What are the health risks of nanos?

What are the health risks of nanos?

By the AVICENN team – Last modification June 2024

Thanks to evolution, the human body has adapted to a relatively stable environment for thousands of years during which it has developed defense mechanisms against external aggressions. However, since the beginning of the industrial era, an exponential number of synthetic chemical molecules have been put on the market, some with harmful effects on our body, which is not necessarily well equipped to deal with them. In addition to lead, mercury, DDT, pesticides, endocrine disruptors, etc., there are manufactured nanoparticles, which, because of their small size, can penetrate and then diffuse in the body, without their effects on living beings having been exhaustively and systematically evaluated.

Combined with their small size, their increased reactivity makes nanomaterials likely to cause a different biological response and, in some cases, potentially stronger toxicity and inflammatory effects than materials of the same chemical nature but larger in size. How, why and with what risks for human health? Many uncertainties remain. The first elements of answer listed below will be supplemented as the scientific knowledge in the matter progresses, but already advocate for greater vigilance to minimize increasing, repeated and continuous exposure to manufactured nanomaterials.

Effects still relatively unknown

Unfortunately, data on the adverse effects of nanomaterials on human health are still incomplete and fragmented. There are many reasons for these scientific shortcomings and uncertainties. To name a few:

• the effects of nanomaterials are very different from one nanomaterial to another because they depend strongly on the physicochemical characteristics of the nanomaterials; such as the shape for example; thus it seems that nanoparticles in the form of fibers are more likely to generate harmful effects than spherical nanoparticles¹See for example Carbon nanotubes, but not spherical nanoparticles, block autophagy by a shape-related targeting of lysosomes in murine macrophages, Cohignac V et al, Autophagy, 14(8), June 2018 – but on the other hand, they also seem less likely to cross the blood-brain barrier that protects the brain²Cf. Can the brain’s gatekeeper fight a nano-attack?E/ Valsami-Jones, EUON, September 2022: “Each nanoparticle tested showed a range of behaviours, influenced by their properties and quantities but in general, smaller particles cross the BBB more easily, but their shape was also found to be important. For example, wire-shaped particles were less successful in crossing the BBB, compared with their spherical counterparts”...

• the effects are also different depending on the environment in which they are found, particularly the acidity or salt content of the various biological fluids (blood, lymph, saliva, gastric juice, mucus…)
  
• Because of their small size and the transformations they undergo as they travel through the body, nanoparticles are difficult to detect, quantify, characterize and track in the human body and even in cells. However, significant progress in measurement tools now makes it possible to advance knowledge, not only in animals but also in humans³Cf. anotoxicology: the need for a human touch?, Miller M & Poland C, Small, July 2020.

The effects highlighted by scientific studies

In a context of increasing exposure (whether by inhalation, ingestion or skin application), the scientific literature highlights many potential undesirable health effects… which however differ according to the chemical nature of nanos, their size, shape and other physicochemical parameters. It is therefore difficult to generalize the harmful effects, but a certain number of effects can be identified, at the cellular level but also at the level of the various large “systems” of the human body.

Effects on cells (cytotoxicity)

In vitro approaches do not reflect the conditions of a real exposure of a whole organism, and therefore do not reproduce all the complex parameters such as the route of exposure, the frequencies, durations and doses of exposure, the vulnerability of the exposed subject (young or old, gestation, sick, etc.) but they allow the identification of the possible response mechanisms of the cells to the exposure to nanomaterials Thus, some nanoparticles can negatively impact the morphology and functioning of cells, even to the point of questioning their viability.

Nanomaterials, because of their small size, can alter the cell membrane⁴Cf. 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 then interact with the different components of the cell, causing possible DNA damage or rearrangements, altered gene expression (see below), oxidative stress or cell inflammation.

The ultimate stage, cell death (apoptosis) has been observed in various categories of cells (epithelial, hepatocytes,…) after exposure to different types of nanomaterials (such as carbon nanotubes, quantum dots, fullerenes, or gold or _TiO2 nanoparticles)⁵See for example:
– Small size gold nanoparticles enhance apoptosis…, Jawaid P. et al, Cell Death Discov. 6, 83, 2020
– Nanoparticles induce apoptosis via mediating diverse cellular pathways, Chen L et al, Nanomedicine, 13(22), 2018
– Nanosized TiO2 is internalized by dorsal root ganglion cells and causes damage via apoptosis, Erriquez J, Nanomedicine, 11(6):1309-19, 2015
These effects were already known at the turn of the 2000s:
– Aillon, KL et al, Effects of nanomaterial physicochemical properties on in vivo toxicity. Advanced Drug Delivery Reviews, 61 (6), 457-466, 2009
– Hussain, S et al, Carbon black and titanium dioxide nanoparticles elicit distinct apoptotic pathways in bronchial epithelial cells, Part Fibre Toxicol, 7, 10, 2010.

