Particle toxicology and health - where are we?

In the paper

“More recently, it became evident that inhaled particles can also affect the central nervous system [10, 11] and reproduction [12].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [10] Heusinkveld H, Wahle T, Campbell A, Westerink RH, Tran L, Johnston H, Stone V, Cassee FR, Schins RP. Neurodegenerative and neurological disorders by small inhaled particles. Neurotoxicology. 2016;56:94. source
• Supported

  The Abstract reports neurological effects of inhaled particles, and the Conclusions state that evidence supports neurotoxicity following air-pollution exposure. This source is cited for the central-nervous-system portion of the sentence; reproduction has a separate citation [12]. (LLM, conf=0.93)

  cites [11] Lucchini R, Dorman DC, Elder A, Veronesi B. Neurological impacts from inhalation of pollutants and the nose-brain connection. Neurotoxicology. 2012;33:838–41. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [12] Hougaard KS, Campagnolo L, Chavatte-Palmer P, Tarrade A, Rousseau-Ralliard D, Valentino S, Park MVDZ, de Jong WH, Wolterink G, Piersma AH, Ross BL, Hutchison GR, Hansen JS, Vogel U, Jackson P, Slama R, Pietroiusti A, Cassee FR. A perspective on the developmental toxicity of inhaled nanoparticles. Reproductive Toxicology. 2015;56:118–40. source

In the paper

“In contrast, only 20% of 20-nm-sized NPs and about 30% of 70-nm-sized NP deposited during inhalation or instillation can be lavaged – see Fig. 2 [54–59].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [54] Kreyling WG, Semmler-Behnke M, Takenaka S, Moller W. Differences in the biokinetics of inhaled nano- versus micrometer-sized particles. Acc Chem Res. 2013;46:714–22. source
• ?Not checked — no full text of the sourcecites [55] Semmler M, Seitz J, Erbe F, Mayer P, Heyder J, Oberdorster G, Kreyling WG. Long-term clearance kinetics of inhaled ultrafine insoluble iridium particles from the rat lung, including transient translocation into secondary organs. Inhalation Toxicology. 2004;16:453–9. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [56] Semmler-Behnke, M., Takenaka, S, Fertsch, S, Wenk, A, Seitz, J, Mayer, P, Oberdorster, G & Kreyling, WG, Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airways epithelium. Environ Health Perspect, 2007. 115: p. 728-233. source
• Partly supported

  In “Particle retention and relocation pathways within the lungs” (page unavailable), Table 1 reports 19% recovery by lavage for inhaled iridium nanoparticles at 6 hours, which is close to the claimed 20%, but recovery varies with time: 46% immediately and 11% at 24 hours. Our copy does not report the claimed 30% lavage recovery for 70-nm nanoparticles or establish these percentages for instillation. (LLM, conf=0.86)

  cites [57] Geiser M, Kreyling W. Deposition and biokinetics of inhaled nanoparticles. Part Fibre Tox. 2010;7:2. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [58] Kreyling W, Semmler M, Erbe F, Mayer P, Takenaka S, Schulz H, Oberdörster G, Ziesenis A. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J. Toxicol. Environ. Health A. 2002;65:1513–30. source
• ?Not checked — no full text of the sourcecites [59] Kreyling WG, et al. Age-Dependent Rat Lung Deposition Patterns of Inhaled 20 Nanometer Gold Nanoparticles and their Quantitative Biokinetics in Adult Rats. ACS Nano. 2018;12(8):7771–90. source

In the paper

“Given some of the unique aspects of NPs, however, such as their tendency to agglomerate at higher concentrations [103], their tendency to interact with biomolecular constituents of their surroundings to form so-called biomolecular coronas [104–106], and the size-modulated cellular uptake mechanisms [107, 108], the bioavailable dose for NPs is poorly understood compared to that for molecular sub”

What the sources say

• ?Not checked — no full text of the sourcecites [103] Yang Y, Oztekin A, Neti S, Mohapatra S. Particle agglomeration and properties of nanofluids. J Nanopart Res. 2012;14:852. source
• ?Not checked — no full text of the sourcecites [104] Lynch, I., Dawson, K.A., Lead, J.R., Valsami-Jones, E., Macromolecular Coronas and Their Importance in Nanotoxicology and Nanoecotoxicology, in Nanoscience and the Environment, J.R. Lead, Valsami-Jones, E., Editor. 2014. source
• ?Not checked — no full text of the sourcecites [105] Cedervall T, Lynch I, Lindman S, Berggård T, Thulin E, Nilsson H, Dawson KA, Linse S. Understanding the Nanoparticle-Protein Corona Using Methods to Quantify Exchange Rates and Affinities of Proteins for Nanoparticles. Proc. Natl. Acad. Sci. U. S. A. 2007;104:2050–5. source
• ?Not checked — no full text of the sourcecites [106] Monopoli MP, Walczyk D, Campbell A, Elia G, Lynch I, Bombelli FB, Dawson KA. Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles. J Am Chem Soc. 2011;133:2525–34. source
• Partly supported

  The Results (section 'Effect of Ag ENM size on cytotoxicity and cell proliferation'; no page available) describe ambiguity in nanoparticle dosimetry: the apparent toxicity ranking changes when dose is expressed by mass rather than particle number or surface area. The Background also identifies inadequate characterization under exposure conditions as a source of discrepancies. The paper does not establish that bioavailable nanoparticle dose is less understood than molecular-substance dose or that this prevents meaningful dose-response curves; it reports concentration responses and calculates IC50 values. (LLM, conf=0.82)

  cites [107] Huk A, Izak-Nau E, Reidy B, Boyles M, Duschl A, Lynch I. Is the toxic potential of nanosilver dependent on its size? Part Fibre Toxicol. 2014;11. https://particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989-014-0065-1 . sourceExperimental — accuracy not yet measured
• Supported

