Plastic pollution has long been one of the top environmental issues due to its abundance and persistence in the aquatic environment, which threatens to double over the next 20 years in a business-as-usual scenario (1), whether it slowly degrades to or is released into the environment as industrial plastic micro- and nanoparticles (PMNPs) (e.g., paints, adhesives, electronics, and cosmetics) (2,3,4,5,6).
Chronic exposure to plastic particles raises great concern for all life, as we interact with them without completely understanding how they affect our planet and much less our bodies through the food chain and surface or even drinking water (3,4,5,6,7,8,9,10). The smaller they are the more easily they penetrate blood, endothelial, intestinal, blood-brain, and blood-placental barriers to reach and accumulate in tissues and organs with different adverse outcomes. Their uptake by different body compartments also depends on their shape and surface chemistry (11).
Because of the ubiquity of plastic materials and their toxic potential, it is imperative to gather reliable, regulatory-relevant, and science-based evidence on how PMNPs affect human health to properly assess and manage risks in the context of circular economy. The main regulatory pathways to collect such data should follow the Integrated Approaches to Testing and Assessment (IATA) supported by the adverse outcome pathway (AOP) concept (12, 13). In 2019, the World Health Organization (WHO) reviewed the state of evidence on PMNPs in drinking water (14), while the European Commission adopted its strategy for plastics in a circular economy in 2018 (15). However, the main challenge is the lack of sensitive analytical methods to detect and quantify PMNPs in different biological and environmental matrices. It is impossible to assess PMNP exposure, toxicokinetics, and toxicodynamics without measuring the number and concentration of particles that reach and accumulate in biological fluids, cells, tissues, and organs. So far, dose-response data in humans are very scarce.
This review aims to synthesise current knowledge on PMNP exposure doses, pathways, and health effects in humans. We also highlight current knowledge gaps and the challenges in assessing plastic exposure and bring recommendations for the development of PMNP-specific AOPs based on the existing scientific evidence on PMNP adverse health effects.
The first step towards collecting current science-based evidence of PMNP effects on human health was a comprehensive literature search across the Web of Science Core Collection (WoSCC) database, using the search phrase “(micro OR nano) AND (plast*) AND (tox*) AND (“
In addition to the literature search in the WoSCC database, we reviewed information in the AOP-Wiki (16) to identify AOPs that may be associated with the health effects reported for PMNPs. This work was based on comparing adverse effects reported in the 43 WoSCC papers (Figure 1) with molecular initiating events (MIEs) or key events (KEs) described in the AOP-Wiki for different AOPs. The value of the AOP framework lies in the fact that AOPs are not specific for particular stressors but can define downstream PMNP effects if proper MIEs or KEs are identified. AOPs can facilitate risk assessment and management by placing mechanistic knowledge in hazard characterisation in a specific regulatory context (17, 18).
Flow chart of literature search in the Web of Science Core Collection (WoSCC) database
Moreover, identifying AOPs relevant for PMNPs can further inform the choice of the most suitable assays for assessing specific adverse outcomes (19). As already demonstrated by several IATA OECD case studies describing AOPs for non-genotoxic carcinogens, skin sensitisation, chemical-induced liver steatosis, and neural development (17), implementation of the AOP framework may improve non-animal
Data on routes of human exposure (Figure 2) show that inhalation and ingestion are much more relevant for PMNP uptake than the transdermal route (20, 21). There are many sources of inhalation exposure, depending on the type of contamination of indoor and outdoor air. Inhaled PMNPs can translocate into the lung tissue or enter the digestive system via mucociliary clearance (7, 22, 23). Oral uptake is mostly owed to contamination of bottled drinks or different food items including table salt (24, 25). PMNPs can also contaminate food during food processing and packaging.
Human exposure routes to plastic micro- and nanoparticles in humans (created with BioRender. com)
For all exposure routes, the mechanism of uptake depends on PMNP size, shape, solubility, and surface characteristics as well as on biological factors, such as the site of particle deposition (7, 26). Depending on the size, PMNPs can spread through passive diffusion, paracellular transfer, or active cellular uptake (7), which also depends on the cell type, e.g., Peyer’s patches in the intestine or alveolar macrophages in the lung (7, 27). Even though dermal contact accounts for a relatively small fraction of PMNP uptake, some studies suggest that PMNPs can be absorbed through hair follicles and sweat ducts, which could lead to systemic exposure (28,29,30).
