What are the health risks of nanos?

What are the health risks of nanos?

By AVICENN Team – Last Modified December 2022

Fruit of 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 of which have harmful effects on our body, which is not necessarily well equipped to deal with it. With lead, mercury, DDT, pesticides, endocrine disruptors, etc. have been added manufactured nanoparticles, which, due to their small size, can penetrate and then spread throughout the body, without their effects on living beings having been evaluated in an exhaustive and systematic manner.

Coupled with their small size, their increased reactivity makes nanomaterials likely to elicit 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 the response listed below will be supplemented as scientific knowledge on the subject advances. And plead for greater vigilance to minimize increasing, repeated and continuous exposure to engineered nanomaterials.

Effects still relatively unknown

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

• the effects of nanomaterials are very different from one nanomaterial to another because they are highly dependent on physico-chemical characteristics nanomaterials; like the form for example; so 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 which protects the brain²See Can the brain's gatekeeper fight a nano-attack?, E/ Valsami-Jones, EUON, September 2022: “Each nanoparticle tested showed a range of behaviors, 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, in particular the acidity or the salt content of the various biological fluids (blood, lymph, saliva, gastric juice, mucus, etc.)
  
• because of their small size and the transformations they undergo during their journey through the body, nanoparticles are difficult to detect, quantify, characterize and track in the human body and into cells. But significant progress in measurement tools now make possible the essential advance in knowledge, not only in animals but also in humans³See Nanotoxicology: the need for a human touch?, Miller M & Poland C, SmallJuly 2020.

The effects highlighted by scientific studies

In a context of increasing exposure (whether by inhalation, ingestion or dermal application), the scientific literature highlights many potential adverse health effects… which however differ according to the chemical nature of the nanos, their size, their shape and other physico-chemical parameters. It is therefore difficult to generalize the harmful effects, however we can list a certain number of effects, at the cellular level but also at the level of the major different "systems" of the human body.

Effects on cells (cytotoxicity)

The approaches vitro do not reflect the conditions of real exposure of an entire 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 elderly, gestation, sick, etc.) but they make it possible to identify the possible response mechanisms of cells to exposure to nanomaterials. Thus, some nanoparticles can negatively impact the morphology and functioning of cells, even calling into question their viability.

Nanomaterials, due to their small size, can alter the cell membrane⁴See 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 be brought to interact with the various components of the cell, causing possible DNA damage or rearrangements, altered gene expression (see below), oxidative stress or cell inflammation . 

Ultimate stage, cell death (apoptosis) has been observed in various categories of cells (epithelial, hepatocytes, etc.) after exposure to different types of nanomaterials (such as carbon nanotubes, quantum dots, fullerenes, or nanoparticles of gold or TiO₂)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 Toxicol Fiber, 7, 10, 2010.

DNA damage (genotoxicity)

Studies show that nanomaterials can lead to DNA disruptions⁶See for example:
-Advances in genotoxicity of titanium dioxide nanoparticles in vivo and vitro, ShiJ et al., Nano Impact, 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 Mutagenesis, May 15, 2020: this review of the scientific literature, carried out by CEA researchers, shows that particles of titanium dioxide (TiO2), of nanometric and microscopic size, cause DNA damage on various types of cells, lungs and intestines, 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 sunscreen), 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 insofar as the DNA has a width of the order of 2 nm. On the other hand, it is relatively worrying, insofar as these DNA disturbances are likely to lead to:

• cancerous mutations if the damage is not, or poorly, repaired (DNA damage and mutations are usually the first step towards cancer, two or three mutations can be enough to trigger 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 nanomaterials⁷See Common Considerations for Genotoxicity Assessment of Nanomaterials, Elespuru RK et al., Forehead. Toxicology., 4:859122, 2022.

Effects on the immune system (immunotoxicity)

Certain nanomaterials seem to be able to increase or lead to disturbances of the immune system 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 defense, 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, Janvier 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, Labor, ANSES, 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. Science. 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 Fiber 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 during repeated exposure
- Immunotoxicity of nanoparticles, Brousseau P et al., speech at the 83rd Acfas Congress, Colloquium 210 – Presence, persistence, fate and effects of nanomaterials in the environment, May 2015 : inflammatory reactions, immunostimulation, immunosuppression or even autoimmune reactions. 

Immunity cells (such as macrophages for example) do not necessarily succeed in eliminating nanomaterials and may themselves find themselves degraded or even eliminated.

In organisms whose immune system is already weak, the harmful effects of nanomaterials seem to be accentuated. Research carried out in Switzerland, for example, has shown that nanoparticles of TiO₂ could aggravate the inflammation suffered by people with inflammatory bowel disease (IBD)⁹See Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome, Ruiz PA et al. good, 66: 1216-1224, 2017.