  The citation cluster is attached to the statement that nanoparticles interact with surrounding biomolecules to form coronas, not directly to the later statement about bioavailable dose. The Introduction says biomolecules adsorb onto nanoparticle surfaces to create an eco-corona; the Abstract likewise describes biomolecule-corona formation. The paper does not establish the separate comparison with molecular substances or the claimed difficulty of determining dose-response curves. (LLM, conf=0.91)

  cites [108] Nasser F, Lynch I. Secreted protein eco-corona mediates uptake and impacts of polystyrene nanoparticles on Daphnia magna. J Proteomics. 2015;S1874-3919:30121–4. source

In the paper

“An exciting more recent development are micellar nanocomplexes (MNCs) for anticancer protein drug delivery, which have anticancer activity themselves (also in the absence of the anticancer protein) [46].”

What the sources say

• Supported

  The supplied passage [4] reports that BSA-loaded MNCs, identified as a drug-free carrier, inhibited growth of BT-474 cancer cells. It attributes the effect to the carrier’s EGCG derivatives, supporting anticancer activity without the anticancer protein. (LLM, conf=0.94)

  cites [46] Chung JE, Tan S, Gao SJ, Yongvongsoontorn N, Kim SH, Lee JH, Choi HS, Yano H, Zhuo L, Kurisawa M, Ying JY. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nat Nanotechnol. 2014;9(11):907–12. source

In the paper

“After loading of the MNCs with the anticancer protein drug Herceptin, synergistic anticancer activity of the MNCs and Herceptin has been observed, which resulted in enhanced antitumor activity in vitro and in vivo compared to Herceptin alone [46].”

What the sources say

• Supported

  The passage labeled Abstract describing Fig. 4a reports that Herceptin-MNC inhibited cancer-cell growth more than free Herceptin through synergistic effects of the carrier and drug. The passage describing Fig. 4b reports a significantly greater anticancer effect than free Herceptin in a BT-474 mouse model, supporting the in vivo comparison. (LLM, conf=0.94)

  cites [46] Chung JE, Tan S, Gao SJ, Yongvongsoontorn N, Kim SH, Lee JH, Choi HS, Yano H, Zhuo L, Kurisawa M, Ying JY. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nat Nanotechnol. 2014;9(11):907–12. source

In the paper

“Ratios in liver, kidneys and the various tissues of the carcass stay below 0.05, but the absorbed TiO2NP ratios in the spleen are about 10.1 at days 1 and 7.”

In the paper

“In addition, prolonged plasma half-life and enhanced accumulation in the tumour tissue of the MNCs compared to the protein drug alone were demonstrated [46].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [46] Chung JE, Tan S, Gao SJ, Yongvongsoontorn N, Kim SH, Lee JH, Choi HS, Yano H, Zhuo L, Kurisawa M, Ying JY. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nat Nanotechnol. 2014;9(11):907–12. source

In the paper

“As a result, the deposited fraction in the lungs reaches a maximum of about 50% of the inhaled aerosol at a size of 20 nm [49, 50] with about 15% alveolar deposition and 35% depositing in the conducting airways of the head and thorax.”

What the sources say

• ?Not checked — no full text of the sourcecites [49] ICRP-66. Human respiratory tract model for radiological protection. A report of a Task Group of the International Commission on Radiological Protection. Annal ICRP. 1994;24:1–482. source
• Not checked yetcites [50] ARA, Multiple-path particle dosimetry model (MPPD version 3.0). 2009.

In the paper

“These data show that accumulation in secondary organs and tissues is predominantly determined by ABB-translocated TiO2NP which, however, occurs mainly during the first few days after IT-instillation (see Fig. 3).”

In the paper

“Interestingly, there is a significant overlap in the toxicology of ultrafine particles and engineered NPs and cross talk between these two areas can boost our understanding of the toxicology of nano-sized particles [14].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [14] Stone V, Miller MR, Clift MJ, Elder A, Mills NL, Møller P, Schins RP, Vogel U, Kreyling WG, Jensen KA, Kuhlbusch TA, Schwarze PE, Hoet P, Pietroiusti A, De Vizcaya-Ruiz A, Baeza-Squiban A, Tran CL, Cassee FR. Nanomaterials versus Ambient Ultrafine Particles: an Opportunity to Exchange Toxicology Knowledge. Environ Health Perspect. 2017;125(10):106002. source

In the paper

“For example, inhalation of particles can cause oxidative stress which may lead to genotoxicity and reversible or persistent inflammation [9].”

What the sources say

• ?Not checked — no full text of the sourcecites [9] Møller P, Danielsen PH, Jantzen K, Roursgaard M, Loft S. Oxidatively damaged DNA in animals exposed to particles. Crit Rev Toxicol. 2013;43:96–118. source

In the paper

“However, the EPR effect would only be relevant with respect to relatively large and well-vascularized tumours, and various challenges remain, including the treatment of leukaemia and metastatic disease.”