DNA damage (genotoxicity)

Studies show that nanomaterials can cause DNA disruption⁶See for example:
–Advances in genotoxicity of titanium dioxide nanoparticles in vivo and in vitro, Shi J et al, NanoImpact, 25, 100377, January 2022
– Toxicity and chemical transformation of silver nanoparticles in A549 lung cells: dose-rate-dependent genotoxic impact, Bobyk L et al, Environmental science. Nano, 8 (3) : 806-821, 2021
– TiO2 genotoxicity: an update of the results published over the last six years, Carriere M et al., Mutation Research/Genetic Toxicology and Environmental MutagenesisMay 15, 2020: this review of the scientific literature by CEA researchers shows that nanoscale and microscopic titanium dioxide (TiO2) particles cause DNA damage in various cell types, lung and intestinal, even at low and realistic doses.
(…)
– Genotoxicity of Manufactured Nanomaterials: report of the OECD expert meeting, OECD, December 2014
– Tiny particles may pose big risk – Some nanoparticles commonly added to consumer products can significantly damage DNA, MIT News, April 8, 2014: researchers from MIT and the Harvard School of Public Health (HSPH) observed the genotoxicity of nanoparticles of zinc oxide (ZnO – used in sunscreens), silver, iron oxide, cerium oxide and silicon dioxide.
In the early 2000s, publications already documented the genotoxicity of nanomaterials. See for example: Nanoparticles can cause DNA damage across a cellular barrier, Bhabra G et al, Nature Nanotechnology, 4: 876 – 883, 2009.

This phenomenon is not so surprising since DNA is about 2 nm wide. On the other hand, it is quite worrying bacause these DNA disruptions are likely to lead to :

• cancerous mutations if the damage is not repaired, or not repaired properly (DNA damage and mutations are usually the first step towards cancer, two or three mutations can be enough to start the process)
• and/or problems with the reproductive system and fetal development (see below).

In 2022, recommendations were issued by scientists to improve the assessment of the genotoxicity of nanomaterials⁷Cf. Common Considerations for Genotoxicity Assessment of Nanomaterials, Elespuru RK et al., Front. Toxicology., 4:859122, 2022.

Effects on the immune system (immunotoxicity)

Some nanomaterials seem to be able to increase or cause immune system disturbances and allergies⁸See for example:
– Synthetic Amorphous Silica Nanoparticles Promote Human Dendritic Cell Maturation and CD4+ T-Lymphocyte Activation, Feret a et al, Toxicological Sciences, Oxford University Press (OUP), 185 (1): 105-116, 2022
– Immunotoxic effects of metal-based nanoparticles in fish and bivalves, Rastgar S et al, Nanotoxicology, 2022
– Toxicity of titanium nano-oxide nanoparticles (_TiO2) on the pacific oyster, Crassostrea gigas: immunity and antioxidant defence, Arash Javanshir Khoei and Kiadokht Rezaei, Toxin Reviews, 41, 2022
– Mechanisms of immune response to inorganic nanoparticles and their degradation products, Mohammapdour R and Ghandehari H, Advanced Drug Delivery Reviews, 180, January 2022
– The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective, Ernst L et al, Nanomaterials, 11(11), 2991, 2021
– The effects of amorphous silica nanoparticles on the immune system, Thierry Rabilloud, The Research Papers. Health, Environment, WorkANSES, 2021, Microplastics and nanomaterials, pp.17-19, 2021
– Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System, Bischoff NS et al, Int. J. Mol. Sci. 2021, 22(1), 207, 2021
– Impacts of foodborne inorganic nanoparticles on the gut microbiota-immune axis: potential consequences for host health, Lamas B et al, Particle and Fibre Toxicology, 17:19, 2020
– A combined proteomic and targeted study of the long-term versus short-term effects of silver nanoparticles on macrophages, Dalzon B et al, Environmental science. Nano, 7: 2032-2046, 2020: repeated exposure to silver nanoparticles (over twenty days) induces more adverse biological effects on mouse macrophages than a single exposure, although less silver is internalized with repeated exposure
– Immunotoxicity of nanoparticles, Brousseau P et al. intervention at the 83rd Acfas Congress, Colloquium 210 – Presence, persistence, fate and effects of nanomaterials in the environment, May 2015 : inflammatory reactions, immuno-stimulation, immunosuppression or autoimmune reactions.

Immune cells (e.g. macrophages) are not necessarily able to eliminate nanomaterials and may themselves be degraded or eliminated.

In organisms with an already compromised immune system, the adverse effects of nanomaterials appear to be accentuated. Research in Switzerland, for example, has shown that _TiO2 nanoparticles could aggravate inflammation suffered by people with chronic inflammatory bowel disease (IBD)⁹Cf. Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome, Ruiz PA et al, Gut, 66: 1216-1224, 2017.

