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VeilleNanos - Entry points and fate of nanomaterials in the human body

Entry points and fate of nanomaterials in the human body

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Entry points and fate of nanomaterials in the human body

By the AVICENN team – Last modification August 2023

Because of their small size, nanomaterials can enter the human body through different channels:
– the air we breathe,
– the food we ingest,
– products that we apply on skin.

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

The three main routes of exposure to nanomaterials:

There are three main routes of potential exposure to nanomaterials:

Inhalation

Inhalation is the main route of penetration of nanomaterials in the human body1See for example:
Human study reveals nanoparticles cross from lungs into blood – Gold nanoparticles accumulate in arterial plaques, Chemical Watch, May 2017 (see Inhaled Nanoparticles Accumulate at Sites of Vascular Disease, Miller MR et al, ACS Nano, 11(5): 4542-4552, April 2017)
Uranium nanoparticles cross the pulmonary barrier, Aktis (IRSN), October-December 2013
Les nanomatériaux, INRS, ED6050, September 2012.
. This is especially true 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 sprays of household products, sun creams or spray paints for example.

Once inhaled, nanomaterials can be released or remain in the respiratory tract (in the nasal cavity, bronchial tubes and pulmonary alveoli) or be carried into the gastrointestinal tract after swallowing.

Nanomaterials with diameters between 10 and 100 nm penetrate more deeply in the pulmonary alveoli than the micrometric particles and then pass, in part, into the blood, which then carries them to the other organs; on the other hand, smaller nanomaterials tend to remain in the upper airways2See Les nanomatériaux, INRS, ED6050, September 2012 and can:

  • be expelled (sneezing, nose blowing)
  • be swallowed and pass into the digestive system and then into the whole body
  • enter the nerve endings lining the nasal cavity, then travel up the neural pathways and enter the brain via the olfactory bulb.

Ingestion

Present in our food, in medicines, in toothpastes, lipsticks or lip balms, nanomaterials can be found in the gastrointestinal system.
The smaller the nanomaterials, the more they seem to be absorbed by the digestive system and then dispersed in the body to the liver, spleen, intestines, endocrine glands and brain.

Read more

Skin contact

Nanomaterials present in cosmetics or clothing, for example, can come into contact with our skin.
Penetration of nanomaterials through the skin – sometimes specifically intended5See for example “Our cosmetics are worth their weight in gold,” Avantages Magazine, December 7, 2018: “By passing through the skin barrier, gold would fight against oxidative stress due to pollution and UV, thus limiting wrinkles. It would also be able to fight against spots and boost the skin’s immune system.”is possible but should be relatively limited6Cf:
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 sun, press release, February 2018 (see also academic article in English: Postmenopausal fibrosing frontal alopecia: a lichenoid reaction to titanium dioxide nanoparticles 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, Techniques de l’Ingénieur, January 2017
Bioengineered sunscreen blocks skin penetration and toxicity, NIBIB, December 2015
Is the skin really impervious to nanoparticles, Vinches L and Halle S, Bulletin de veille scientifique, No. 27, ANSES, September 2015
Nanoparticles skin absorption: New aspects for a safety profile evaluation, Regulatory Toxicology and Pharmacology, 2015: according to this literature review:
– nanoparticles smaller than 4 nm in diameter can penetrate and impregnate intact skin,
– nanoparticles with a diameter 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 injured 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, Small, October 2014
Dermal exposure potential from textiles that contain silver nanoparticles, International 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 protection, Archives of Occupational and Environmental Diseases, 74(5), 488-498, November 2013
Reigniting the controversy over the ability of nanoparticles to cross the skin barrier, veillenanos.co.uk, 3 October 2012
Titanium dioxide and zinc oxide nanoparticles in cosmetic products: State of knowledge on skin penetration, genotoxicity and carcinogenesis – Information point AFSSAPS, June 14, 2011 (see pp. 28-29 of the state of knowledge report for a presentation of the Gulson study): the French Agency for the Sanitary Safety of Health Products (Afssaps) noted that scientific studies did not show significant cutaneous penetration of titanium dioxide (TiO2) nanoparticles for healthy skin, but did not allow for any conclusion in either direction for damaged skin. Afssaps has therefore recommended not to apply creams containing nano TiO2 on injured skin (for example, sunburn) because of the potential risks to human health; it has also advised against using cosmetics containing nanoparticles in spray form on the face or in closed premises
. Even if the results are often contradictory and not very usable due to insufficient physicochemical characterization of nanomaterials and/or the diversity of experimental setups7A synthesis 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 on dermal absorption of nanomaterials highlight the lack of comparable and quality data and recommend well-organized and structured research programs in line with the 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. Bio Mater., 2020
.

