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VigilNanos - The gateways & the future of nanomaterials in the human body

Gateways & the future of nanomaterials in the human body

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Entry points and the fate of nanomaterials in the human body

By AVICENN Team – Last Modified September 2022

Due to their small size, nanomaterials can enter the human body through different channels:
– the air we breathe,
– the food we eat,
– products that are applied to the skin.

The small size of nanomaterials also explains their propensity to spread in the body through the nervous, blood and lymphatic systems.

The three main routes of exposure to nanomaterials:

Three main routes of potential exposure to nanomaterials are commonly distinguished:

Inhalation

Inhalation is the main route of entry of nanomaterials into the human body1See for example:
- Human study reveals nanoparticles cross from lungs into blood – Gold nanoparticles accumulate in arterial plaques, Chemical Watch, May 2017 (cf. Inhaled Nanoparticles Accumulate at Sites of Vascular Disease, Miller MR et al., DHW Nano, 11(5): 4542-4552, Apr 2017)
- Uranium nanoparticles cross the pulmonary barrier, Aktis (IRSN), October-December 2013
- Nanomaterials, INRS, ED6050, September 2012.
, especially for workers involved in the manufacture or handling of nanomaterials in powder form.
The nanomaterials likely to be inhaled by the general public are those contained in powder form or in the sprays of household products, sun creams or aerosol paints for example.


Once inhaled, nanomaterials can be released or remain in the respiratory tract (on the nasal cavities, bronchi and pulmonary alveoli) or even be transported into the gastrointestinal system after swallowing.

Nanomaterials with a diameter between 10 and 100 nm penetrate deeper in the alveoli than micrometric particles and then pass, in part, in the blood which then conveys them to the other organs; on the other hand, smaller nanomaterials would tend to remain in the upper airways2See Nanomaterials, INRS, ED6050, September 2012 and can:

  • being thrown out (sneezing, blowing your nose)
  • be swallowed during swallowing and pass in the digestive system then throughout the body
  • enter the nerve endings lining the nasal cavities, then ascend along the neural processes and enter in the brain through the olfactory bulb.

Ingestion

Present in our foodWithin pharmaceuticalsWithin toothpaste, lipsticks or lip balms, nanomaterials can end up in the gastrointestinal system.
The smaller the nanomaterials, the more they seem to be absorbed by theDigestive and then dispersed throughout the body until liver, rates, intestines the endocrine glands and brain.

