Grouping Hypotheses and an Integrated Approach to Testing and Assessment of Nanomaterials Following Oral Ingestion
Abstract
:1. Introduction
2. Results
2.1. Generation of Oral Ingestion Hypotheses (H-O)
2.1.1. Linking Purpose to Implications for Grouping
2.1.2. Lifecycle/Exposure via Oral Ingestion
2.1.3. What They Are
2.1.4. Where They Go
Where They Go: OGI Tract
Where They Go: NM Translocation and Cellular Uptake
2.1.5. What They Do
2.2. General Description of IATAs for Ingested NFs
2.2.1. Instantaneous Dissolving NFs (H-O-I)
2.2.2. Quick Dissolving NFs (H-O-Q 1, 3)
2.2.3. Gradual Dissolving NFs (H-O-G 1, 2, 3)
2.2.4. Very Slow Dissolving NFs (H-O-S 1, 2, 3)
2.3. Decision Nodes and Their Associated Tiered Testing Strategies
2.3.1. OGI Dissolution DN (H-O-I; H-O-1, 3; H-O-G 1,2,3; H-O-S 1,2,3)
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- Measurement of dissolution property by cascade in vitro dissolution assay. This method includes the consecutive addition of simulant OGI fluids (saliva, stomach and intestine) which result in molecular composition and pH jumps, transit times and volume changes, in order to reflect the passage of food through the human OGI tract [64,89,90,91]. The measurement of dissolution rate can be obtained at different elapsed times of incubation. Inclusion of a temporal point at 30 min after the addition of the intestinal simulant juice (corresponding to the sampling time of 155 min since the beginning of the test) is preferred according to the EFSA guideline [9]. The method suggested is not currently standardised, but it has been validated as an SOP within an EU project (see method in supporting information), and it is under validation through the OECD Working Party on Manufactured Nanomaterials (WPMN) (ENV/CHEM/NANO(2019)5/ADD1) [92]. Standardized fluid compositions applicable to the cascade in vitro dissolution test are accessible from ISO documents or an EU project derived SOP (NANoREG D2.08 SOP 06; ISO/TR 19057 and DIN 19738). The dissolution unit expression is based on t1/2 following the calculation described in Keller et al. [93,94] and is consistent with the first-order dissolution kinetics of the ISO method [95].
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- Measurements of other properties linked to dissolution and NF accumulation which may vary during the biotransformation process in the OGI.
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- Size, composition and shape. In line with recent EFSA considerations which put emphasis on establishing analytical criteria to predict the durability of particles based on size analysis of pristine nanomaterials [56], further characterization studies of the biotransformation in the OGI tract are suggested by the TTS in support of the dissolution kinetics. Such characterization is mainly focused on size, elemental and shape analyses. At least two techniques are proposed, one of which must be microscopy based. Specifically, transmission electron microscopy (TEM) characterization coupled with a spectroscopy technique (e.g., Energy Dispersive X-ray Analysis, EDS) is suggested for nanoform size/shape distribution and elemental analysis. Standardized and validated methods are available for a semi-quantitative description of particle number distribution (ISO 21363 or NANoREG D2.10 SOP 02). Moreover, solution- based techniques can be applied, such as the CLS (ISO 13318) and PTA (ISO 19430) techniques. Dynamic Light Scattering (DLS) is not considered suitable for such analysis as it suffers a greater perturbation from large particles in polydispersed samples.
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- Surface charge and coating modifications of NFs may influence dissolution kinetics. This may impact NF dispersion stability, agglomeration state, hydrophilicity, cytotoxicity, cellular penetration and circulation time in blood stream, and also their biodistribution and clearance [58]. To this regard, it is important to define whether surfaces of NFs are modified through the use of surfactants, capping agents or attached ligands. The production process provides information on surface properties. A number of methodologies could be applied depending on the nature of the NF tested as suggested by OECD No. 86. Here, only one tier level is proposed, and the user should assess the method most suitable for their NF. However, it is worth mentioning that the OECD No.86 does not currently suggest standardized assays to characterize surface coating in the OGI or lysosome like biotransformation conditions. With the growing emergence of better performing analytical techniques for the characterization of surface properties, the TTS will be updated. A list of methods includes:
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- Zeta potential analysis (DLS) in the simulant OGI fluids (NANoREG D2.10 SOP 02).