Overall, the literature nevertheless suggests that the penetration rate of nanoparticles may be higher than for larger particles, which are normally blocked by the upper layers of the epidermis.
Many uncertainties remain and work is in progress, particularly in France8Research work is underway in 2021 at the CEA in Grenoble in particular, on the development of an experimental model for the study of skin decontamination after exposure to metal nanoparticles (NaPeauLi), funded under the 2019 Anses APR-EST., to clarify these aspects.
Their passage through the skin could be facilitated by sebum, sweat, repeated bending of the skin, as well as by skin lesions (in case of eczema or pimples, burns due to a sunburn, micro-cuts resulting from shaving, etc.). In this case, it cannot be excluded that nanoparticles can be distributed in the body and reach internal tissues or even other organs – but in a very low proportion (except in the case of frequent and chronic applications?).

The fate of nanoparticles in hair follicles raises questions because the presence of stem cells, which can migrate, could make it possible to transport nanoparticles inside the body via this channel. Dermatologists from the Bichat and Rothschild Hospitals observed at the Sun Synchrotron the presence of titanium dioxide (TiO2) nanoparticles along the hair follicles of a patient suffering from fibrosing frontal alopecia (hair loss at the top of the forehead) who had used daily, for 15 years, sunscreens containing TiO29Cf. Sunscreen, nanoparticles, and frontal alopecia, Synchrotron sun, February 2018.

Other routes of exposure :

Actually, there are many more routes of exposure to nanomaterials:

Urogenital tract

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: Testing for HIV with the naked eye or countering 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 proteins, Journal of Nanobiotechnology, 9:38, 2011. Do they then cross the physiological barriers? Avicenn has not identified any studies on this topic.

Skin breakdown

Several teams of researchers have warned about the risks linked to the transfer of nanoparticles contained in tattoo inks and/or needles to the blood, lymphatic vessels and nodes (leading to their chronic swelling) and various organs, which can cause hypersensitivity or allergy reactions11See in particular:
Tattoo : nanoparticles, I have you in my skin, Science & Vie, 20 October 2021
Tattoo inks and permanent make-up, ECHA, 2020 ?
After the ink… Tattoos: needles could cause allergies, Allô Docteurs, 27 August 2019 and Metal particles abraded from tattooing needles travel inside the body, Synchrotron de Grenoble, 26 August 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 have responded by downplaying the risks, while still denouncing “the vagueness maintained by the industrialists supplying the pigments (CI = Color index) to the ink manufacturers, under cover of commercial secrecy. Our national distributors, respectful of the requirements imposed by the law, do not have themselves details on the CI of the labels. It is indeed today the only zone of shade on our tattoo inks. The real evolution expected from now on by the tattooers and the tattooed aims at a bigger transparency of the pigments suppliers… For a better knowledge of tattoo products”. Nanoparticles : Don’t 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
– University of Bradford (UK) press release and Friends of the Earth Australia article: Nanoparticles in tattoos could cause cancer, 4 November 2013
.

Parenteral (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 with nanocoatings are also tested or developed (pace-makers, prostheses).

Nanoparticles are also present in vaccines:

Oral mucosa (toothpastes, oro-dispersible medicines, chewing gums, etc.)

The oral mucous membranes are permeable; this is why granules and other so-called “oro-dispersible” drugs must be placed under the tongue (this is called a “sublingual” mode of administration) to “melt” there and be rapidly absorbed by the body. A part of the nanoparticles contained in toothpastes, medicines or chewing gums is “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, March 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
.

What happens to nanomaterials in the human body?

