 (Data and knowledge on nanomaterials – evaluation of socially relevant scientific facts; grant no 03X0131). We also like to acknowledge the EU-FP7 collaborative project SOLUTIONS (grant agreement no. 603437). Supplementary data The tables in the supporting information contain a collection of all evaluated studies. They are classified according to the applied in vitro/ in vivo biological test system. Table 8 represents an extended version of Table 1 in the main document and gives a more detailed overview of the assumptions underlying Fig. 3. Supplementary data to this article can be found online at https://doi.org/10.1016/j.scitotenv.2018.04.180.

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