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- Proton nuclear magnetic resonance spectroscopy (H-NMR).
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- Fourier transform infra-red (FTIR) spectroscopy.
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- High-resolution transmission electron microscopy (HR-TEM).
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- Inductively coupled plasma mass spectrometry (ICP-MS).
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- UV-vis spectroscopy.
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- X-ray photoelectron spectroscopy (XPS).
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- Thermogravimetric analysis (TGA).
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- In vivo toxicokinetic studies of ingested NFs may provide quantitative information on absorption and tissue distribution of NFs. Guidance for the studies may be found on OECD TG 417, which is currently under revision in order to improve the guidance applicability on nanospecific issues. One of the main limitations, in the case of ingested NFs, is that the majority of the studies quantify the total content of corresponding ions or molecules within the considered organs or tissues (e.g., blood, urine, liver) by quantitative in bulk techniques only upon tissue mineralization (e.g., Inductively Coupled Plasma Mass Spectrometer, ICP-MS). Then, limited or only indirect information on particle durability can be extrapolated. Single molecule-based techniques (microscopy or single particle ICP) may overcome such limitations, however, most of the information generally extracted is qualitative. To this regard, recently, there have been advancements in the field with the identification by spICP-MS of TiO2, both in the form of constituent ions and NFs [30,96,97]. For instance, in the large intestine of mice treated for three weeks with repeated administration of the food additive, E171 (5 mg/Kg/bw), there was a significant accumulation in the large intestine of Ti4 cations. However, TiO2 particle determination showed that the number of particles detected in treated mice increased as a consequence of E171 administration, and the particle size distribution closely resembled that of the original material, suggesting a slow dissolution kinetics of the tested TiO2 food additive [30].
2.3.2. Lysosomal Dissolution DN (H-O-Q1, 3; H-O-G2; H-O-S2)
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- For lysosomal dissolution, standardized assays that describe the use of both static and dynamic systems are available. However, testing NF dissolution in dynamic conditions is considered the preferred method as the experimental results were found consistent with data available from in vivo studies [83], thus indicating the physiological relevance of the fluid motion during the dissolution process. Standardized recipes for PSF are available from ISO/TR 19057:2017. The dissolution rate is expressed, as for the dissolution measurement in the OGI tract as t1/2.
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- This tier examines the durability in cellular systems. Cellular models to assess durability are not yet well standardized, and so there is currently no SOP available. However, studies have shown incubation of NMs with macrophages to be at least as predictive of biodurability as acellular assays for NFs and useful to clarify the specific mechanism of particle degradation [83].
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- The determination of biopersistence of NFs in vivo requires long-term in vivo assays. To look at accumulation of NFs in secondary tissues, oral repeated exposure studies are recommended (OECD TG 408).
2.3.3. Reactivity DN (H-O-Q1, 3; H-O-G1, 2, 3 and H-O-S1, 2, 3)
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- DCFH2-DA (Dichlorodihydrofluorescin diacetate) assay [98].
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- FRAS (Ferric Reduction Ability of Serum) assay [98].
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- DCFH2-DA (NANoREG D5.06 SOP 03) to assess the presence of ROS in cellular 2D/co-cultures/3D models (intestine, liver, kidney, etc.) following a single short term (24 h) or repeated exposure to a range of NF concentrations. This assay tends to provide a negative (no ROS) or positive (ROS identified) answer but does not seem to be sufficiently sensitive to determine values in between.
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- A variety of assays are currently under evaluation, including glutathione (GSH) antioxidant depletion and glutathione disulfide (GSSG) accumulation at short time points [100], lipid peroxidation [101] and heme oxygenase 1 (HMOX-1) expression [102]. Again, such assays could be conducted using 2D/co-cultures/3D models (intestine, liver, kidney, etc.) following a single short term (24 h) or repeated exposure to a range of NF concentrations.