Estimations of PMNP intake by humans significantly vary between studies (Table 1) and depend on the type of PMNP and exposure route(s) considered by a particular study. For example, individual dietary PMNP intake in the USA is estimated to 39,000–52,000 particles per year, while the total intake increases to 74,000–121,000 particles per year if we include the inhalation route (31). It is important to note that all estimations presented in Table 1 are based on limited data and may not be representative of a specific population or geographic region. Furthermore, reliable, accurate, and precise methods for identification, characterisation, and quantification of PMNPs in complex matrices like environmental and biological samples are still scarce (8, 14, 15, 20, 32). This problem is especially frustrating for the development and implementation of particle dosimetry in PMNP risk assessment and management whose aim is to quantify the number of plastic particles in a particular analytical sample.
Overview of human-relevant exposure pathways for plastic micro- and nanoparticles with numerical data for levels of intake where available
Ecotoxicity, human cells, humans | Ingestion route: 11,000 particles from shellfish, 4000 particles from drinking water, and 7–1000 particles from edible sea salt per person per year | (36) |
Ecotoxicity, human cells, humans | Ingestion route. Sources: seafood, tea bags, honey, sugar, beverage drinks, commercial salts, milk, beer, tap and bottled drinking water | (37) |
Ecotoxicity, humans | Ingestion sources: drinking water, food containing plastic particles or weathering from plastic containers, salts and honey, and beer | (5) |
Ecotoxicity, human cells and exposure | Ingestion through the food chain | (27, 31, 38,39,40,41,42,43,44,45) |
Human exposure | Ingestion route: ≤30 particles/day from tap water and beverages, 37–100 particles/year from sea salt; in total ≤250 pg/kg body weight per day for an adult from tap water, beverages, and sea salt | (11) |
Rodent model | 5-day oral exposure to 60 nm polystyrene particles: 10 % of the dose found in the gastrointestinal tract | (46) |
Exposure experiments with red blood cells, peripheral blood mononuclear cells, and mast cells | (47) | |
Exposure experiments with intestinal epithelial cell lines, LS174T, HT-29, and CaCo-2 | (22, 48) | |
/ | (49) | |
Invertebrates and vertebrates | Exposure through the food chain | (50) |
Exposure experiments with epithelial HeLa and cerebral T98G cells | (51) | |
Ingestion route: 12,000–204,000 particles per person per year via plastic-contaminated seafood (fish and shellfish), beer, table salt, sugar, and honey | (52) | |
Annual ingestion: 123,000 particles for adults (714 mg/day), 81,000 particles for children (449 mg/day). | (53) | |
Ingestion via the food chain | (54, 55) | |
Human exposure | Annual ingestion: 11,000 particles from shellfish for European top consumer. Ingestion sources: 50.97 particles/L of beer, 24.53 particles/L of soft drinks, 5.79 particles/L of energy drinks, 5.26 particles/L of cold tea, 3 to 11 particles/L of milk; the highest mean concentrations of particles from drink consumption in the US (9.24–11.8 particles/L) and the lowest in Germany (0.91–1.29 particles) | (56) |
The primary route of exposure: ingestion of food and water contaminated with PMNP; annual consumption of 39,000 and 52,000 particles per person in the US | (57) | |
Ingestion of PMNP does not provide a significant contribution to the transfer of absorbed chemicals from the water to the biota via the gut | (10) | |
The oral bioavailability of 50 nm-sized polystyrene particles differs between 0.2 and 2 % in rodents ( |
(58) | |
Estimated exposure from the consumption of |
(59) | |
Annual ingestion via shellfish: 11,000 particles for the European population. It is also reported that a regular consumer of sea salt ingests approximately 37 synthetic fibres daily | (60) | |
Estimated exposure for adults: 258 to 312 particles daily | (26) | |
Uptake of ≤0.144 % of polystyrene microparticles across the Caco-2 monolayer | (2, 61) | |
Absorption of more than 70 % of nanoparticles with a significant reduction of rate to 30–50 % for microparticles | (62) |
Due to the resistance of plastic materials to degradation, bioaccumulation should be considered a serious health issue, as inhaled and ingested plastic particles may remain in different tissues for long and cause chronic health effects (28,29,30, 33). Deng et al. (34) reported that plastic microparticles in the liver, kidney, and gut tissue accumulate in a range of 0.07–0.41 mg of plastic material per gram of tissue. Another animal study (23) reported very low accumulation in the intestinal cell layer and no plastic materials in the liver, spleen, or kidney. Unfortunately, most studies report difficulties in properly assessing the toxicokinetic/toxicodynamic profiles of PMNPs (35).