The small size of nanomaterials also explains their propensity to diffuse in the body through the nervous, blood and lymphatic systems. Nanomaterials can indeed cross the different physiological barriers: nasal barriers16Inhaled nanoparticles can travel via 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 particles, Environ Health Perspect, 113(7) :823-839, 2005, bronchial / alveolar17Cf:
Biopersistence and translocation to extrapulmonary organs of titanium dioxide nanoparticles after subacute inhalation exposure to aerosol in adult and elderly rats, Gaté L et al, Toxicol. Lett, 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 file prepared for the Restitution of the National Research Program on Environment and Health at Work (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, See our section on the risks associated with nanomaterials in food
, placental18See 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 materno-foetal transfer of food-grade TiO2 nanoparticles in an ex vivo placental perfusion model, A. Guillard et al, Particle and Fibre 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 Centre for the Working Environment, April 2020
Ambient black carbon particles reach the fetal side of human placenta, Bové H et al, Nature Communications, volume 10, 2019
Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes, Hawkins S J 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 nanoparticles between 0 and 17 days of gestation at doses up to 100 mg/kg bw/day, the concentration of Ti increases in the mother’s serum, in the placenta and in the fetus. Abnormalities in weight and skeletal development are also found in the fetus. These results indicate that TiO2 nanoparticles can cross the placental barrier in mice with consequences for fetal development.“Maternal exposure to TiO2 NPs” in Bilan des connaissances relatives aux effets des nanoparticules de dioxyde de titane (TiO2) sur la santé humaine; caractérisation de l’exposition des populations et mesures de gestion, HCSP, April 2018 (made public in June 2018)
The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTEST, Carreira C S et al, Nanotoxicology, 9 Suppl 1: 66-78, May 2015
– “Biometrology of ultrafine particles: application in two studies” (including one on placental translocation), by Rinaldo M et al, in Participant’s file prepared for the Restitution of the National Environment Health and Work Research Program (PNREST), October 2015
The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTEST, Nanotoxicology, Sept. 2013
Kinetics of silica nanoparticles in the human placenta, Nanotoxicology, July 2013
Nanotoxicology: Nanoparticles versus the placenta, Nature Nanotechnology, May 2011
Barrier capacity of human placenta for nanosized materials, Environ Health Perspect, 2010
Transfer of Quantum Dots from Pregnant Mice to Pups Across the Placental Barrier, Small, 2010
Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in miceParticle and Fibre Toxicology, 2010
, blood-brain barrier19The 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.):
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 vol 7,1 12196, 2017
Do nanoparticles harm the brain, Bencsik A., Pour la science, n°448, February 2015
Is the brain safe from the impact of nanomaterial exposure, Anna Bencsik, Biology Today, 208 (2): 159-165, 2014
– PRESS RELEASE: Titanium dioxide nanoparticles alter, in vitro, the blood-brain barrier, CEA, October 26, 2011; related academic publication: In vitro evidence of dysregulation of blood-brain barrier function after acute and repeated/long-term exposure to TiO(2) nanoparticles, Brun E, Carrière 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 blood-brain barrier specific to this organ (based on analyses of brain samples from 37 deceased people of all ages, all living in polluted cities: Mexico City and Manchester)20Cf. Magnetite pollution nanoparticles in the human brain, Maher BA et al, PNAS, July 2016(the barrier normally protects the brain from pathogens and toxins circulating in the blood).

Some nanomaterials can damage21Researchers at Imperial College London have shown, for example, that medium-sized nanoparticles (25-35 nm) generally adhere to the surface and cause some distortion, while small gold nanoparticles (5-10 nm) significantly deform cell membranes, sometimes bending them inwards with several stacked nanoparticles, causing tubular distortion. Cf. 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 and even cross cell membranes22See in particular:
Size determines how nanoparticles affect biological membranes, Dunning, H., Imperial College London, September 17, 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, Environ Health Perspect, 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 over time:

Some useful information

  • The ability to cross physiological barriers, the affinity of nanomaterials for a given type of organ or cell, as well as their toxicity, vary greatly from one nanomaterial to another because they are highly dependent on their physicochemical characteristics.
  • Some nanomaterials can be degraded and/or eliminated through urine and feces, but that does not mean that they are not a problem. When the body has to get rid of chemicals, it implements a number of detoxification strategies whose processes themselves can lead to toxicity28A study on Oryzias latipes (fish) livers 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? It is not known today and the answer will be different again depending on the nanomaterial considered.

Finally, what are the effects on human health once the nanomaterials or their residues have penetrated our organs and cells? There are still many uncertainties, but the initial results are quite worrying.

Any questions or comments? This information sheet compiled by AVICENN is intended to be completed and updated. Please feel free to contribute.

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File originally created in November 2013

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