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- DCFH2-DA (NANoREG D5.06 SOP 03) to assess ROS production in in vitro microbiota models (single strain bacterial cultures or multi-strain biofilms and in vitro microbiome models isolated from healthy individuals) following a single short term (24 h) or repeated exposure to a range of NF concentrations.
2.3.4. Cytotoxicity DN (H-O-Q1, 3; H-O-G1, 2, 3 and H-O-S1, 2, 3)
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- Cell viability assays using 2D cellular models (intestine, liver, kidney, etc.) following a single short term (24 h) exposure to a range of NF concentrations.
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- Bacteria viability using single strain bacterial cultures following a single short term (24 h) exposure to a range of NF concentrations.
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- Cell viability assays using co-cultures or 3D cellular models (intestine, liver, kidney, etc.) following repeated exposure to a range of NF concentrations.
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- Bacteria viability using multi-strain biofilms and in vitro microbiome models isolated from healthy individuals following a repeated exposure for up to five days to a range of NF concentrations.
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- Bodyweight and organ gross necropsy of the target organ after oral acute or repeated exposure (OECD TG 420 and TG 408).
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- DNA sequencing of microbiota population using in vivo models after repeated exposure (e.g., from rats, mice and zebrafish) (no SOPs available) to derive alteration in the microbiota population, such as a decrease or increase in some bacteria species.
2.3.5. Barrier Integrity DN (H-O-Q1, 3; H-O-G1, 3 and H-O-S1, 3)
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- TEER measurement on the monolayer of 2D cellular models (NANoREG D5.03 SOP 3) following a single short term (24 h) exposure to a range of NF concentrations.
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- Damage to the bacterial cell wall and membrane on single strain bacterial cultures by AFM imaging [105] or other microscope suitable techniques following a single short term (24 h) exposure to a range of NF concentrations.
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- TEER measurement of co-cultures or 3D cellular models (NANoREG D5.03 SOP 3) following a repeated exposure to a range of NF concentrations.
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- Damage to the bacterial cell wall and membrane on multi-strain biofilms and in vitro microbiome models isolated from healthy individuals by atomic force microscopy (AFM) imaging [105] or other suitable techniques following a repeated exposure to a range of NF concentrations.
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- Intestine gross necropsy after oral acute or repeated exposure (OECD TG 420 and TG 408).
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- DNA sequencing of the microbiota population using in vivo models after repeated exposure (e.g., from rats, mice and zebrafish) (no SOPs available) to derive alteration in the microbiota population, such as structure damage of some bacteria species.
2.3.6. Inflammatory Response DN (H-O-Q1; H-O-G1, 2 and H-O-S1, 2)
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- Cytokine secretion measurement on supernatants collected from 2D cellular models (intestine, liver, kidney, etc.) following a single short term (24 h) exposure to a range of sub-lethal NF concentrations (NANoREG D5 06 DR SOP 06).
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- Cytokine secretion measurement on supernatants collected from co-culture or 3D cellular models (intestine, liver, kidney, etc.) following a repeated exposure to a range of sub-lethal NF concentrations (NANoREG D5 06 DR SOP 06).
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- Clinical biochemistry of inflammatory markers in blood after oral acute or repeated exposure (OECD TG 420 and TG 408).
2.3.7. Genotoxicity Response DN (H-O-Q1; H-O-G1,2 and H-O-S1,2)
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- Gene mutation assay using the Hprt and xprt genes (OECD TG 476) or the Thymidine Kinase Gene (OECD TG 490) using 2D cultures (intestine, liver, kidney, etc.) following a single short term (24 h) sub-lethal exposure to a range of NF concentrations.
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- Chromosomal damage by the quantification of micronuclei (OECD TG 487) and the identification of structural chromosomal aberrations (OECD TG 473) using 2D cultures (intestine, liver, kidney, etc.) following a single short term (24 h) sub-lethal exposure to a range of NF concentrations.
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- Chromosomal damage by the quantification of micronuclei (OECD TG 487) using 3D cultures (intestine, liver, kidney, etc.) following a repeated exposure to a range of sub-lethal NF concentrations.