Effects on the brain and nervous system (neurotoxicity)

Damage to brain functions 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, Forehead. 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 from 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 rat, Nicolosi A et al., Neurotoxicology, 67, 150-160, July 2018)
- 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 SJS Chapter 8—The applications, neurotoxicity, and related mechanism of gold nanoparticles. In: Jiang X., Gao H., editors. Neurotoxicity of Nanomaterials and Nanomedicine. AcademicPress; Cambridge, MA, USA: 179–203, 2017
-  Nanoparticles and the brain: state of play, Anna Bencsik, J3P, October 2016
- Is the brain immune to the impact of exposure to nanomaterials?, 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 the direct or indirect effects of cognitive problems, memory and learning disorders, degeneration of nerve cells or even neuronal death and brain damage, a drop in locomotor capacities… So many deleterious effects likely to promote or accelerate neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases for example.

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

Effects on the lungs and respiratory system

Like the so-called “ultra-fine” particles (UFP) of air pollution, certain manufactured nanomaterials can cause deleterious effects on the lungs¹¹See 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, October 17, 2019
- " Nanoparticles and respiratory diseases: where is our knowledge?“, Conference 5 to 7, December 2017, led by Doctor Fabrice Nesslany – Director of the genetic toxicology laboratory at the Institut Pasteur de Lille and Dr Patricia de Nada.
Macrophages (essential in the defense against infectious agents) do not always manage to eliminate nanomaterials, the accumulation of which in the lungs can ultimately cause or aggravate chronic respiratory pathologies (asthma, chronic obstructive pulmonary disease) or even very severe lung infections such as after exposure to asbestos or silica (pleural plaques, lung cancer).
Long, stiff carbon nanotubes in particular raise concerns about their ability to induce asbestos-like lung reactions¹²See our file Risks associated with carbon nanotubes and titanium dioxide particles, classified as a category 2 carcinogen by inhalation, are potentially even more to be feared at the nanoscale¹³See our file Risks associated with titanium dioxide nanoparticles.

The greatest concerns concern personnel exposed to manufactured nanoparticles at their workplace, because this professional exposure is added to the exposure experienced by the general population through air pollution and, to a lesser extent , the release of nanos from everyday consumer products.

In France, the INRS has been working on this subject for years¹⁴recently via the European project SmartNanoTox (2016-2020) and other research is in progress, in France¹⁵See for example:
- the project NanoLily funded by the ANR (2018-2022) on "lysosomal dysfunction in the respiratory toxicity of nanoparticles"
- the project "Nanomuc” selected in 2021 by ANSES on the interactions and their toxicological consequences between nanoparticles and the mucus of the lung, essential in the defense against environmental attacks 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, which may increase the risk of heart attack.

Researchers from 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 heart attack; even a limited number of these nanoparticles can have serious consequences¹⁶See Inhaled Nanoparticles Accumulate at Sites of Vascular Disease, Miller MR et al., DHW Nano 2017.  

Other researchers in Italy showed in 2019 that inhaling titanium dioxide nanoparticles in people with hypertension induces irreversible (hemodynamic) blood flow impairment, associated with cardiac damage that can lead to heart failure.¹⁷See Subchronic exposure to titanium dioxide nanoparticles modifies cardiac structure and performance in spontaneously hypertensive rats, Rossi S et al., Particle and Fiber Toxicology, 16:25, 2019.

A review of the literature on the cardiovascular risks associated with silica nanoparticles, published in 2021, reports as possible effects an increase in blood pressure, dyslipidemia (very high concentration of lipids in the blood), arrhythmia (irregularity of heart rate), a risk of thrombosis (clot that obstructs a blood vessel), atherosclerosis (formation of atherosclerotic plaques in the arteries), ischemia or even myocardial infarction¹⁸See Adverse effects of amorphous silica nanoparticles: Focus on human cardiovascular health, Guo C et al., Journal of Hazardous Materials, 406(15), 124626, 2021.

Worsening of symptoms of myocardial infarction has also been observed for zinc nanoparticles¹⁹See 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.