Find out more

Skin contact

The nanomaterials present in cosmetics or clothing, for example, can come into contact with our skin.
Penetration of nanomaterials through the skin – sometimes expressly sought5See for example “Our cosmetics are worth gold”, Magazine Benefits, December 7, 2018: “By passing through the skin barrier, gold would make it possible to fight against oxidative stress due to pollution and UV rays, thus limiting wrinkles. It would also be able to fight against stains and boost the immune system of the skin. » - is possible but would be relatively limited6See:
- NanoTiO2 Sunscreen Does Not Prevent Systemic Oxidative Stress Caused by UV Radiation and a Minor Amount of NanoTiO2 is Absorbed in Humans, Pelclova D et al., Nanomaterials, 9(6), 888, 2019
- Support for the Safe Use of Zinc Oxide Nanoparticle Sunscreens: Lack of Skin Penetration or Cellular Toxicity after Repeated Application in Volunteers, Mohammed YH, Journal of Investigative Dermatology, 139(2): 308–315, February 2019
- Sunscreen, nanoparticles and frontal alopecia, Synchrotron soleil, press release, February 2018 (see also the academic article in English: Postmenopausal fibrosing frontal alopecia: a lichenoid reaction to titanium dioxide nanoparticles present in hair follicles?, Gary C et al., Annals of Dermatology and Venereology, 144 (12), S206, 2017)
- Titanium dioxide and silver nanoparticles - Dermal exposure, Proust N, Engineering TechniquesJanuary 2017
- Bioengineered sunscreen blocks skin penetration and toxicity, NIBIB, December 2015
- Is the skin really impermeable to nanoparticles?, Vinches L and Halle S, Scientific watch bulletin, No. 27, ANSES, September 2015
- Nanoparticles skin absorption: New aspects for a safety profile evaluationRegulatory Toxicology and Pharmacology, 2015: according to this literature review:
– nanoparticles with a diameter of less than 4 nm can penetrate and impregnate intact skin,
– nanoparticles with a diameter of between 4 and 20 nm can potentially penetrate intact and injured skin,
– nanoparticles with a diameter between 21 and 45 nm can only penetrate and impregnate damaged skin,
– nanoparticles with a diameter greater than 45 nm cannot penetrate or impregnate the skin.
– other aspects play an important role, especially for metallic nanoparticles, namely their dissolution in physiological media, which can cause local and systemic effects, their sensitizing or toxic potential and the tendency to create aggregates.
- Interactions of Skin with Gold Nanoparticles of Different Surface Charge, Shape, and Functionality, Fernandes R et al., SmallOctober 2014
- Dermal exposure potential from textiles that contain silver nanoparticlesInternational Journal of Occupational and Environmental Health, 20(3), July 2013
- Dermal Absorption of Nanomaterials, Danish Environmental Protection Agency, 2013
- Occupational exposure to nanoparticles and skin protectionArchives of Occupational and Environmental Diseases, 74(5), 488-498, November 2013
- Renewed controversy over the ability of nanoparticles to cross the skin barrier,veillenanos.fr, October 3, 2012
- Nanoparticles of titanium dioxide and zinc oxide in cosmetic products: State of knowledge on skin penetration, genotoxicity and carcinogenesis – Information point, AFSSAPS, 14 June 2011 (see pp. 28-29 of the state of knowledge report for a presentation of the Gulson study): the French Agency for the Safety of Health Products (Afssaps) had noted that the studies scientists did not show any significant cutaneous penetration of titanium dioxide nanoparticles (TiO2) for healthy skin, but did not allow any conclusion to be drawn one way or the other for injured skin. The Afssaps therefore recommended not applying a cream containing nano TiO2 to damaged skin (for example by sunburn) because of the potential risks for human health; it also advised against using cosmetics containing nanoparticles and in the form of a spray on the face or in closed rooms
, even if the results are often contradictory and rendered difficult to use due in particular to an insufficient physico-chemical characterization of the nanomaterials and/or the diversity of the experimental setups7A summary was published in May 2020: Are nanomaterials getting under your skin?, RIVM & RPA consortium of Triskelion, ECHA, EUON, May 2020: Experts from the Netherlands commissioned by the European Chemicals Agency (ECHA) to analyze research work on the dermal absorption of nanomaterials highlight the lack of comparable and quality data and recommend well-organized and structured research programs in line with OECD testing guidelines.
A study, also published in May 2020, reports interesting results: Penetration of Zinc into Human Skin after Topical Application of Nano Zinc Oxide Used in Commercial Sunscreen Formulations, Holmes AM et a., ACS Appl. Organic Mater. 2020
.

Overall, the literature nevertheless suggests that the penetration rate of nanoparticles may be higher than for larger particles, which are more blocked by the upper layers of the epidermis.
Many uncertainties remain and work is in progress, in France in particular8Research work is underway in 2021 at the CEA in Grenoble, in particular, on the development of an experimental model for the study of the decontamination of the skin after exposure to metallic nanoparticles (NaPeauLi), financed within the framework of the APR-EST of ANSES 2019., to see more clearly.
Their passage through the skin would be facilitated by sebum, sweat, repeated bending of the skin, as well as by skin lesions (in case of eczema or pimples, burns due for example to sunburn, micro-cuts resulting from shaving, etc.). In this case, it cannot be excluded that the nanoparticles can be distributed in the body and reach the internal tissues or even other organs - but in a proportion beforehand very low (unless frequent and chronic applications?).

The fate of nanoparticles in hair follicles raises questions because the presence of stem cells, which can migrate, could make possible the transport of nanoparticles inside the body via this channel. Dermatologists from Bichat and Rothschild Hospitals observed the presence of nanoparticles of titanium dioxide (TiO2) along the hair follicles of a patient suffering from fibrosing frontal alopecia (hair loss above the forehead) using the Synchrotron soleil, who used daily, for 15 years, sunscreens containing TiO29See Sunscreen, nanoparticles and frontal alopecia, Sun Synchrotron, February 2018.

Other routes of exposure:

In fact, the routes of exposure to nanomaterials are actually more numerous:

Urogenital route

Nanomaterials such as nanosilver are used in the composition of underwear, antibacterial and spermicidal vaginal gels10See our inventories of marketed products containing nanomaterials, or for example: Screen for HIV with the naked eye or counter it with a cream?, January 2014 and Use of silver nanoparticles increased inhibition of cell-associated HIV-1 infection by neutralizing antibodies developed against HIV-1 envelope proteinsJournal of Nanobiotechnology, 9:38, 2011. Do they then cross physiological barriers? Avicenn did not identify any studies on this subject.