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- Comet or Histone H2AX phosphorylation assays (PATROLS SOPs) using 3D cultures (intestine, liver, kidney, etc.) following a repeated exposure to a range of sub-lethal NF concentrations.
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- Transgenic Rodent (TGR) mutation assays (OECD TG 488) using tissues (intestine, liver, kidney, etc.) from exposed animals after oral acute or repeated exposure (OECD TG 420 and TG 408).
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- Quantification of micronuclei (OECD TG 474) in the cytoplasm of interphase cells of erythrocytes from bone marrow and/or peripheral blood cells after oral acute or repeated exposure (OECD TG 420 and TG 408).
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- Evaluation of the DNA strand breaks by alkaline comet assay using tissues (intestine, liver, kidney, etc.) from exposed animals (OECD TG 489) after oral acute or repeated exposure (OECD TG 420 and TG 408).
2.4. Testing the Oral IATAs: Preliminary Grouping by Dissolution in the OGI Tract
2.4.1. Does the NF Dissolve Instantaneously, Quickly, Gradually and Very Slowly after Intestinal Digestion?
2.4.2. Does the NF Dissolve Quickly, Gradually and Very Slowly in Lysosomal Simulant Fluid?
2.4.3. Preliminary Grouping Exercise
2.5. Tier 1 Data of Oral IATAs: Are They Predictive of Tier 3?
2.5.1. Toxicokinetics Results from In Vivo Literature Data ì
- In rats, after single dose oral administration of commercialized ZnO NFs, zinc ions that correspond to 90% of initial administered particle mass were found to be excreted via faeces three days post exposure. Zinc ions and not zinc particles were found mainly distributed among organs such as the liver, lung and kidney [67].
- Long term administration (270 consecutive days) to mice of food replenished with commercialized ZnO-NPs showed no significant accumulation of zinc in the main tissues/organs, even though some focal-like inflammatory cells appeared to accumulate in the liver, both in the parenchyma and around the central vein [40].
- Sub-acute oral exposure to commercialized ZnO NFs (28 consecutive days) of mice reported that 60–65% of zinc in tissue (liver and kidney) is in the ionic form, and one third part, or 30–35%, is in the non-ionic form, demonstrating a fast dissolution of zinc particles during oral administration. Moreover, ZnO NFs caused an up-regulation of the hepatic pro-inflammatory cytokines, leading to the activation of acute phase response (APR) [44].
- In mice exposed to a single dose oral administration of commercialized ZnO NFs, the concentrations of Zn in the blood, liver, kidneys, spleen and lungs were significantly increased at 4 h and 12 h after ZnO NFs administration, whereas at 24 h, the accumulation of Zn could only be detected in liver and kidneys, suggesting a fast recovery of Zn levels in mice within 24 h [45].
- Very limited bioavailability after single oral exposure to rats is reported for realistic doses of TiO2 NFs (NM100, NM101, NM102, NM103 and NM104); however, there was evidence that absorption is possible in the gastrointestinal tract, as increased levels of titanium could be detected in the livers and mesenteric lymph nodes in exposed animals. Elimination was very slow (no clear differences between titanium dioxide-exposed animals and vehicle-treated controls) up to 90 days post-exposure, suggesting a potential tissue accumulation. Moreover, this process was most pronounced for the pigment-sized (NM100), and one of the nano-sized, titanium particles (NM102) [112].
- By using spICP-MS, Talamini and co-workers demonstrated that TiO2 E171 particles were located in the intestines of treated mice after repeated oral exposure (3 days/week for 3 weeks) [30].
- After a single oral exposure to commercialized colloidal silica NFs by rats, particles were identified by TEM analysis in their pristine form in the liver [68].
2.5.2. Hazard Results from In Vivo Literature Data (Table 2)
- Systemic Toxicity (H-O-S2)
- Liver accumulation of titanium was also associated with an increased number and size of necro-inflammatory foci containing tissue monocytes/macrophages in E171 fed mice [30].