Effects on the brain and nervous system (neurotoxicity)

Damage to brain function has been reported in animals under the effect of various nanomaterials¹⁰See for example:
– Bencsik A and Lestaevel P, The Challenges of 21st Century Neurotoxicology: The Case of Neurotoxicology Applied to Nanomaterials, Front. Toxicol., 3:629256, 2021
– Hussain Z et al, Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and future prospects, Journal of Controlled Release, 328: 873-894, 2020
– Neurotoxicology of Nanomaterials, Boyes WK and van Thriel C, Chem. Res. Toxicol., 33, 5: 1121-1144, April 2020
– Neurotoxicity and biomarkers of zinc oxide nanoparticles in main functional brain regions and dopaminergic neurons, Science of The Total Environment, 705, February 2020
– Penetration, distribution and brain toxicity of titanium nanoparticles in rodents’ body: a review, Zeman T et al, IET Nanobiotechnology, 12(6), September 2018
– Nano- and neurotoxicology: An emerging discipline, Bencsik A et al, Prog Neurobiol, 160:45-63, January 2018
– the work of researchers at the University of Bordeaux: Exposure to nanoparticles: a risk for the brain to be taken very seriously, Didier Morin and Laurent Juvin, The Conversation, August 2018 (Acute exposure to zinc oxide nanoparticles critically disrupts operation of the respiratory neural network in neonatal rats, Nicolosi A et al, NeuroToxicology, 67, 150-160, July 2018)
– Maternal exposure to titanium dioxide nanoparticles during pregnancy and lactation alters offspring hippocampal mRNA BAX and Bcl-2 levels, induces apoptosis and decreases neurogenesis, Exp Toxicol Pathol., 5;69(6): 329-337, juillet 2017
– 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, September 2017
– Flora S.J.S. Chapter 8-Theapplications, neurotoxicity, and related mechanism of gold nanoparticles. In: Jiang X., Gao H., editors. Neurotoxicity of Nanomaterials and Nanomedicine. Academic Press; Cambridge, MA, USA: 179-203, 2017
– Nanoparticles and the brain: state of play, Anna Bencsik, J3P, October 2016
– Is the brain safe from the impact of nanomaterial exposure, Bencsik A, Biology Today, 208 (2), 159-165, September 2014
– Developmental neurotoxicity of engineered nanomaterials: identifying research needs to support human health risk assessment, Powers CM, et al, Toxicological Sciences, 134(2), 225-242, 2013
– Cognitive impairment in rats induced by nano-CuO and its possible mechanisms, An L et al, Toxicology Letters, 213(2), 2012
– Hu R et al, Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles, Biomaterials, Volume 31, Issue 31, 2010 with direct or indirect effects such as cognitive problems, memory and learning disorders, degeneration of nerve cells or even neuronal death and brain lesions, a decrease in locomotor capacities… All these deleterious effects are likely to promote or accelerate neurodegenerative diseases, such as Alzheimer’s or Parkinson’s for example.

Moreover, nanomaterials that can cross the blood-brain barrier (which protects the brain), are also likely to damage it and could make it more permeable to other potentially neurotoxic products (see also below the so-called “Trojan Horse” effect).

Effects on the lungs and respiratory system

Like the so-called “ultra-fine” particles (UFP) of air pollution, some manufactured nanomaterials can cause deleterious effects at the pulmonary level¹¹See in particular:
– Effects of FW2 Nanoparticles Toxicity in a New In Vitro Pulmonary Vascular Cells Model Mimicking Endothelial Dysfunction, Jeweirdt J et al,Cardiovascular Toxicology, 22: 14-28, 2022
– Exposure to TiO2 Nanostructured Aerosol Induces Specific Gene Expression Profile Modifications in the Lungs of Young and Elderly Rats, Valentino S et al, Nanomaterials, 11, 1466, 2021
– “Impact of physicochemical characteristics on the respiratory inflammatory and pro-allergenic effect of manufactured nanoparticles”, Françoise Pons, University of Strasbourg, in Air research – Sources, health effects and perspectives – Participant’s file, ADEME & Anses, 17 October 2019
–“Nanoparticles and Respiratory Diseases: where do we stand with our knowledge?“, Conference 5 to 7, December 2017, led by Dr. Fabrice Nesslany – Director of the Genetic Toxicology Laboratory at the Pasteur Institute of Lille and Dr. Patricia de Nada.
Macrophages (essential in the defense against infectious agents) are not always able to eliminate nanomaterials, whose accumulation in the lungs can eventually lead to or aggravate chronic respiratory pathologies (asthma, chronic obstructive pulmonary disease) or even very serious lung infections as after an exposure to asbestos or silica (pleural plaques, lung cancer).
Rigid and long carbon nanotubes in particular raise concerns about their ability to cause pulmonary reactions similar to those induced by asbestosSee¹²our sheet Risks associated with carbon nanotubes and titanium dioxide particles, classified as category 2 carcinogens by inhalation, are potentially even more dangerous at the nano scaleSee¹³our Infosheet Risks associated with titanium dioxide nanoparticles.

The greatest concerns are for employees exposed to manufactured nanoparticles in the workplace, because this occupational exposure is in addition to the exposure of the general population through air pollution and, to a lesser extent, the release of nanoparticles from everyday consumer products.

In France, the INRS has been working on this subject for years¹⁴via the European SmartNanoTox project (2016-2020) – and other research is underway, in France¹⁵See for example:
– The ANR-funded NanoLys project (2018-2022) on “lysosomal dysfunction in the respiratory toxicity of nanoparticles”
– the “Nanomuc” project selected in 2021 by ANSES on the interactions and their toxicological consequences between nanoparticles and lung mucus, essential in the defense against environmental aggressions in the respiratory tract and elsewhere in the world.