An increased risk of thrombosis by silver nanoparticles was demonstrated in 2022 in mice suffering from hypertension²⁰See 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 appearance, color or texture of the latter, nanos can also be present for their bactericidal properties (silver, zinc, titanium, etc.) with potentially deleterious effects on the intestinal flora (it is itself composed of bacteria whose reduction or even destruction disrupts proper functioning).
The effects of nanoparticles of silver, silica, titanium dioxide, iron oxide and zinc oxide 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, Metal., Int. J.Mol. science., 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 Fiber Toxicology, 17:19, 2020 : irritable bowel syndrome, inflammatory bowel disease, celiac disease, colorectal cancer…

Effects on fertility and offspring

Although studies are still lacking²²In 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 capacities. see 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, we can fear that the nanos disturb the reproduction and the good development of the following generations:

Effects on Reproductive Organs, Hormones and Fertility

Some studies report toxicity of nanoparticles to the male reproductive system²³See for example:
- Silica nanoparticles cause spermatogenesis dysfunction in mice via inducing cell cycle arrest and apoptosis, Life 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(disruption of testosterone production, decline in sperm quality and quantity) and female²⁴See for example:
- Ovarian toxicity of nanoparticles, Santacruz-Marquez 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 the 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 a decrease in fertility.

Nanomaterials could lead to hormonal disruptions²⁵See for example:
- 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, NM Luabi, NA Zayed, LQ Ali, Journal of Physics: Conference Series, September 1, 2019
- Maternal Engineered Nanomaterial Inhalation During Gestation Disrupts Vascular Kisspeptin Reactivity, Bowdridge EC et al., Toxicological SciencesJune 2019
-Isabelle Passagne Silver nanoparticles: impacts on glutamatergic transmissions and on the hormonal regulation of the reproductive function, Scientific watch bulletin from ANSES, 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 offspring

The small size and high mobility of nanos allows them to pass through the reproductive organs but also through the placental barrier (and on which the latter can have harmful effects even before affecting the fetus / embryo²⁷See for example:
- Recent insights on indirect mechanisms in developmental toxicity of nanomaterials, Dugershaw BB et al., Particle and Fiber Toxicology, 17, 2020
- Maternal Engineered Nanomaterial Inhalation During Gestation Disrupts Vascular Kisspeptin Reactivity, Bowdridge EC et al., Toxicological SciencesJune 2019
- Gestational exposure to titanium dioxide nanoparticles impairs the 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 both on the health of the fetus and the embryo (effects, etc.) and on the offspring after birth (respiratory problems²⁸See for example:
- Effect of chronic prenatal exposure to titanium dioxide nanoparticles on development and function of respiratory nerve centers in newborn mice, Eloïse Colnot, Doctoral 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 Fiber 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 2015, cardiovascular problems and growth retardation²⁹See for example:
- Effect of gestational age on maternal vascular function following single maternal engineered nanoparticle exposure, Fournier SB et al., Cardiovascular toxicology, 1-13, 2019: In rats, exposure to titanium dioxide nanoparticles during early gestation has a significant impact on the circulatory system of the fetus. Later exposure affects fetal growth
- Maternal engineered nanomaterial inhalation during gestation alters the fetal transcriptome, Stapleton PA et al., Particle and Fiber 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 offspring³⁰See 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”) are of particular concern.

Effects on the skin and the dermal system

the nanos, widely used in cosmetics, find themselves in direct contact with the skin, one of the largest organs of the human body.

Data show skin sensitization caused by nanoparticles of silver and zinc oxides in particular³¹See Prediction of Skin Sensitization Potential of Silver and Zinc Oxide Nanoparticles Through the Human Cell Line Activation Test, Gautam R et al., Forehead. Toxicol.May 2021 or copper nanoparticles³²See 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 you passage of nanos through the skin seems very limited on healthy skin, it is on the other hand probable on damaged skin but, in the light of current knowledge, in proportions which are undoubtedly very low, with associated risks less than those implied by exposure by inhalation or ingestion.

In view of the strong presence of nanoparticles in cosmetics, additional studies are nevertheless necessary.³³Evaluation of immunoresponses and cytotoxicity from skin exposure to metallic nanoparticles, Wang M et al., International Journal of Nanomedicine, 13, 2018in particular to verify the absence of significant distribution of nanoparticles in the body after cutaneous application, especially in the event of frequent and chronic applications.

Note: dermatologists from Bichat and Rothschild Hospitals have observed the presence of nanoparticles of titanium dioxide (TiO₂) along the hair follicles of a patient with frontal fibrosing alopecia (hair loss above the forehead) who had used sunscreens containing TiO15 daily for 2 years³⁴See Sunscreen, nanoparticles and frontal alopecia, Sun Synchrotron, February 2018. However, this remains an isolated study and nothing has apparently been published since on this subject.

Differences in effects according to gender and age

Gender differences in effects

The differences in health effects of nanoparticles according to gender are still relatively understudied, but should be more so in the years to come.³⁵See 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 nanoparticles³⁶See 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., I, 45: 387–398, September 2021.

In 2022, other researchers found that the gold nanoparticles present in the food additive E175, for example, cause more marked effects in female mice than in male mice.³⁷See A 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 Fiber Toxicology, 2022 (in review).