- Adverse systemic effects were also reported in the heart [32], where a 90-day exposure to commercialized anatase TiO2 NFs provoked changes in heart rate and blood pressure, with cardiac impairment detectable at the level of blood molecular markers.
- Microbiota Dysbiosis (H-O-S3)
- Commercial SiO2 NFs can activate intestinal infection and inflammatory responses by diminishing the function of the intestinal mucus barrier [35].
- Increased pro-inflammatory cytokine levels (IL-1β, IL-6 and TNF-α) were observed in the colon of mice that ingested a commercialized SiO2 NF [36].
- A 90-day oral exposure to SiO2 NFs (NM203) induced enlarged sinusoids in the liver of male rats [38].
- A vacuolization of tubular epithelial cells occurred in the kidney (after 18 months of exposure via drinking water to NM200), as well as a reported inflammatory response in the livers of exposed animals. Here, the urine test detected proteinuria that the authors associate to a glomerular dysfunction [37].
- Short-term exposure (from 24 to 45 h) to SiO2 NFs (NM202, NM203, NM200 and NM201) did not induce DNA damage in various organs of rats, either directly or through oxidative stress, as assessed by the comet and micronucleus assays. However, the authors did not exclude that some secondary genotoxic effects following long-term exposure to SiO2 NFs may occur [115]. Indeed, during biomonitoring of workers involved in colloidal SiO2 NF production, some evidence of early, still reparable, genotoxic and oxidative effects were reported, but the authors conclude that discrimination between the effects due to NFs or other chemicals used in the NM production process are not possible, and further studies are needed [116].
- Exposure to food grade SiO2 NFs led to changes in gut microbiota, especially in mucus associated bacteria, decreasing some bacteria families in a dose dependent manner [35].
- Commercialized SiO2 NFs ingestion in mice increased microbial species richness and diversity within the intestinal tract and, in particular, an obvious increase in the genus Lactobacillus was recorded [36].
3. Discussion
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Purpose of Grouping and Context | ||
Lifecycle and Exposure | What they are | |
Where they go | ||
What they do | ||
Implications of grouping | ||
Human oral hypotheses | ||
H-O-I | NFs with an instantaneous dissolution: Following oral exposure, the toxicity is driven by and is therefore similar to that of the constituent ions or molecules. | |
H-O-Q1 | NFs with a quick dissolution: Following oral exposure, both NFs and constituent ions or molecules may contribute to local inflammation in the OGI tract, but there is no concern for NF accumulation. | |
H-O-Q3 | NFs with a quick dissolution: Following oral exposure, both NFs and constituent ions or molecules may drive antimicrobial impacts (e.g., reducing microbial content and diversity within the OGI tract), but there is no concern for NF accumulation. | |
H-O-G1 | NFs with a gradual dissolution: Following oral exposure, both NFs and constituent ions or molecules may lead to local inflammation in the OGI tract. | |
H-O-G2 | NFs with a gradual dissolution: Following oral exposure, both NFs and constituent ions or molecules may translocate to secondary target organs and may lead to systemic toxicity in secondary organs. | |
H-O-G3 | NFs with a gradual dissolution: Following oral exposure, both NFs and constituent ions or molecules may drive antimicrobial impacts, such as reducing microbial content and diversity within the OGI tract. | |
H-O-S1 | NFs with a very slow dissolution: Following oral exposure, NFs will maintain nanospecific activity that may lead to local inflammation within the OGI tract. | |