Effects on the heart and cardiovascular system

Manufactured nanoparticles are likely to have deleterious effects on the cardiovascular system, possibly increasing the risk of cardiac events.

Researchers from the Center for Cardiovascular Science at the University of Edinburgh showed in 2017 that once present in the blood, gold nanoparticles tend to accumulate on the damaged and fragile vessels of patients who have already suffered a cardiac accident; even a limited number of these nanoparticles can have serious consequences¹⁶Cf. Inhaled Nanoparticles Accumulate at Sites of Vascular Disease, Miller MR et al, ACS Nano, 2017.

Other researchers in Italy showed in 2019 that inhalation of titanium dioxide nanoparticles in people with hypertension induces irreversible blood flow (hemodynamic) impairment, associated with cardiac damage that can lead to heart failure¹⁷Cf. Subchronic exposure to titanium dioxide nanoparticles modifies cardiac structure and performance in spontaneously hypertensive rats, Rossi S et al, Particle and Fibre Toxicology, 16:25, 2019.

A review of the literature on cardiovascular risks related to silica nanoparticles, published in 2021, reports as possible effects an increase in blood pressure, dyslipidemia (very high concentration of lipids in the blood), arrhythmia (irregular heartbeat), a risk of thrombosis (clot that clogs a blood vessel), atherosclerosis (formation of atherosclerotic plaques in arteries), ischemia or even myocardial infarction¹⁸Cf. Adverse effects of amorphous silica nanoparticles: Focus on human cardiovascular health, Guo C et al, Journal of Hazardous Materials, 406(15), 124626, 2021.

The aggravation of myocardial infarction symptoms was also observed for zinc nanoparticles¹⁹Cf. Preparation of Nano Zinc Particles and Evaluation of Its Application in Mouse Myocardial Infarction Model, Song, Y et al., J. Nanosci. Nanotechnol., 21:1196-1201, 2021.

Increased risk of thrombosis by silver nanoparticles was demonstrated in 2022 on mice with hypertension²⁰Cf. Ferdous Z et al, Exacerbation of Thrombotic Responses to Silver Nanoparticles in Hypertensive Mouse Model, Oxidative Medicine and Cellular Longevity, 2022.

Effects on the digestive system

Used in food products to modify the aspect, color or texture of food, nanos can also be present for their bactericidal properties (silver, zinc, titanium, …) with potentially harmful effects on the intestinal flora (it is itself composed of bacteria whose reduction or even destruction disrupts the proper functioning).
The effects of silver, silica, titanium dioxide, iron oxide and zinc oxide nanoparticles could disrupt the intestinal microbiota and lead to various pathologies²¹See for example:
– A systematic review on the effects of nanomaterials on gut microbiota, Utembe W et al, Current Research in Microbial Sciences, 3, 100118, 2022
– Nanoparticles in the Food Industry and Their Impact on Human Gut Microbiome and Diseases, Ghebretatios, M et al., Int. J. Mol. Sci., 22(4) :1942, 2021
– Impacts of foodborne inorganic nanoparticles on the gut microbiota-immune axis: potential consequences for host health, Lamas B et al, Particle and Fibre Toxicology, 17:19, 2020 irritable bowel syndrome, inflammatory bowel disease, celiac disease, colorectal cancer…

Effects on fertility and progeny

Although studies are still incomplete²²In 2020, a review of the literature highlighted the lack of data regarding the impact of nanomaterials on female fertility and the need for studies on their effects on reproductive capacity. Cf. Female fertility data lacking for nanomaterials, European Observatory of Nanomaterials, 6 April 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, it is to be feared that the nanos will disturb the reproduction and the good development of the next generations:

Effects on reproductive organs, hormones and fertility

Some studies report toxicity of nanoparticles on the male reproductive system²³See for example:
– Silica nanoparticles cause spermatogenesis dysfunction in mice via inducing cell cycle arrest and apoptosis, Zhiyi G et al, Ecotoxicology and Environmental Safety, 231, February 2022
– Habas K et al, Toxicity mechanisms of nanoparticles in the male reproductive system, Drug Metabolism Reviews, 53:4, 604-617, 2021
– Can nanomaterials induce reproductive toxicity in male mammals? A historical and critical review, Souza MR et al, Sci Total Environ, 15;769:144354, May 2021 (disturbance of testosterone production, decrease in sperm quality and quantity) and female²⁴See for example:
– Ovarian toxicity of nanoparticles, Santacruz-Márquez R et al, Reproductive Toxicology, 103, 2021
– Comparative effects of TiO2 and ZnO nanoparticles on growth and ultrastructure of ovarian antral follicles, Santacruz-Marques R et al, Reproductive Toxicology, 96: 399-412, September 2020
– Gold nanoparticles used for drug delivery could disrupt a woman’s fertility, press release, UW Milwaukee, February 2015: see academic article: Low-dose gold nanoparticles exert subtle endocrine-modulating effects on the ovarian steroidogenic pathway ex vivo independent of oxidative stress, Nanotoxicology, 8(8): 856-866, December 2014 – biological parameters associated with decreased fertility.