In the paper

“Although 2-3 decades of toxicological research have taught us a lot, there is still a lot of uncertainty on how low levels of particles can cause so many different effects in humans, and a ranking of substances or sources of emissions can be presented to guide risk management and policy measures is still missing [8].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [8] Cassee F, Héroux ME, Gerlofs-Nijland ME, Kelly FJ. Particulate matter beyond mass: recent health evidence on the role of fractions, chemical constituents and sources of emission. Inhal Toxicol. 2013;25:802–12. source

In the paper

“Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses.”

In the paper

“Lessons learned from the past can prove helpful for the future of the field, notably for understanding novel particles and fibres and for defining appropriate risk management and governance approaches.”

In the paper

“Anticancer nanomedicines have various beneficial properties. These include enhanced accumulation in solid tumours with reduced off-target delivery and improved safety.”

In the paper

“Apart from the known lung diseases like asthma and chronic-obstructive pulmonary disease, cardiovascular diseases and cancer were noted to be impacted by exposure to outdoor PM.”

In the paper

“The levels of PM at which the associations were reported were well below prevailing air quality standards, and particle toxicology was needed to prove causality and provide plausible biological mechanisms that could explain and support these associations [7].”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Schlesinger R, Kunzli N, Hidy GM, Gotschi T, Jerrett M. The health relevance of ambient particulate matter characteristics: coherence of toxicological and epidemiological inferences. Inhal Toxicol. 2006;18:95–125. source

In the paper

“Although inflammation in itself can be seen as a host response that should protect us, excessive inflammation, especially if it persists over prolonged time, can cause fibrosis, oedema as well as the formation and progression of tumours.”

In the paper

“The EPR effect is based on leaky blood vessels and impaired lymphatics in tumour tissue, which leads to enhanced extravasation of NPs into tumour tissue and reduced clearance by lymphatic drainage [26–28].”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Revi Ther Drug Carrier Syst. 1989;6(3):193–210.
• ?Not checked — no full text of the sourcecites [27] von Roemeling C, Jiang W, Chan CK, Weissman IL, Kim BYS. Breaking Down the Barriers to Precision Cancer Nanomedicine. Trends Biotechnol. 2017;35(2):159–71. source
• ?Not checked — no full text of the sourcecites [28] Cabral H, Kataoka K. Progress of drug-loaded polymeric micelles into clinical studies. J Control Release. 2014;190:465–76. source

In the paper

“By the end of the previous century (i.e. the late 1990s), scientific attention shifted from occupational exposure to environmental exposures as a number of epidemiological studies indicated that ambient PM exposures were associated with premature mortality and worsening of several diseases.”

In the paper

“Additionally, the dynamic nature of NPs and their tendency to evolve and transform during storage [111] or upon interaction with media [112] makes dose characterisation challenging.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [111] Izak-Nau E, Huk A, Reidy B, Uggerud H, Vadset M, Eiden S, Voetz M, Himly M, Duschl A, Dusinska M, Lynch I. Impact of Storage Conditions and Storage Time on Silver: Nanoparticles’ Physicochemical Properties and Implications for their Biological Effects. RSC Advances. 2015;5:84172–85. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [112] Sabuncu AC, Grubbs J, Qian S, Abdel-Fattah TM, Stacey MW, Beskok A. Probing nanoparticle interactions in cell culture media. Colloids and Surfaces B: Biointerfaces. 2012;95:96–102. source

In the paper

“Obviously, dissolution rates of NPs can vary widely, which has to be considered because the biopersistence will be affected depending on the dissolution rate.”

In the paper

“Taken together, these studies suggest that there is still a major gap from fundamental science to regulatory relevance, but that progress is being made, and that the biomolecule corona may provide important insights and lead to the potential for predictive toxicology based on the bioprocessing signalling predicted from maps or fingerprints of NP-associated biomolecules.”

In the paper

“While there is a strong drive to reduce reliance on animal testing, this can only be achieved once in vitro and in silico methods have proven to be predictive of in vivo health outcomes.”

In the paper

“Other biomodification routes include lysosomal degradation of NPs as a result of the low pH in the lysosomes coupled with their high enzymatic composition and indeed their role as the “dustbin” of the cell.”

In the paper

“For example, the corona adsorbed to NPs has been shown to slow dissolution by blocking oxidative processes [121] or by promoting sulfidation process and entrapping nanocrystals of Ag2S in the hard corona [122], while in other cases, adsorbed coronas have been found to accelerate dissolution, especially where there is a strong affinity for the metal ions by the proteins and an excess of the prote”

What the sources say

• ?Not checked — no full text of the sourcecites [121] Levak M, et al. Effect of Protein Corona on Silver Nanoparticle Stabilization and Ion Release Kinetics in Artificial Seawater. Environ Sci Technol. 2017;51(3):1259–66. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [122] Miclăuş T, Beer C, Chevallier J, Scavenius C, Bochenkov VE, Enghild JJ, Sutherland DS. Dynamic protein coronas revealed as a modulator of silver nanoparticle sulphidation in vitro. Nature Communications. 2016;7:11770. source
• Not checked yetcites [123] Stepien G, Moros M, Pérez-Hernández M, Monge M, Gutiérrez L, Fratila RM, Las Heras M, Menao Guillén S, Puente Lanzarote JJ, Solans C, Pardo J, de la Fuente JM. Effect of Surface Chemistry and Associated Protein Corona on the Long-Term Biodegradation of Iron Oxide Nanoparticles In Vivo. ACS Appl Mater Interfaces. 2018;10(5):4548–60. source