H-O-S2 | NFs with a very slow dissolution: Following oral exposure, NFs will maintain nanospecific activity that may drive translocation across the intestinal wall, subsequent biopersistence in the body and systemic toxicity in secondary organs. | |
H-O-S3 | NFs with a very slow dissolution: Following oral exposure, NFs will maintain nanospecific activity that may drive antimicrobial impacts, such as reducing microbial content and diversity within the OGI tract. |
Nm | Type | Model | Dose | Exposure Time | Effect | Reference | |
---|---|---|---|---|---|---|---|
Where they go | What they do | ||||||
TiO2 | E171 (food additive) | Rats | 10 mg/kg/bw | 100 days by drinking water | Titanium was detected in the immune cells of Peyer’s patches (PP) | Preneoplastic lesion formation in the colon and induction of mucosal low-grade inflammation | [27] |
TiO2 | Anatase NM | Rats | * 2, 10, 50 mg/kg/bw | 90 days by oral gavage | not assessed | Diversity of gut microbiota in rats increased in a dose-dependent manner. LPS produced by gut microbiota increased significantly; Hepatotoxicity, including clear mitochondrial swelling at highest dose | [28] |
TiO2 | E171 (food additive) | Mice | * 5 mg/kg/bw | 21 days by oral gavage | not assessed | Induction of oxidative stress and immune response pathways, activated genes for DNA repair and both up- and down-regulated genes involved in development of cancer (e.g., colon cancer) | [29] |
TiO2 | E171 (food additive) | Mice | * 5 mg/kg/bw | 3 weeks by dripping of the NF suspension into the mouth of mice | Accumulation of Ti in the liver and the intestine; TiO2 particle accumulation in large intestine | Liver and intestine inflammation; Oxidative stress in the stomach | [30] |
TiO2 | E171 (food additive) | Mice | * 5 mg/kg/bw | 10 weeks by oral gavage | Some particles were internalized in colonic cells | Dysplastic alterations were observed in the distal colon | [31] |
TiO2 | Anatase | Rats | * 2, 10, 50 mg/kg/bw | 90 days by oral gavage | not assessed | Impairment of cardiac function induced by inflammatory events (increase in TNF-α and IL-6 in serum) | [32] |
TiO2 | Anatase | Rats | * 2, 10, 50 mg/kg | 90 days by oral gavage | Limited absorption and distribution of Ti in organs | Increase in ROS markers mostly in liver | [33] |
TiO2 | Anatase | Rats | * 1, 50 and 100 mg/kg/bw | 7 and 14 days | Ti accumulated in the intestine and liver. Feces excretion | Inflammation in colonic tissue; Gut microbiota alteration | [34] |
TiO2 | Anatase Food-grade micro and nano | Mice | 10, 40, and 160 mg/kg/bw (micro-TiO2); 10, 40, and 160 mg/kg/bw (nano-TiO2) | 28 days by oral gavage | No significant difference in Ti content tissues compared with the control | Intestine inflammation (greatest for nano-TiO2); Alteration of gut microbiota | [35] |
SiO2 | Amorphous | Mice | * 2.5 mg/kg bw | 7 days by oral gavage | not assessed | Increased pro-inflammatory cytokine in the colon; Alteration of gut microbiota | [36] |
SiO2 | Amorphous | Mice | * 4.8 mg/kg bw | 18 months by drinking water | Si levels higher in kidneys and liver | Histological abnormalities in kidneys, Inflammatory responses in livers; perivascular amyloid accumulation in liver | [37] |
SiO2 | Amorphous | Mice | 25, 160, and 300 mg/kg/bw | 28 days by oral gavage | Si content in the colon was significantly higher (160 mg/kg/bw) | Intestine inflammation; Alteration of gut microbiota | [35] |
SiO2 | Amorphous | Rats | * 2, * 5, 10, 20 and 50 mg/kg/bw | 90 days by oral gavage | Si accumulation in liver and in spleen (female rats) | Enlarged sinusoids in liver (male); Thyroid stimulating hormone (TSH) and creatinine levels were affected (female), higher levels of total IgG antibodies in serum (female); blood cell count reduction (male) | [38] |
ZnO | Mice | 300 mg/kg/bw | 14 days by oral gavage | Zn ions accumulation in the liver | Elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP); Pathological lesions in the liver; Genotoxicity damage in liver and kidneys | [39] | |