Skin rash

Several teams of researchers have warned of the risks associated with the transfer of nanoparticles contained in tattoo inks and/or needles to the blood, lymphatic vessels and nodes (causing their chronic swelling) and various organs, which can lead to hypersensitivity reactions. or allergies11See in particular:
Tattooing: nanoparticles, I have you under my skin!Science & Life, Oct. 20 2021
Tattoo inks and permanent makeup, ECHA, 2020?
After the ink… Tattoos: needles could lead to allergies, Hello Doctors, August 27, 2019 and Metal particles abraded from tattooing needles travel inside the body, Grenoble Synchrotron, August 26, 2019
Scientists find that nanoparticles from tattoos travel inside the body, ESRF, September 12, 2017 (Synchrotron-based ν-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin, Schreiver I et al., Scientific reports, 2017); professionals reacted by minimizing the risks, while denouncing all the same “the vagueness maintained by manufacturers supplying pigments (CI = Color index) to ink manufacturers, under cover of commercial secrecy. Our national distributors, respectful of the requirements imposed by law, do not themselves have details of the ICs of the labels. It is today the only gray area on our tattoo inks. The real evolution now expected by tattoo artists and tattooed people is aimed at greater transparency of pigment suppliers... For a better knowledge of tattoo products », cf. Nanoparticles: Do not panic!Tattoo Magazine, n°119, November-December 2017
Size and metal composition characterization of nano- and microparticles in tattoo inks by a combination of analytical techniques, Bocca B et al., J. Anal. At.Spectrom.,32, 616-628, January 2017
- the communicated from the University of Bradford (UK) and the article from Friends of the Earth Australia: Nanoparticles in tattoos could cause cancer November 4, 2013
.

Parenteral route (intravenous, vaccines, etc.)

This route is used in medicine: it is the intravenous, subcutaneous, intradermal or intramuscular routes, by which nanomaterials can be introduced into the human body.
Implantable medical devices comprising nanocoatings are also tested or developed (pace-makers, prostheses).

Nanoparticles are also present in vaccines :

Oral mucosa (toothpastes, oro-dispersible drugs, chewing gum, etc.)

The oral mucous membranes are permeable; it is for this reason that the granules and other so-called "orodispersible" drugs must be placed under the tongue (we speak of a "sublingual" mode of administration) to "melt" there and be quickly absorbed by the body. Some of the nanoparticles contained in toothpaste, medicine or chewing gum are “absorbed” at this level15See for example:
- Use of single particle ICP-MS to estimate silver nanoparticle penetration through baby porcine mucosa, Zanoni I et al., Nanotoxicology, 15(8): 1005-1015, 2021
- Nano‐TiO2 penetration of oral mucosa: in vitro analysis using 3D organotypic human buccal mucosa models, Konstantinova V et al., Journal of Oral Pathology & Medicine, 46(3): 214-222, Mar 2017
- The buccal mucosa as a route for TiO2 nanoparticle uptake, Teubl BJ et al., Nanotoxicology, 9:253–261, 2015
- Interactions between nano-TiO2 and the oral cavity: Impact of nanomaterial surface hydrophilicity/hydrophobicity, Teubl BJ et al., Journal of Hazardous Materials, 286: 298-305, 2015
- In vitro permeability of silver nanoparticles through porcine oromucosal membrane, Mauro M et al., Colloids Surf B Biointerfaces, 1;132:10-6, 2015
- Evaluation of a physiological in vitro system to study the transport of nanoparticles through the buccal mucosa, Roblegg E et al., Nanotoxicology, 1–15, 2011
.

And after: what becomes and behavior of nanomaterials in the human body?