In the paper

“On the other hand, Au NPs delivered tracheally to rats resulted in the majority of NPs remaining in the lungs (> 95% of the initial dose, ID) with < 1% of the ID translocated to the kidneys, liver, blood and urine, and < 0.01 of the ID reaching the spleen, uterus and heart [131].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [131] Kreyling WG, Hirn S, Möller W, Schleh C, Wenk A, Celik G, Lipka J, Schäffler M, Haberl N, Johnston BD, Sperling R, Schmid G, Simon U, Parak WJ, Semmler-Behnke M. Air–Blood Barrier Translocation of Tracheally Instilled Gold Nanoparticles Inversely Depends on Particle Size. ACS Nano. 2014;8(1):222–33. source

In the paper

“Also, radiolabelled Au NPs in different sizes (1.4-200 nm) exposed by intra-oesophageal instillation into healthy adult female rats resulted in detectable NPs (ng/g organ) in the stomach, small intestine, liver, spleen, kidney, heart, lung, blood and brain after 24 h as measured by gamma-spectroscopy, with the highest accumulation in secondary organs being for the smallest particles, while the 18”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [132] Schleh C, Semmler-Behnke M, Lipka J, Wenk A, Hirn S, Schäffler M, Schmid G, Simon U, Kreyling WG. Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology. 2012;6(1):36–46. source

In the paper

“The low NP recovery becomes plausible since NPs deposit rather uniform on the surface of an alveolus by diffusion. Indeed, macrophages on the epithelial surface will rapidly phagocytize all NP which happen to be deposited close to where a macrophage happens to reside, while distant NP are not recognized due to the weak opsonizing signal of NPs.”

In the paper

“Empirical evidence shows that all three components of NPs (core, shell and corona) may degrade individually in vivo and can drastically modify the life cycle and biodistribution of the whole heterostructure, such that the biodistribution and fate of each sub-component would need to be analyzed individually for regulatory and nanomedical approval purposes [136].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [136] Feliu N, Docter D, Heine M, del Pino P, Ashraf S, Kolosnjaj-Tabi J, Macchiarini P, Nielsen P, Alloyeau D, Gazeau F, Stauber RH, Parak WJ. In vivo degeneration and the fate of inorganic nanoparticles. Chemical Society Reviews. 2016;45(9):2440–57. source

In the paper

“With respect to inhalation as the main route of exposure - involving acute, subchronic or chronic rodent studies - a minimum of three exposure concentrations plus sham-exposed controls should be used [84].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [84] Oberdörster G, Castranova V, Asgharian B, Sayre P. Inhalation exposure to carbon nanotubes (CNT) and carbon nanofibers (CNF): Methodology and dosimetry. J Toxicol Environ Health Part B. 2015;18:121–212. source

In the paper

“Deposition of inhaled NPs is governed by their diffusivity in the air leading to a rather homogeneous deposition density on the epithelium of the various regions of the respiratory tract.”

In the paper

“On the other hand, enormous effort in nanomedicine has been devoted to the development of so-called stealth NPs that can evade the immune system and avoid uptake by phagocytes, either by reducing overall protein binding or by selectively binding the so-called deopsonising proteins such as albumin [34].”

What the sources say

• ?Not checked — no full text of the sourcecites [34] Huynh NT, Roger E, Lautram N, Benoit JP, Passirani C. The rise and rise of stealth nanocarriers for cancer therapy: passive versus active targeting. Nanomedicine (Lond). 2010;5(9):1415–33. source

In the paper

“The chemokine IL-8 is another example: It is produced very early and can be defined as a relatively unspecific alert signal, which indicates local inflammation that can be extreme enough to induce cytotoxicity [149–152].”

What the sources say

• ?Not checked — no full text of the sourcecites [149] Gornati R, Longo A, Rossi F, Maisano M, Sabatino G, Mauceri A, Bernardini G, Fasulo S. Effects of titanium dioxide nanoparticle exposure in Mytilus galloprovincialis gills and digestive gland. Nanotoxicology. 2016;10(6):807–17. source
• ?Not checked — no full text of the sourcecites [150] Horie M, Shimizu K, Tabei Y. Validation of metallothionein, interleukin-8, and heme oxygenase-1 as markers for the evaluation of cytotoxicity caused by metal oxide nanoparticles. Toxicol Mech Methods. 2018;28(8):630–8. source
• ?Not checked — no full text of the sourcecites [151] Xi C, Zhou J, Du S, Peng S. Autophagy upregulation promotes macrophages to escape mesoporous silica nanoparticle (MSN)-induced NF-κB-dependent inflammation. Inflammation Research. 2016;65(4):325–41. source
• ?Not checked — no full text of the sourcecites [152] Galbiati V, Cornaghi L, Gianazza E, Potenza MA, Donetti E, Marinovich M, Corsini E. In vitro assessment of silver nanoparticles immunotoxicity. Food Chem Toxicol. 2018;112:363–74. source

In the paper

“Thus, approaches to assess biomodification, bioprocessing, and bioclearance are emerging, and these are intrinsically linked.”

In the paper

“This is reasonable, since the immune system has evolved to recognize non-self and to decide whether a defensive action is appropriate.”

In the paper

“The classical strategy for reducing interactions with the reticuloendothelial system is to modify the surface of the medical NPs with polyethylene glycol (PEGylation), which hinders opsonisation (binding of proteins recognised by phagocytotic cells), but may shield targeting ligands [34].”