Nanomaterials could cause hormonal disruption²⁵See for example:
– Exposure to Zinc Oxide Nanoparticles Increases Estradiol Levels and Induces an Antioxidant Response in Antral Ovarian Follicles In Vitro, Santacruz-Márquez R et al., Toxics, 11(7):602, 2023
– Carbon Black Nanoparticles Selectively Alter Follicle-Stimulating Hormone Expression in vitro and in vivo in Female Mice, Avet C et al, Frontiers in Neuroscience 15:780698, December 2021
– Hormonal and molecular alterations induced by sub-lethal toxicity of zinc oxide nanoparticles on Oreochromis niloticus, Saudi Journal of Biological Sciences, 27(5): 1296-1301, May 2020
– Zinc oxide nanoparticles effect on thyroid and testosterone hormones in male rats, N M Luabi, N A Zayed, LQ Ali, Journal of Physics: Conference Series, 1 September 2019
– Maternal Engineered Nanomaterial Inhalation During Gestation Disrupts Vascular Kisspeptin Reactivity, Bowdridge EC et al, Toxicological Sciences, June 2019
– Isabelle Passagne, Silver nanoparticles: impacts at the level of glutamatergic transmissions and on hormonal regulation of reproductive function, ANSES Scientific Watch Bulletin, n°33, April 2018
– Silver nanoparticles disrupt regulation of steroidogenesis in fish ovarian cells, Degger N et al, Aquat Toxicol, 4;169:143-151, November 2015
– Engineered Nanomaterials: An Emerging Class of Novel Endocrine Disruptors, Larson JK et al, Biology of Reproduction, 91(1):20, 2014 and be considered endocrine disruptors²⁶See in particular:
Nanoparticles as Potential Endocrine Disruptive Chemicals, Gunjan Dagar & Gargi Bagchi, NanoBioMedicine, February 4, 2020
Engineered Nanomaterials: An Emerging Class of Novel Endocrine Disruptors, Larson JK, Carvan MJ, Hutz RJ, Biology of Reproduction, 91(1): 20, 2014).

Effects on the embryo and progeny

The small size and high mobility of nanos allow their passage into the reproductive organs but also through the placenta barrier (on which they can have adverse effects even before affecting the fetus / embryo²⁷See for example:
– Nanoparticles Dysregulate the Human Placental Secretome with Consequences on Angiogenesis and Vascularization, Dugershaw-Kurzer B et al., Advanced Science, 2024 : some nanoparticules (titanium dioxide, silica and diesel soot)  impair the release of chemical messengers in the placenta and thus the formation of blood vessels. Low birth weight, autism and respiratory diseases are among the possible consequences for the child.²⁸
– ²⁹Recent insights on indirect mechanisms in developmental toxicity of nanomaterials, Dugershaw BB et al, Particle and Fibre Toxicology, 17, 2020
– Maternal Engineered Nanomaterial Inhalation During Gestation Disrupts Vascular Kisspeptin Reactivity, Bowdridge EC et al, Toxicological Sciences, June 2019
– Gestational exposure to titanium dioxide nanoparticles impairs placentation through dysregulation of vascularization, proliferation and apoptosis in mice, Zhang L et al, Int J Nanomedicine, 13: 777-789, 2018). However, the effects of nanoparticles are worrying, both on the health of the fetus and embryo and on the offspring after birth (respiratory problems³⁰See for example:
– Effect of chronic prenatal exposure to the food additive titanium dioxide E171 on respiratory activity in newborn mice., Colnot E, O’Reilly J and Morin D, Frontiers in Pediatrics, 12:1337865, 2024
– Effect of chronic prenatal exposure to titanium dioxide nanoparticles on the development and function of respiratory nerve centers in newborn mice, Eloïse Colnot, PhD thesis in Neuroscience defended in December 2021 (in English : Chronic maternal exposure to titanium dioxide nanoparticles alters breathing in newborn offspring, Colnot E et al, Particle and Fibre Toxicology, 19:57, 2022)
– Pulmonary exposure to metallic nanomaterials during pregnancy irreversibly impairs lung development of the offspring, Paul E et al, Nanotoxicology, 11 (4): 484-495, 2017
– A perspective on the developmental toxicity of inhaled nanoparticles, Hougaard KS et al, Reproductive Toxicology, 11, June 2015cardiovascular problems and growth retardation³¹See for example:
– Effect of gestational age on maternofetal vascular function following single maternal engineered nanoparticle exposure, Fournier SB et al, Cardiovascular toxicology, 1-13, 2019: In rats, exposure to titanium dioxide nanoparticles in early gestation has a significant impact on the fetal circulatory system. Later exposure affects fetal growth
– Maternal engineered nanomaterial inhalation during gestation alters the fetal transcriptome, Stapleton PA et al, Particle and Fibre Toxicology, 15:3, 2018
–Maternal exposure to nanosized titanium dioxide suppresses embryonic development in mice, Hong F et al, Int J Nanomedicine, 12: 6197-6204, 2017, deleterious effects on the brain of the offspring³²See for example Maternal exposure to titanium dioxide nanoparticles during pregnancy and lactation alters offspring hippocampal mRNA BAX and Bcl-2 levels, induces apoptosis and decreases neurogenesis, Exp Toxicol Pathol., 5;69(6): 329-337, July 2017 : “The potential impact of nanoparticle exposure for millions of pregnant mothers and their offspring across the world is potentially devastating”).