According to the reviewed scientific literature (Figure 1), PMNPs may cause various detrimental effects on cell viability, inflammatory response, lipid metabolism, oxidative status, intestinal microbiota, ion transport, signalling pathways, DNA integrity, hepatic function, and more. Table 2 lists the reported PMNP effects on human and animal cells and tissues. The sheer number of different adverse health effects following exposure to PMNPs raises concern about the ever-increasing plastic pollution.
Science-based evidence of adverse health effects of plastic micro and nanoparticles (PMNP)
Ecotoxicity, human cells, human exposure | PE-, PS, PVC-, PET- and PLGAMPs; PS-NPs | Reactive oxygen species (ROS) production (63, 64), activation of antioxidant enzymes (50), increase in glutathione S-transferase (GST) activity (65) and mitogen-activated proteins kinase signalling pathways (66), a decline in lipid digestion and inhibition of digestive enzymatic activities (67), impact on the cell morphology and cell proliferation of immune cells (68, 69) | (36) |
Ecotoxicity, human cells, human exposure | PE- and PS-MPs | DNA damage via oxidative stress, distortion of cellular proteins involved in cell division, an aberration in signalling responses, down-regulation of transcriptional genes related to apoptotic expressions (70), increased DNA fragmentation in liver tissue, altered activity of antioxidant enzymes and increased lipid peroxidation (71, 72) | (37) |
Ecotoxicity, human cells | PS-MPs; PS-NPs | Disturbance in lipid metabolism, oxidative stress and neurotoxicity (34), aggregation of serum proteins (73) | (5) |
Ecotoxicity, human blood cells | PS-NPs | Conformational changes in blood proteins, cytotoxic and genotoxic effects in lymphocytes and erythrocytes | (74) |
Ecotoxicity | MPs of few microns or less | Adsorption of proteins and local inflammation in the gastrointestinal system (75) | (27) |
Ecotoxicity, human exposure | Nylon fibres of a respirable size; PE-MPs | Persistent inflammation (7) | (41) |
Ecotoxicity, animal models, human exposure | PS- and PEMPs; PS-NPs | Decrease in hepatic triglyceride and total cholesterol levels, decrease in gene expression related to lipogenesis and triglyceride synthesis in liver, reduction of intestinal mucus secretion (76), metabolic disorders due to alteration of intestinal microbiota (77), induction of IL-6 and IL-8 expression in gastric adenocarcinoma cells (68), induction of oxidative stress inT98G cells (63), increased AChE activity in the liver (34) | (42) |
PS-MPs | Absence of histologically detectable lesions and no inflammatory responses in mice (23) | (43) | |
PS- and PE-MPs | No cytotoxicity (23, 63) | (39) | |
PS-NPs | Inflammation, oxidative stress, lysosomal dysfunction and apoptosis in cultured cells | (11) | |
PS-NPs | Oxidative stress and DNA damage (78) | (39) | |
Invertebrates and vertebrates | PS-, PE-, HDPE-MPs | Decreased mucus secretion and mucus secretion-related gene expression (79), down-regulation of genes related to ion transport (76), modified serum levels of IL1α and granulocyte colony-stimulating factor G-CSF, decreased regulatory T cell count and increased the proportion of Th17 cells in splenocytes (80), blood neutrophil counts and IgA levels elevated in dams, and spleen lymphocytes were altered in both dams and offspring (81) | (46) |
PS-MPs | No cytotoxic effects on PBMCs and mast cells, haemolysis of erythrocytes, increased IL-6 production | (47) | |
PS-NPs | Reduced cell viability | (22) | |
Rodents | PS-MPs | Accumulation in the liver, kidney, and gut; energy and lipid metabolism disorders, liver inflammation (34), decreased intestinal mucus, changes in intestinal biota (77, 79) | (82) |
PS-MPs | Cells: binding of blood plasma coagulation factors VII and IX leading to a decrease in thrombin generation Mice: accumulation in the liver, kidney and gut with evidence of oxidative stress, energy balance disturbance, and neurotoxicity (83, 84) | (51) | |
PS- and PE-MPs | Blood clots (85), blood cell cytotoxicity (86), oxidative stress (34, 87) | (50) | |
PET-NPs | No effect on cell viability and membrane integrity, no significant change in apoptosis and necrosis | (48) | |
PS-MPs | Altered hepatic lipid metabolism, decrease in body weight, liver weight, decreased serum triglycerides and total cholesterol, mucus secretion, changes in gut microbiota, impairment of bile acid metabolism (77, 79) | (2) | |