What the sources say

• ?Not checked — no full text of the sourcecites [34] Huynh NT, Roger E, Lautram N, Benoit JP, Passirani C. The rise and rise of stealth nanocarriers for cancer therapy: passive versus active targeting. Nanomedicine (Lond). 2010;5(9):1415–33. source

In the paper

“One example of a biomodification pathway, proposed for iron oxide NPs, showed that 10 nm iron oxide NPs were degraded in macrophages and the resulting free iron was transformed to ferritin and hemosiderin iron-protein complexes and used to make haemoglobin and myoglobin [135]. In this case the biotransformation also leads to bioclearance of the NPs.”

What the sources say

• Not checked yetcites [135] Arami H, Khandhar A, Liggitt D, Krishnan KM. In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles. Chemical Society Reviews. 2015;44(23):8576–607. source

In the paper

“In other words, two thirds of the deposited 20 nm sized NP will be cleared rapidly within 24 hours by mucociliary action within the ciliated conducting airways and one third will be long-term retained in the lung periphery.”

In the paper

“It becomes clear from the snapshot of studies presented above that it is very difficult to untangle the 5Bs – they are interrelated and inter-dependent, but a clear understanding of each, and their combined impact, is vital for regulatory certainty.”

In the paper

“Other transformations included under the broad term bioprocessisng include enzymatic digestion [128], such as has been reported for carbon nanotubes [129] and graphene materials [130].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [128] Bhattacharya K, Mukherjee SP, Gallud A, Burkert SC, Bistarelli S, Bellucci S, Bottini M, Star A, Fadeel B. Biological interactions of carbon-based nanomaterials: From coronation to degradation. Nanomed Nanotechnol Biol Med. 2016;12(2):333–51. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [129] Zhao Y, Allen BL, Star A. Enzymatic Degradation of Multiwalled Carbon Nanotubes. J. Phys. Chem. A. 2011;115(34):9536–44. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [130] Lalwani G, Xing W, Sitharaman B. Enzymatic Degradation of Oxidized and Reduced Graphene Nanoribbons by Lignin Peroxidase. Journal of materials chemistry. B Mater Biol Med. 2014;2(37):6354–62. source

In the paper

“The degree of in vivo processing of NP can be evaluated with HRTEM which, coupled with dose-response monitoring, could provide further information for NP risk assessment.”

In the paper

“Clearly, the route of introduction will affect this proportion, with direct intravenous injection resulting in close to 100% bioavailability, while oral or nasal introduction for example, might result in lower bioavailability due to the biological barriers that exclude some of the compound.”

In the paper

“More recently, Thorley and co-workers [65] provided evidence for prominent NP uptake by EC1 while they ruled out uptake by alveolar epithelial type 2 cells (EC2) and the passage of NPs by paracellular transport was also discounted.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [65] Thorley AJ, Ruenraroengsak P, Potter TE, Tetley TD. Critical determinants of uptake and translocation of nanoparticles by the human pulmonary alveolar epithelium. ACS Nano. 2014;8(11):11778–89. source

In the paper

“Whereas small spherical NPs accumulate within the center of blood vessels, disc-like particles display enhanced lateral drift due to tumbling, and also have larger surface areas for endothelial adhesion [38].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [38] Toy R, Peiris PM, Ghaghada KB, Karathanasis E. Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond). 2014;9(1):121–34. source

In the paper

“Because of the associated ethical concerns (requiring large number of animals) and high costs of longer duration exposures, subacute (28-day) studies with sufficient post-exposure recovery time have been suggested as replacements for longer-term studies. Their usefulness for risk characterization still needs to be validated however [84].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [84] Oberdörster G, Castranova V, Asgharian B, Sayre P. Inhalation exposure to carbon nanotubes (CNT) and carbon nanofibers (CNF): Methodology and dosimetry. J Toxicol Environ Health Part B. 2015;18:121–212. source

In the paper

“Among the intrinsic physico-chemical properties that impact on NP toxicity, surface properties are, in theory, most influential because of the direct interaction of the particle surface with cells and subcellular components.”

In the paper

“The findings indicated that the kidney was the main target organ for <5nm NPs, whereas for the 20-150nm spheres, positive charge correlated with enhanced accumulation in liver and spleen. Discs appeared to show most accumulation, collecting in liver, spleen and lungs, with the order of accumulation for shapes being discs > rods > spheres [138].”

What the sources say

• Not checked yetcites [138] Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33:941–51. source

In the paper

“Similar findings have suggested that cellular response to the presence of NPs also involves secretion of proteins in response to the initial form of the NP taken up by the organism, causing the “initial” corona to evolve, which can lead to altered uptake and impacts not currently considered in assessing toxicity [124].”

What the sources say

• ?Not checked — no full text of the sourcecites [124] Albanese A, Walkey CD, Olsen JB, Guo H, Emili A, Chan WCW. Secreted Biomolecules Alter the Biological Identity and Cellular Interactions of Nanoparticles. ACS Nano. 2014;8(6):5515–26. source

In the paper

“Systemically circulating NPs may accumulate in secondary organs and tissues by two particle clearance pathways, (i) NP translocation across the air-blood-barrier (ABB) either directly into blood circulation or via the thoracic lymph duct and (ii) NP absorption across the GIT walls, again either directly into blood circulation or via the thoracic lymph duct, of those NP which were eliminated from”

In the paper

“especially as numerous studies show that bare particles are both more toxic, and rapidly acquire a biomolecule corona from their surroundings.”