Effects on the skin and dermal system

Nanos, widely used in cosmetics, come into direct contact with the skin, one of the largest organs of the human body.

There is evidence of skin sensitization caused by nanoparticles of silver and zinc oxides in particular³³See Prediction of Skin Sensitization Potential of Silver and Zinc Oxide Nanoparticles Through the Human Cell Line Activation Test, Gautam R et al, Front. Toxicol.May 2021 or copper nanoparticles³⁴Cf. Evaluation of the skin sensitization potential of metal oxide nanoparticles using the ARE-Nrf2 Luciferase KeratinoSens ^TM assay, Kim SH et al, Toxicol Res, 1;37(2):277-284, January 2021.

If the passage of nanos through the skin seems very limited on healthy skin, it is however likely on injured skin but, in view of current knowledge, in proportions that are probably very low, with associated risks that are less than those involved in exposure by inhalation or ingestion.

In view of the high presence of nanoparticles in cosmetics, further studies are nevertheless needed³⁵Evaluation of immunoresponses and cytotoxicity from skin exposure to metallic nanoparticles, Wang M et al, International Journal of Nanomedicine, 13, 2018 in particular to verify the absence of significant distribution of nanoparticles in the body after cutaneous application, especially in the case of frequent and chronic applications.

Note: dermatologists from Bichat and Rothschild Hospitals have observed the presence of titanium dioxide (TiO₂) along the hair follicles of a patient suffering from fibrosing frontal alopecia (hair loss at the top of the forehead) who had used sunscreens containing TiO2³⁶Cf. Sunscreen, nanoparticles and frontal alopecia, Synchrotron sun, February 2018.. However, this remains an isolated study and nothing seems to have been published on this subject since.

Differences in effects by gender and age

Differences in effects by gender

Differences in effects of nanoparticles depending on gender are still relatively unstudied, but should be in the coming years³⁷See for example:
– The role of sex as a biological variable in the efficacy and toxicity of therapeutic nanomedicine, Sharifi S et al, Advanced Drug Delivery Reviews, Volume 174, 337-347, July 2021
– Sex-Dependent Bioaccumulation of Nano Zinc Oxide and Its Adverse Effects on Sexual Behavior and Reproduction in Japanese Medaka, Paul V et al, ACS Applied Bio Materials, 4 (10) , 7408-7421, 2021.

A Quebec study in 2021 highlighted the fact that women’s cells are more affected than men’s cells by the inflammatory effects of nanoparticles³⁸Cf. Are the effects of nanoparticles on the body different in men and women, IRSST, December 2022 and Evaluating the Apoptotic Cell Death Modulatory Activity of Nanoparticles in Men and Women Neutrophils and Eosinophils, Vanharen M et al, Inflammation 45: 387-398, September 2021.

In 2023, French researchers found that gold nanoparticles in the food additive E175 caused stronger effects in female mice than in male mice (gut microbiota alterations likely to promote the worsening of metabolic disorders)³⁹A 90-day Oral Exposure to Food-grade Gold at Relevant Human Doses Impacts the Gut Microbiota and the Local Immune System in a Sex-dependent Manner in Mice, Evariste L et al, Particle and Fibre Toxicology, 20(27), July 2023⁴⁰.

The effects of TiO₂ administered orally also appear to be more detrimental to the cardiac and neurobehavioral abilities of young female rats⁴¹Oral administration of TiO2 nanoparticles during early life impacts cardiac and neurobehavioral performance and metabolite profile in an age- and sex-related manner, Mortensen NP, Particle and Fibre Toxicology, 19, 2022.

Differences in effects by age

There are few studies on the impact of age on the adverse effects of nanomaterials, but infants, children and the elderly are most likely to be more vulnerable to chronic exposure to nanos.

In addition to the effects observed in animals exposed in utero mentioned above, other animal studies (rats or mice) have shown that young individuals exposed to nanoparticles (_TiO2 for example) are more affected by their toxicity than adults⁴²See for example:
– The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice, Hu, H et al, About. Toxicol., 35, 443-456, 2019
– Susceptibility of Young and Adult Rats to the Oral Toxicity of Titanium Dioxide Nanoparticles, Wang, Y et al, Small 9, 1742-1752, 2013.

Researchers have observed more pronounced and/or persistent adverse effects in older rodents than in young or middle-aged individuals⁴³See for example:
– Adversities of Nanoparticles in Elderly Populations, Devi, A et al. in Kesari, K.K., Jha, N.K. (eds) Free Radical Biology and Environmental Toxicity. Molecular and Integrative Toxicology. Springer, Cham., 2021
– Exposure to _TiO2 Nanostructured Aerosol Induces Specific Gene Expression Profile Modifications in the Lungs of Young and Elderly Rats, Valentino S et al, Nanomaterials, 11, 1466, 2021
– Aging influence on pulmonary and systemic inflammation and neural metabolomics arising from pulmonary multi-walled carbon nanotube exposure in apolipoprotein E-deficient and C57BL/6 female mice, Youg TL et al, Inhalation toxicology, 2022
– Aggravated hepatotoxicity occurs in aged mice but not in young mice after oral exposure to zinc oxide nanoparticles, Wei Y et al, NanoImpact, 2016.