The small size of nanomaterials also explains their propensity to spread in the body through the nervous, blood and lymphatic systems. Nanomaterials can indeed cross the various physiological barriers : nasal barriers16Inhaled nanoparticles can travel up the olfactory nerves to the olfactory lobes (in the brain): Oberdörster et al., Translocation of inhaled ultrafine particles to the brain, 2004 ; Oberdörster et al., Nanotoxicology: an emerging discipline evolving from studies of ultrafine particlesAbout Health Perspective, 113(7) :823-839, 2005, bronchial / alveolar17See:
- Biopersistence and translocation to extrapulmonary organs of titanium dioxide nanoparticles after subacute inhalation exposure to aerosol in adult and elderly rats, Gate L et al., Toxicol. Let., 4; 265: 61-69, January 2017
– “Internalization and translocation of silica oxide and titanium oxide nanoparticles in bronchial epithelial, pulmonary endothelial and muscle cells” by Mornet S et al. and “Study of the passage of the air-blood barrier of carbon nanotubes after pulmonary exposure” by Czarny et al, in Participant's file prepared for the Restitution of the National Environmental and Occupational Health Research Program (PNREST)October 2015
- Pathophysiological impacts of inhaled nanoparticles, Baeza-Squiban A, Biology Today, 208 (2), 151-158, September 2014 (paragraph “The respiratory system, target of inhaled nanoparticles”)
- Nanomaterials, INRS, ED6050, September 2012
, intestinal18See our department on the risks associated with nanomaterials in food, placental19See in particular these few studies on the passage of nanomaterials through the placental barrier (non-exhaustive list):
- Titanium dioxide nanoparticles: E171 crosses the placental barrier, INRAE, October 7, 2020; Basal Ti level in the human placenta and meconium and evidence of a maternal-fetal transfer of food-grade TiO2 nanoparticles in an ex vivo placental perfusion model, A. Guillard et al., Particle and Fiber Toxicology, 17 (51), 2020
- Female fertility data lacking for nanomaterials, European Observatory of Nanomaterials, April 6, 2020 and A critical review of studies on the reproductive and developmental toxicity of nanomaterials, ECHA / Danish National Research Center for the Working Environment, April 2020
- Ambient black carbon particles reach the fetal side of human placenta, Bove H et al., Nature Communications, Volume 10, 2019
- Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes, Hawkins SJ et al., Nature Nanotechnology, 13:427–433, 2018
- Maternal exposure to nanosized titanium dioxide suppresses embryonic development in mice, Hong F et al., Int J Nanomedicine, 12: 6197–6204, 2017, cited by the High Council for Public Health (HCSP): “In pregnant mice exposed orally to TiO2 NPs between 0 and 17 days of gestation at doses up to 100 mg/kg bw/day, the concentration of Ti increases in the serum of the mother, in the placenta and in the fetus. Weight and skeletal development abnormalities are also found in the fetus. These results indicate that TiO2 NPs can cross the placental barrier in mice with consequences in fetal development”: “Maternal exposure to TiO2 NPs” in Review of knowledge relating to the effects of titanium dioxide nanoparticles (TiO2) on human health; characterization of population exposure and management measures, HCSP, April 2018 (released in June 2018)
- The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTEST, Carreira CS et al., Nanotoxicology, 9 Suppl 1:66-78, May 2015
– “Biometrilogy of ultrafine particles: application in the context of two studies” (including one on placental translocation), by Rinaldo M et al., in Participant's file prepared for the Restitution of the National Environmental and Occupational Health Research Program (PNREST)October 2015
- The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTESTNanotoxicology, Sep 2013
- Kinetics of silica nanoparticles in the human placentaNanotoxicologyJuly 2013
- Nanotoxicology: Nanoparticles versus the placentaNature NanotechnologyMay 2011
- Barrier capacity of human placenta for nanosized materialsAbout Health Perspective. 2010
- Transfer of Quantum Dots from Pregnant Mice to Pups Across the Placental BarrierSmall 2010
- Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in miceParticle and Fiber Toxicology 2010
, blood-brain20The passage of nanoparticles in the brain has been demonstrated for nanoparticles of various types (silver, titanium dioxide (TiO2), manganese dioxide, iron oxides, iridium, carbon, polystyrene, etc.) Cf. notably :
- Can the brain's gatekeeper fight a nano-attack?, E/ Valsami-Jones, EUON, September 2022 > Nanomaterials shape and form influences their ability to cross the blood brain barrier, University of Birmingham, July 2021 (press release); Biotransformation modulates the penetration of metallic nanomaterials across an artificial blood–brain barrier model, Guo Z et al., PNAS, 118 (28), July 2021
- Brain Inflammation, Blood Brain Barrier dysfunction and Neuronal Synaptophysin Decrease after Inhalation Exposure to Titanium Dioxide Nano-aerosol in Aging Rats, Disdier C et al., Scientific reports flight. 7,1 12196, 2017
- Do nanoparticles harm the brain?, Bencsik A., for science, No. 448, February 2015
- Is the brain immune to the impact of exposure to nanomaterials?, Anna Bencsik, Biology today, 208 (2): 159-165, 2014
– the press release: Titanium dioxide nanoparticles alter the blood-brain barrier in vitro, CEA, October 26, 2011; the corresponding academic publication: In vitro evidence of dysregulation of blood-brain barrier function after acute and repeated/long-term exposure to TiO(2) nanoparticles, Brown E, Career M, Mabondzo A., biomaterials, 33(3):886-96, January 2012
.
In humans, researchers have recently demonstrated that metallic nanoparticles (magnetite) from polluted air reach our brain, crossing the barrier specific to this organ, the blood-brain barrier (based on analysis of brain samples from 37 deceased people, of all ages, and all residing in polluted cities: Mexico City and Manchester)21See Magnetite pollution nanoparticles in the human brain, Maher BA et al., PNASJuly 2016(which normally protects the brain from pathogens and toxins circulating in the blood).