In the paper

“In particular, a portion of the original NPs were partially dissolved and secondary SiO2-reaction zones (precipitates) formed as a result of in vivo processing (also called bioprocessing – see section “The 5Bs” below) as shown in Fig. 5 ([102], previously not published).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [102] Graham, U.M., Jacobs, G., Yokel, R.A., Davis, B.H., Dozier, A.K.,. Birch, M.E., Tseng, M.T., Oberdörster, G., Elder, A., DeLouise, L., From Dose to Response: In Vivo Nanoparticle Processing and Potential Toxicity, in Modelling the Toxicity of Nanoparticles. Advances in Experimental Medicine and Biology, B.M. Tran L., Rallo R., Editor. 2017, Springer: Cham. source

In the paper

“Recent work using the model organism Daphnia magna has shown that proteins secreted by the Daphnia into the media induce some agglomeration of NPs but since this brings the NP-agglomerates into the size range of Daphnia’s normal food source, it appears to increase uptake / bioavailability of the NPs [108].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [108] Nasser F, Lynch I. Secreted protein eco-corona mediates uptake and impacts of polystyrene nanoparticles on Daphnia magna. J Proteomics. 2015;S1874-3919:30121–4. source

In the paper

“Indeed, due to interactions with their surroundings, the dispersion media play an important role in defining the NPs dose, but also in determining the NPs “biological” identity, which is the set of proteins and other biomolecules associated with the NP and specifically the outer surface of the absorbed corona which forms the interface to engage with biological receptors [113–116].”

What the sources say

• ?Not checked — no full text of the sourcecites [113] Maiorano G, Sabella S, Sorce B, Brunetti V, Malvindi MA, Cingolani R, Pompa PP. Effects of Cell Culture Media on the Dynamic Formation of Protein−Nanoparticle Complexes and Influence on the Cellular Response. ACS Nano. 2010;4(12):7481–91. source
• ?Not checked — no full text of the sourcecites [114] Lesniak A, Campbell A, Monopoli MP, Lynch I, Salvati A, Dawson KA. Serum heat inactivation affects protein corona composition and nanoparticle uptake. Biomaterials. 2010;31:9511–8. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [115] Lesniak A, Fenaroli F, Monopoli MP, Åberg C, Dawson KA, Salvati A. Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells. ACS Nano. 2012;6:5845–57. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [116] Strojan K, Leonardi A, Bregar VB, Križaj I, Svete J, Pavlin M. Dispersion of Nanoparticles in Different Media Importantly Determines the Composition of Their Protein Corona. PLOS ONE. 2017;12(1):e0169552. source

In the paper

“The majority of immune responses indeed result in tolerance, which can be a source of misinterpretation.”

In the paper

“There is clear evidence that each of these parameters also influences the nature of the biomolecules bound [139–141], and that different coronas lead to different biodistributions of NPs in vivo, as indicated above and demonstrated by Wang et al. [142]”

What the sources say

• ?Not checked — no full text of the sourcecites [139] Albanese A, Tang PS, Chan WCW. The Effect of Nanoparticle Size, Shape, and Surface Chemistry on Biological Systems. Annu. Rev. Biomed. Eng. 2012;14:1–16. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [140] Lundqvist, M.S., J.; Elia, G.; Lynch, I.; Cedervall, T.; Dawson, K.A. , Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl. Acad. Sci. U.S.A., 2008. 105: 14265–14270. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [141] Foroozandeh P, Aziz AA. Merging Worlds of Nanomaterials and Biological Environment: Factors Governing Protein Corona Formation on Nanoparticles and Its Biological Consequences. Nanoscale Research Letters. 2015;10:221. source
• ?Not checked — no full text of the sourcecites [142] Wang J, Bai R, Yang R, Liu J, Tang J, Liu Y, Li J, Chai Z, Chen C. Size- and surface chemistry-dependent pharmacokinetics and tumor accumulation of engineered gold nanoparticles after intravenous administration. Metallomics. 2015;7(3):516–24. source

In the paper

“Essential for the evaluation of the results of inhalation studies is to determine the retained dose (lung burden) at the end of exposure to establish dose-response relationships.”

In the paper

“However, most contacts with non-self do not result in defence, due to the lack of danger signals. Still, the immune system will respond: Either with homeostatic fluctuations of no further consequence, or with the development of tolerance via several active mechanisms.”

In the paper

“Clearly, the specific proteins that bind to NPs will be influenced by the route of internalisation, with the lung surfactant proteins being the main candidates for binding following inhalation, serum proteins being the first binders in the case of intravenous exposure, and a range of enzymes and food biomolecules being potential corona constituents for gastric exposure [127].”

What the sources say

• ?Not checked — no full text of the sourcecites [127] Cao Y, Li J, Liu F, Li X, Jiang Q, Cheng S, Gu Y. Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: A review. Environ Toxicol Pharmacol. 2016;46:206–10. source

In the paper

“In addition, immune cells are concentrated at the potential routes of entry for pathogens, which are the same routes by which NPs enter the body.”

In the paper

“The latter mimics more closely the in vivo situation, whereas the former can reflect in vitro conditions.”

In the paper

“This suggests that there is more than one biological identity for each NP and that this identity evolves as the NPs interact and are internalised and processed by organisms and cells.”

In the paper

“As noted above, the highly reactive surface area of NPs leads to adsorption of a biomolecule corona, which plays a key role in the subsequent bioprocessing of NPs, determining for example the rate of dissolution, the uptake mechanism, and the subsequent biodistribution.”

In the paper

“Nanosafety assessment requires distinguishing whether a response is merely adaptive or truly defensive, which can be addressed by the choice of endpoints.”