The effects of TiO nanoparticles₂ administered orally also seem to be more harmful to the cardiac and neurobehavioral capacities of young female rats³⁸See Oral 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 Fiber Toxicology , 19, 2022.

Differences in effects according to age

Few studies focus on the impact of age on the adverse effects of nanomaterials, but infants, children and the elderly are most likely more vulnerable in the event of chronic exposure to nanomaterials.

In addition to the effects observed on animals exposed in utero mentioned above, other animal studies (rats or mice) have shown that young individuals exposed to nanoparticles (from TiO₂ for example) are more affected by their toxicity than adults³⁹See 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 more persistent adverse effects in older rodents than in young or middle-aged individuals⁴⁰See for example:
- Adversities of Nanoparticles in Elderly Populations, Devi, A et al. in Kesari, KK, Jha, NK (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., Nano Impact, 2016.

Who says more nanos in the environment says more resistance to certain treatments

Nanomaterials are used for their bactericidal, fungicidal (toxic to fungi), antiviral properties⁴¹See for 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 thanks to the infinitely small, Le temps, February 2016 or even antiretrovirals (HIV and hepatitis B for silver nanoparticles⁴²See Nanosilver 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 pathogens⁴³See for example: 
In French : Ecodesign of new biocidal agents based on silver nanoparticles with bio-inspired coating, thesis by Marianne Marchioni, Grenoble Alpes, October 2018 (3.5 – “Establishment of mechanisms of resistance to silver and silver nanoparticles”)
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., DHW 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., MaterialsToday, 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) thus, like others before them, warned against the widespread use of silver nanoparticles in consumer products (washing machines, textiles paints, etc.) and reminded that the use of silver nanoparticles must be reserved for medical applications only in order to limit bacterial resistance⁴⁴See 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 NanotechnologyJune 2021.

At the beginning of 2022 again, Australian scientists this time alerted to the increased resistance of bacteria generated by silver nanoparticles and the negative impact on both the environment and human health.⁴⁵See The 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 cause directly within the bacterial species, cells and organisms into which they can penetrate, nanomaterials can bring in external molecules. It's'Trojan horse effect ; it is therefore feared in particular that they promote the transport of other contaminants – heavy metals or pesticides attached to their surface for example⁴⁶See 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 aggravating their harmful 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 Fiber Toxicology, 11:14, 2014
- Association of Hg2+ with Aqueous (C60)n Aggregates Facilitates Increased Bioavailability of Hg2+ in Zebrafish (Danio rerio), About. Science. Technology., 47 (17), pp 9997-10004, July 2013which is problematic.

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 nanos and pollutants taken in isolation; then we're talking aboutcocktail effect » with a scientific corpus that is beginning to build up on those involving nanomaterials⁴⁷See 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 the endocrine functions of metallic nanoparticles alone and in mixture with endocrine disrupting organic compounds for the analysis of the cocktail effect, Aurelien Deniaud, The Research Papers. Health, Environment, Labor, ANSES, Microplastics and nanomaterials, 2021
- The effects of BaP co-exposure with nanoparticles: Effects of B(a)P alone or in co-exposure with nanoparticles and involvement of the Ah (or AhR) receptor in the integrity and function of two physiological barriers: broncho -pulmonary and placental, Xavier Coumoul, The Research Papers. Health, Environment, Labor, ANSES, 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 et 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, Aug 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, Feb 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, Oct 2018
- Nanoparticles Are Even More Harmful Than We Thought, Maxisciences, August 2018 (and in English: Co-exposure to silver nanoparticles and cadmium induce 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., Scientific watch bulletin No. 30, ANSES, October 2016
- What interactions between nanoparticles and other environmental contaminants?, Camille Larue, Scientific watch bulletin (BVS), ANSES, December 2014.

What mechanisms explain the toxicity of nanomaterials?

The toxicity of nanomaterials can be the result of:

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

Aggregates are not necessarily less toxic than primary nanoparticles

Since 2020, the results of research carried out in Belgium have been published showing that aggregates larger than 100 nm should not be considered as necessarily less toxic than their nanometric counterparts, whether they are silica nanoparticles⁴⁸See 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 Fiber Toxicology, 17 (1), 2020 or titanium dioxide nanoparticles⁴⁹See Agglomeration of titanium dioxide nanoparticles increases toxicological responses in vitro and in vivo, Murugadoss S et al., Particle and Fiber Toxicology, 17 (10), 2020.

Faced with these health risks, what actions?

Because of all these “delayed effects” risks and all these uncertainties, it is urgent to deploy not only research efforts (with a financial contribution from companies who produce and use nanomaterials) but also information and training actions (for health professionals but also public and private decision-makers), as well as concrete preventive and precautionary measures.

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

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