More nanos in the environment means more resistance to certain treatments

Nanomaterials are used for their bactericidal, fungicidal (toxic for fungi), antiviral properties⁴⁴for example:
Ayipo Y, et al, Recent advances on therapeutic potentials of gold and silver nanobiomaterials for human viral diseases, Current Research in Chemical Biology, Volume 2, 2022
– Gold nanoparticles capable of destroying viruses, EPFL, December 18, 2017
– Fighting respiratory viruses with the infinitely small, Time, February 2016 or even antiretroviral (HIV and hepatitis B for silver nanoparticles⁴⁵Nanosilver particles in medical applications: synthesis, performance, and toxicity, Ge L et al, Int J Nanomedicine, 9: 2399-2407, 2014). However, their large-scale use and dissemination in the environment could increase the resistance of bacteria and other pathogens⁴⁶See for example:
In French: Ecoconception de nouveaux agents biocides à base de nanoparticules d’argent à enrobage bio-inspiré, thesis by Marianne Marchioni, Grenoble Alpes, October 2018 (3.5 – “Mise en place de mécanismes de résistance à l’argent et aux nanoparticules d’argent”)
In English:
–Impact of engineered nanoparticles on the fate of antibiotic resistance genes in wastewater and receiving environments: A comprehensive review, Cui H and Smith AL, Environmental Research, 204, D, March 2022
– Bacterial resistance to silver nanoparticles and how to overcome it, Nature Nanotechnology, Panáček A et al, 13, 65-71, December 2017-
– Widespread and Indiscriminate Nanosilver Use: Genuine Potential for Microbial Resistance, Gunawan C et al, ACS Nano, 2017 and Rampant use of antibacterial nanosilver is a resistance risk, Physorg, (press release) March 2017
– Nanosilver: Safety, health and environmental effects and role in antimicrobial resistance, Hartemann P et al, Materials Today, 18(3): 122-123, April 2015
– Opinion on Nanosilver: safety, health and environmental effects and role in antimicrobial resistance, SCENIHR, June 2014.

In 2021, researchers from the University of Pittsburgh (USA), like others before them, warned against the widespread use of silver nanoparticles in consumer products (washing machines, textiles, paints, etc.) and reminded us that the use of silver nanoparticles should be reserved for medical applications only in order to limit bacterial resistance⁴⁷Cf. Are silver nanoparticles a silver bullet against microbes?”, University of Pittsburgh, July 13, 2021 and Role of bacterial motility in differential resistance mechanisms of silver nanoparticles and silver ions, Stabryla LM et al, Nature Nanotechnology, June 2021.

Early 2022 again, Australian scientists this time warned about the increased resistance of bacteria generated by silver nanoparticles and the negative impact on both the environment and human health⁴⁸The impact of silver nanoparticles on microbial communities and antibiotic resistance determinants in the environment, Yonathan K et al, Environmental Pollution, 293, January 2022.

“Trojan horse effect” and “cocktail” effect

In addition to the toxic effects that they can directly cause within the bacterial species, cells and organisms in which they can penetrate, nanomaterials can bring in external molecules. This is the“Trojan horse” effect; it is therefore feared that they may promote the transport of other contaminants – heavy metals or pesticides attached to their surface, for example⁴⁹See in particular:
– Mechanistic study of the adsorption and penetration of modified _SiO2 nanoparticles on cellular membrane, Yuan S et al, Chemosphere, 294, May 2022
– Like a Trojan horse, graphene oxide can act as a carrier of organic pollutants to fish, Campusa (University of the Basque country), May 2021 and Uptake and effects of graphene oxide nanomaterials alone and in combination with polycyclic aromatic hydrocarbons in zebrafish, Martinez-Alvarez I et al, Science of The Total Environment, 775, June 2021
– Dussert F et al., Toxicity to RAW264.7 Macrophages of Silica Nanoparticles and the E551 Food Additive, in Combination with Genotoxic Agents, Nanomaterials, MDPI, 10 (7): 1418, 2020: Silica nanoparticles are likely to carry genotoxic agents on their surface which leads to aggravate their adverse effects on DNA
– Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells, Particle and Fibre Toxicology, 11:14, 2014
– Association of Hg2+ with Aqueous (C60)n Aggregates Facilitates Increased Bioavailability of Hg2+ in Zebrafish (Danio rerio), About. Sci. Technol., 47 (17), pp 9997-10004, July 2013, an obvious problem.