Some nanomaterials can damage22Researchers at Imperial College London have, for example, shown that medium-sized nanoparticles (25-35 nm) generally adhere to the surface and cause some distortion, while small gold nanoparticles ( 5-10 nm) dramatically distort cell membranes, sometimes bending them inward with multiple stacked nanoparticles, causing tubular distortion. see Size determines how nanoparticles affect biological membranes, Dunning, H., Imperial College London, September 17, 2020 (press release) and Size dependency of gold nanoparticles interacting with model membranes, Contini, C et al., Nature Communications Chemistry, 130, 2020 indeed cross cell membranes23See in particular:
- Size determines how nanoparticles affect biological membranes, Dunning, H., Imperial College London, 17 September 2020 (and Size dependency of gold nanoparticles interacting with model membranes, Contini, C et al., Nature Communications Chemistry, 130, 2020)
– Singh, S et al., Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: Role of the specific surface area and of surface methylation of the particles, Toxicology and Applied Pharmacology, 222 (2), 141-151, 2007
– Geiser, M et al., Ultrafine Particles Cross Cellular Membranes by Nonphagocytic Mechanisms in Lungs and in Cultured Cells, About Health Perspective., 113 (11), 1555-1560, 2005
– Limbach, LK et al., Oxide Nanoparticle Uptake in Human Lung Fibroblasts: Effects of Particle Size, Agglomeration, and Diffusion at Low Concentrations, Environmental Science & Technology, 39 (23), 9370-9376, 2005.
.

Nanomaterials (especially metallic nanoparticles) can accumulate with time :

Source: Oberdörster 2005, translated by ANSE 2014

Namely

  • The ability to cross physiological barriers, the affinity of nanomaterials for this or that type of organ or cell, as well as their toxicity vary greatly from one nanomaterial to another because they strongly depend on their physico-chemical characteristics.
  • Some nanomaterials can be degraded and/or eliminated through urine and faeces, but that doesn't mean they aren't a problem : when the body needs to get rid of chemicals, it implements a number of detoxification strategies whose processes can lead to toxicity29A study on the livers of Oryzias Latipes (fish) showed detoxification mechanisms (induction of metallothionein, CYP 450, GST, etc.) Cf. Evaluation of the toxic impact of silver nanoparticles on Japanese medaka (Oryzias latipes), Chae et al., Aquat Toxicol., 94(4):320-7, 2009.

How long can nanomaterials persist in the body? We do not know today and the answer will again be different depending on the nanomaterial considered.

Last but not least, what are the effects on human health once the nanomaterials or their residues have entered our organs and cells? There are still many uncertainties, but the first results are quite worrying.

A question, a remark ? This sheet produced by AVICENN is intended to be supplemented and updated. Please feel free to contribute.

The next nano appointments

15
Feb.
2023
Unnoticed and ungoverned: How nanomaterials are slipping through the cracks (ECOS, Brussels and online)
Brussels and online
Conference
  • Hybrid event (face-to-face and online)
  • Organizers: Environmental Coalition on Standards (ECOS), Friends of the Earth Germany (FEDERATION)
  • Speakers: representatives of the European Commission, civil society and research  
  • Website : https://ecostandard.org/…
5
June
2023
NanoSafe conference 2023 (CEA, Grenoble)
Grenoble
Conference
  • 8th International Conference on Health Issues for a Responsible Approach to Nanomaterials
  • June 5-9, 2023
  • Organizer: Commissariat for Atomic Energy and Alternative Energies (CEA)
  • Website : www.cea.fr/cea-tech/pns/nanosafe/…  
22
June
2023
How the world deals with Materials on the Nanoscale – Responsible Use and Challenges (OECD-BMUV, Berlin)
Berlin
Conference
  • International conference from June 22 to 23, 2023
  • Organizers: OECD, German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV)
  • Website : https://www.bmuv.de/…

Sheet initially created in November 2013

Notes & references

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