In the paper

“In addition, NPs can have effects on the development of a systemic antibody-mediated response, but it is not well known under which circumstances and to which extent this takes place in the body.”

In the paper

“However, , there is a risk of false positives when a normal homeostatic fluctuation in response to a stimulus is mistaken for an indication of danger to the body. Even worse, inflammation may be due to contamination, most commonly with the ubiquitous bacterial compound LPS [153] .”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [153] Li Y, Fujita M, Boraschi D, Endotoxin Contamination in Nanomaterials Leads to the Misinterpretation of Immunosafety Results. Front Immunol. 2017;8(472). source

In the paper

“Overall, NP translocation through the placenta is likely dependent on particle surface modification [195, 196], chemical composition [197], and the timing of the exposure during pregnancy [196].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [195] Yang H, Sun C, Fan Z, Tian X, Yan L, Du L, Liu Y, Chen C, Liang XJ, Anderson GJ, Keelan JA, Zhao Y, Nie G. Effects of gestational age and surface modification on materno-fetal transfer of nanoparticles in murine pregnancy. Sci Rep. 2012;2:847. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [196] Grafmueller S, Manser P, Diener L, Maurizi L, Diener PA, Hofmann H, Jochum W, Krug HF, Buerki-Thurnherr T, von Mandach U, Wick P. Transfer studies of polystyrene nanoparticles in the ex vivo human placenta perfusion model: key sources of artifacts. Sci Technol Adv Mater. 2015;16:044602. source
• ?Not checked — no full text of the sourcecites [197] Myllynen P, Loughran MJ, Howard CV, Sormunen R, Walsh AA, Vähäkangas KH. Kinetics of gold nanoparticles in the human placenta. Reprod Toxicol. 2008;26:130–7. source

In the paper

“Small rounded opacities are specific to silicosis, while small irregular opacities are observed in asbestosis or mixed-dust pneumoconiosis.”

In the paper

“The characteristics of X-ray findings of this pneumoconiosis are irregular opacities and ill-defined small rounded opacities. Histopathologically interstitial fibrosis and fibrotic stellate nodules are observed in mixed dust pneumoconiosis.”

In the paper

“Drosophila, which has a short life span and 77% of the human disease genes [189]”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [189] Reiter LT, Potocki L, Chien S, Gribskov M, Bier E. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 2001;11:1114–25. source

In the paper

“While the prevalence or incidence of silicosis has been decreasing, there are concerns with pneumoconiosis which may be induced by different kinds of particles other than silica. Mixed dust pneumoconiosis may be one such pneumoconiosises.”

In the paper

“Lastly the prevalence of this disease is 34% of the entire pneumoconiosis [161].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [161] Vallurupalli S, Chawla K, Kupfer Y, Tessler S. Mixed dust pneumoconiosis occurring in an unusual setting. BMJ Case Rep. 2013;2013:bcr2013200976. source

In the paper

“Ming-Wei Chao et al. reported an increase in reactive oxygen species and several cytokines in the amniotic fluid, and changes in microRNA expression profile in the cerebral cortex and hippocampus of foetal brains in rats following exposure to PM2.5 [174].”

What the sources say

• ?Not checked — no full text of the sourcecites [174] Chao M, Yang CH, Lin PT, Yang YH, Chuang YC, Chung MC, Tseng CY. Exposure to PM2.5 causes genetic changes in fetal rat cerebral cortex and hippocampus. Environ Toxicol. 2017;32:1412–142. source

In the paper

“Inflammation is often considered to be synonymous with innate immunity. This is an evolutionary ancient package of defensive mechanisms, which has the attractive feature that similar readouts can be made in invertebrates, offering opportunities to directly link human toxicology and ecotoxicology.”

In the paper

“So far, no case has been described where NPs act as allergens [157], but it has been shown that binding of allergens to NPs can enhance their allergenicity [158].”

What the sources say

• ?Not checked — no full text of the sourcecites [157] Himly M, Grotz B, Sageder M, Geppert M, Duschl A. Immune Frailty and Nanomaterials: The Case of Allergies. Curr Bionanotechnol. 2016;2(1):20–8. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [158] Radauer-Preiml I, Andosch A, Hawranek T, Luetz-Meindl U, Wiederstein M, Horejs-Hoeck J, Himly M, Boyles M, Duschl A. Nanoparticle-allergen interactions mediate human allergic responses: protein corona characterization and cellular responses. Part Fibre Tox. 2015;13:3. source

In the paper

“As in the case of innate immunity, a response is not the same as a defensive action. T-cells may be activated to proliferate and differentiate, but if they should be of the Treg type (regulatory T-cells), they will produce immunosuppressive cytokines and thus promote tolerance.”

In the paper

“So far, most studies have investigated immune effects of NPs as single agents.”

In the paper

“Type 2 responses are associated with parasites, but are for many people more familiar as a pathophysiological response in allergic diseases. IgE antibodies mediate these responses. They have very low levels in serum, but are bound to high-affinity receptors on the surface of effector cells (basophils, mast cells, eosinophils).”

In the paper

“Gastrointestinal tract cancer rates maybe higher in cities that also have elevated asbestos in the supply, but how much of this can be attributed to asbestos compared to other risk factors such as occupation, diet, smoking and alcohol consumption etc., is unclear [252].”