Moreover, the interactions between nanomaterials and other pollutants are difficult to identify and control and can give rise to reactions that are even more undesirable than the sum of the toxicities of the nanomaterials and pollutants taken in isolation. We talk about a “cocktail” effect and a scientific corpus is beginning to be built on those involving nanomaterials⁵⁰See for example:
– Zinc oxide, titanium dioxide and _C60 fullerene nanoparticles, alone and in mixture, differently affect biomarker responses and proteome in the clam Ruditapes philippinarum, Marisa I et al, Science of the Total Environment, 838 (2), September 2022
– Nanoplastics enhance the toxic effects of titanium dioxide nanoparticle in freshwater algae Scenedesmus obliquus, Das S et al, Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 256, June 2022
– Combined lead and zinc oxide-nanoparticles induced thyroid toxicity through 8-OHdG oxidative stress-mediated inflammation, apoptosis, and Nrf2 activation in rats, Khayal EE et al, Environmental Toxicology, 36(12): 2589-2604, 2021
– Effects of Co-Exposure of Nanoparticles and Metals on Different Organisms: A Review , Abd-Elhakim YM et al, Toxics, 9 (11), 284, 2021
– Metallic nanoparticles and endocrine disruptors: Impact on endocrine functions of metallic nanoparticles alone and in mixture with endocrine disrupting organic compounds for the analysis of the cocktail effect, Aurélien Deniaud The Research Papers. Health, Environment, WorkANSES, Microplastics and nanomaterials, 2021
– Effects of co-exposure of BaP with nanoparticles: Effects of B(a)P alone or in co-exposure with nanoparticles and involvement of the Ah receptor (or AhR) in the integrity and function of two physiological barriers: bronchopulmonary and placental, Xavier Coumoul, The Research Papers. Health, Environment, WorkANSES, Microplastics and nanomaterials, 2021
– Co-exposure to the food additives SiO2 (E551) or TiO2 (E171) and the pesticide boscalid increases cytotoxicity and bioavailability of the pesticide in a tri-culture small intestinal epithelium model: potential health implications, Cao X e al, Environmental Science: Nano, 9, 2019
– Are gold nanoparticles and microplastics mixtures more toxic to the marine microalgae Tetraselmis chuii than the substances individually?, Davarpanah E, Guilhermino L, Ecotoxicology and Environmental Safety, 181: 60-68, October 2019
– Mixture toxicity effects and uptake of titanium dioxide (TiO2) nanoparticles and 3,3′,4,4′-tetrachlorobiphenyl (PCB77) in juvenile brown trout following co-exposure via the diet, Lammel T et al, Aquat Toxicol, 213:105195, August 2019
– Parental co-exposure to bisphenol A and nano-TiO2 causes thyroid endocrine disruption and developmental neurotoxicity in zebrafish offspring, Science of the total environment, Guo Y et al, 650(1): 557-565, February 2019
– TiO2 nanoparticles enhance bioaccumulation and toxicity of heavy metals in Caenorhabditis elegans via modification of local concentrations during the sedimentation process, Wang J et al, Ecotoxicology and Environmental Safety, 162(30): 160-169, October 2018
– Nanoparticles would be even more harmful than previously thought, Maxisciences, August 2018 (and in English: Co-exposure to silver nanoparticles and cadmium induces metabolic adaptation in HepG2 cells, Miranda RR et al, Nanotoxicology, July 2018)
– Nanoparticle interactions with co-existing contaminants: joint toxicity, bioaccumulation and risk, Deng R et al, Nanotoxicology, 11:5, 591-612, 2017
– Influence on the toxic effects of simultaneous exposure to nanoparticles and metals, Chakroun R., Science Watch Bulletin No. 30, ANSES, October 2016
– What interactions between nanoparticles and other environmental contaminants, Camille Larue, Bulletin de veille scientifique (BVS), Anses, December 2014.

What mechanisms explain the toxicity of nanomaterials?

Toxicity of nanomaterials may be the result of:

• the production of free radicals (reactive oxygen species: ROS), the most frequently demonstrated, including at a distance from the nanomaterials (in particular for metal oxides): these free radicals cause oxidative stress

Aggregates are not necessarily less toxic than primary nanoparticles

Since 2020, research results from Belgium have been published showing that aggregates larger than 100 nm should not necessarily be considered less toxic than their nanometric counterparts, whether they are silica nanoparticles⁵¹Cf. Assessing the Toxicological Relevance of Nanomaterial Agglomerates and Aggregates Using Realistic Exposure In Vitro, Murugadoss S et al, Nanomaterials, 11, 1793, 2021 and Is aggregated synthetic amorphous silica toxicologically relevant, Murugadoss S et al, Particle and Fibre Toxicology, 17(1), 2020 or titanium dioxide nanoparticles⁵²Cf. Agglomeration of titanium dioxide nanoparticles increases toxicological responses in vitro and in vivo, Murugadoss S et al, Particle and Fibre Toxicology, 17(10), 2020.

What actions should be taken to address these health risks?

Because of all these “delayed-effect” risks and uncertainties, there is an urgent need for not only research efforts (with a financial contribution from companies who produce and use nanomaterials) and also information and training actions (for health professionals but also for public and private decision makers), as well as concrete measures of prevention and precaution.

Action 13 of the National Health and Environment Plan (PNSE 4) published in 2021 is in line with this, but there is much to do, with little time and money.

Everyone has a role to play: residents, consumers, researchers, associations, unions, public authorities, companies, health professionals, media, etc. AVICENN does its part… help us speed things up