ZnO | NM, microparticles and Zn ions | Mice | 1600 mg/kg/bw | 270 days by food | Excretion mainly through feces. Zn ions accumulated only in the digestive tract organs | Liver lesions induced by microparticles, but fewer by NF and Zn ions | [40] |
ZnO | NM and zinc sulfate | Mice | 250 mg/kg/bw | 7 days by oral gavage | Elevated Zn concentrations in serum, liver, and kidney | Zinc sulfate shows more severe and acute toxicity; Zinc NFs reduce the body weight and increase serum glutamic-pyruvic transaminase activity | [41] |
ZnO | Mice | 26 mg/kg/bw | 30 days by oral gavage | not assessed | Neurobehavioral impairment; Alteration of gut microbiota | [42] | |
ZnO | NM | Rats | 100 mg/kg/bw | 75 days by oral gavage | not assessed | Hepatic and renal damages that may subsequently cause mitochondrial dysfunctional which instigating the generation of ROS and oxidative stress | [43] |
ZnO | NM | Mice | 10, 30, and 300 mg/kg/bw | 28 days by oral gavage | Elevated Zn concentration in liver and kidney | Severe damages in liver and kidney tissue; Hepatic proinflammatory cytokines up-regulated; increased in expression of hepatic acute phase proteins; Altered interlinked iron signaling biomarkers | [44] |
ZnO | NM | Mice | 1 g/kg/bw | Single dose by oral gavage | Elevated Zn concentrations in liver and kidneys | Enriched Fe level in the blood and slight increase in Liver; Decreased Fe level in the kidneys, spleen and lungs; Limited organ damages in the livers and kidneys | [45] |
Fe2O3 | Rats | 100 and 200 mg/kg/bw | Single dose by oral gavage | Iron deposits in hepatocytes and Kupffer cells. | Inflammation in the liver | [46] | |
CuO | Rats | * 1 to 512 mg/kg/bw | 5 days by oral gavage | not assessed | Changes in hematology parameters; Clinical chemistry markers (liver damage) histopathological alterations in bone marrow, stomach and liver | [47] | |
Ag NMs | Mice | 20 mL/kg/dose | 7 days by oral gavage | not assessed | Shifts in the intra- and inter abundance of families of gut bacteria | [36] | |
Ag NMs | Rats | 20, 40, 60, 80 and 100 mg/kg bw | 12 weeks by oral gavage | Accumulation of silver in liver, not completely eliminated from the body | Impairment of liver and kidney enzymes | [48] |
H-O-Q (1,3), H-O-G (1,2,3) and H-O-S (1,2,3) | ||
Hazard descriptors (Reactivity, Inflammation, Genotoxicity Cytotoxicity, Barrier impairment) | ||
Group by hazard descriptors | ||
H-O-Q1 Locally toxic NF but not biopersistent | H-O-G1 Locally toxic NF | H-O-S1 Locally and chronic toxic NF |
H-O-G2 Biopersistent and systemically toxic NF | H-O-S2 Highly biopersistent and chronic systemically toxic NF | |
H-O-Q3 Inducer of microbiota dysbiosis but not biopersistent | H-O-G3 Inducer of microbiota dysbiosis | H-OS3 Chronic inducer of microbiota dysbiosis |
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Di Cristo, L.; Oomen, A.G.; Dekkers, S.; Moore, C.; Rocchia, W.; Murphy, F.; Johnston, H.J.; Janer, G.; Haase, A.; Stone, V.; et al. Grouping Hypotheses and an Integrated Approach to Testing and Assessment of Nanomaterials Following Oral Ingestion. Nanomaterials 2021, 11, 2623. https://doi.org/10.3390/nano11102623
Di Cristo L, Oomen AG, Dekkers S, Moore C, Rocchia W, Murphy F, Johnston HJ, Janer G, Haase A, Stone V, et al. Grouping Hypotheses and an Integrated Approach to Testing and Assessment of Nanomaterials Following Oral Ingestion. Nanomaterials. 2021; 11(10):2623. https://doi.org/10.3390/nano11102623
Chicago/Turabian StyleDi Cristo, Luisana, Agnes G. Oomen, Susan Dekkers, Colin Moore, Walter Rocchia, Fiona Murphy, Helinor J. Johnston, Gemma Janer, Andrea Haase, Vicki Stone, and et al. 2021. "Grouping Hypotheses and an Integrated Approach to Testing and Assessment of Nanomaterials Following Oral Ingestion" Nanomaterials 11, no. 10: 2623. https://doi.org/10.3390/nano11102623