What the sources say

• ?Not checked — no full text of the sourcecites [252] Sigurdson EE, Levy BS, Mandel J, McHugh R, Michienzi LJ, Jagger H, Pearson J. Cancer morbidity investigations: lessons from the Duluth study of possible effects of asbestos in drinking water. Environ Res. 1981;25:50–61. source

In the paper

“For example, IL-1 is a major pro-inflammatory, fever inducing cytokine produced by several immune cell types, so detecting substantial IL-1 secretion would suggest a systemic inflammation which is certainly not indicating tolerance [154].”

What the sources say

• ?Not checked — no full text of the sourcecites [154] Boraschi D, Tagliabue A. The interleukin-1 receptor family. Seminars Immunol. 2013;25(6):394–407. source

In the paper

“Nanomedicine can address these issues more easily, since it deals with high concentrations and controlled exposure.”

In the paper

“The number of nano-scaled particles showed significant positive association with the total number of normal to normal heart beat rate (N-N) and negative association with the mean N-N interval, RR50+, and percentage of RR50 +/- 1 min delay.”

In the paper

“Specific effects of particles can be typically observed in silicosis and asbestosis.”

In the paper

“The transparency of the embryo enables observation of all the cells from early larval stages and facilitates real-time imaging of NP distribution in vivo during the embryonic development [178].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [178] Lee KJ, Nallathamby PD, Browning LM, Osgood CJ, Xu XH. In vivo imaging of transport and biocompatibility of single silver nanoparticles in early development of zebrafish embryos. ACS Nano. 2007;1:133–43. source

In the paper

“Since adaptive reactions develop more slowly than innate ones (days vs. hours), it makes sense that type 1 effectors like IgG1 interact productively with innate immune mechanisms.”

In the paper

“These markers are readily measured and convenient for simple and affordable tests, but their use with not well characterized materials and cells requires care to confirm that an observed response is indeed defensive.”

In the paper

“Although there may be problems theoretically to use the difference in the number between CPC and OPC as shown, it is believed that this can be used as an indicator reflecting the number of small particles.”

In the paper

“In contrast, adaptive immunity has fully developed first in teleost fish and is thus limited to vertebrates.”

In the paper

“The related cytokine IL-18 shares many functions of IL-1 (but not fever induction) and offers the advantage that it is produced by numerous cell types [155].”

What the sources say

• Not checked yetcites [155] Dinarello, C., Novick, D., Kim, S., Kaplanski, G., Interleukin-18 and IL-18 Binding Protein. Front Immunol, 2013. 4(289). source

In the paper

“Adaptive immune responses can develop in three directions, of which the “default” is tolerance. Type 1 and type 2 responses are defensive, the first being directed mainly against bacteria and viruses, the second mainly against macroparasites.”

In the paper

“There is some evidence that air pollution impacts the ecosystem services provided by forests [263].”

What the sources say

• ?Not checked — no full text of the sourcecites [263] Paoletti E, Schaub M, Matyssek R, Wieser G, Augustaitis A, Bastrup-Birk AM, Bytnerowicz A, Günthardt-Goerg MS, Müller-Starck G, Serengil Y. Advances of air pollution science: from forest decline to multiple-stress effects on forest ecosystem service. Environ Pollution. 2010;158:1986–9. source

In the paper

“Some NPs have been shown to influence the development of antibodies, even though they are themselves only rarely recognized by antibodies [156].”

What the sources say

• ?Not checked — no full text of the sourcecites [156] Farrera C, Fadeel B. It takes two to tango: Understanding the interactions between engineered nanomaterials and the immune system. European Journal of Pharmaceutics and Biopharmaceutics. 2015;95:3–12. source

In the paper

“The diameter of the majority of primary particles was more than 100 nm, but certainly part of the primary particles are less than 100 nm in diameter.”

In the paper

“the annual mortality attributed to PM2.5 is around 2.1 million deaths, but past climate change may account for approximately 2,200 annual deaths from PM2.5 [239].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [239] Silva RA, West JJ, Zhang Y, Anenberg SC, Lamarque JF, Shindell DT, Collins WJ, Dalsoren S, Faluvegi G, Folberth G, Horowitz LW. Global premature mortality due to anthropogenic outdoor air pollution and the contribution of past climate change. Environ Res Letters. 2013;8:034005. source

In the paper

“The analytical SEM analysis showed that the particles were titanium dioxide. Distributions of titania and oxygen completely merged on the image of particles.”

In the paper

“the amenity value of green spaces and/or the coastal zone to human health are also important in terms of exercise/cardiovascular health, mental health and general wellbeing [262].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [262] Sandifer PA, Sutton-Grier AE, Ward BP. Exploring connections among nature, biodiversity, ecosystem services, and human health and well-being: Opportunities to enhance health and biodiversity conservation. Ecosystem Services. 2015;2:1–15. source

In the paper

“maternal inhalation studies showed that exposure to nanoparticulate TiO2 during the foetal period decreased visits to, and duration of, stay in the central zone during evaluation with the open field test in mice [198] and impairments of working or short-term memory and initial motivation in rats [227].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [198] Hougaard K, Jackson P, Jensen KA, Sloth JJ, Löschner K, Larsen EH, Birkedal RK, Vibenholt A, Boisen AM, Wallin H, Vogel U. Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part Fibre Toxicol. 2010;7:16. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [227] Engler-Chiurazzi E, Stapleton PA, Stalnaker JJ, Ren X, Hu H, Nurkiewicz TR, McBride CR, Yi J, Engels K, Simpkins JW. Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition. J Toxicol Environ Health A. 2016;79:447–52. source