PS-MPs | Mechanical injury, false satiation, low growth rate, increased immune response, energy depletion, blocked enzyme production, decreased fecundity, oxidative stress, morbidity and mortality (88, 89) | (55) | |
PS-MPs; PS-NPs | Inflammatory response, reduced intestinal mucus secretion, damage to the intestinal barrier function leading to an increase in the permeability of the gut mucosa, trigger an imbalance of gut microbiota, and alter metabolism, such as lipogenesis, triglyceride synthesis (77, 79), induction of pro-inflammatory responses (pro-inflammatory cytokines IL6, IL8 and IL1β), and inhibition of cell viability (68) | (54) | |
LDPE-MPs | No toxic effects | (90) | |
PLA particles | No cytotoxicity and no altered cell viability | (9) | |
Plastic fibres; PS-MPs | Bioaccumulation of synthetic microfibres in the gastro-intestinal tract and lungs of humans (91), inflammation, genotoxicity, oxidative stress, and apoptosis in the human body (92) | (60) | |
PS-MPs | (23) | ||
PS-MPs; PS-NPs | Increase in intracellular ROS levels, mitochondrial depolarisation, and increased cytotoxicity | (93) | |
Ecotoxicity | PS-NPs | Up-regulation of cytokines involved in gastric pathologies (68), disruption of iron transport (94), induction of apoptosis (22), endoplasmic reticulum stress (95) and oxidative stress (96) | (97) |
Molecularly imprinted polymers; PS-NPs | No significant toxicity | (98, 99) |
HDPE – high-density polyethylene; LDPE – low-density polyethylene; MPs – microplastics; NPs – nanoplastics; PE – polyethylene; PET – polyethylene terephthalate; PLA – polylactic acid; PLGA – poly(lactic-co-glycolic acid); PS – polystyrene; PVC – polyvinyl chloride
The AOP framework (13) enables collection and logical organisation of experimental data from different sources for efficient identification of essential biological events affected by exposure of living organisms to chemical stressors. Here we used the AOP framework to identify molecular initiating events (MIEs) and key events (KEs) associated with biological effects of PMNPs given in Table 2. The main aim was to generate hypothesis-based AOPs relevant to PMNPs by linking PMNP-induced toxicity endpoints reported so far with existing AOPs in the AOP-Wiki (16). However, it is important to note that many of these AOPs are under development.
Our analysis shows that PMNPs reported to induce biological effects have already been described either as MIEs or as KEs in 170 different AOPs (Table 3), which is an alarming finding that urges for more focused risk assessment of plastic across all steps in its value chain.
AOPs in AOP-Wiki related to the observed PMNP effects found in the literature search (see Figure 1)[Reported biological effects of PMNP are denoted as molecular initiating events (MIE) or key events (KE) for each AOP. AOPs marked in the last column with an asterisk are “under development”]
Increased reactive oxygen species (ROS); oxidative stress induction | Decreased population growth rate/Decreased population size | ||
Lung fibrosis/Lung cancer/Decreased lung function/Dysfunction of the respiratory system | |||
Liver fibrosis/Cholestasis/Steatohepatitis/Liver injury | |||
Breast cancer | |||
Increased mortality | |||
Reproductive failure/Decreased fertility/Decreased reproductive success/Impaired fertility | |||
Treatment-resistant gastric cancer | |||
Decreased cognitive function | |||
Inflammatory events in light-exposed tissues | |||
Insulin resistance | |||
Chronic kidney disease | |||
Apoptotic cell death | |||
Increased oxidative damage | |||
Increased mesotheliomas | |||
Acute myeloid leukaemia | |||
DNA damage/DNA strand breaks | Decreased population growth rate/Decreased population size/Decreased population trajectory | ||
Lung cancer | |||
Breast cancer | |||
Decreased fertility/Reduced sperm count | |||
Increased mesotheliomas | |||
Acute myeloid leukaemia | |||
Microcephaly | |||
Apoptotic cell death | |||
Increased chromosomal aberrations | KE in AOP 296 (endorsed) | ||
Cataracts | |||
Learning and memory impairment | |||
Vascular remodelling | |||
Increased lipid peroxidation | Increased mortality | ||
Impaired fertility | |||
Apoptosis | Decreased population growth | ||
Decreased fertility/Reproductive failure/Decreased reproduction | |||
Orofacial cleating | |||
Breast cancer | |||
Decreased lung function/Chronic obstructive pulmonary disease | |||
Prostate cancer | |||
Apoptosis/Necrosis | |||
Testicular atrophy | |||
Liver injury | |||
Thyroid hormone interference | |||
Neurodegeneration | |||
Kidney failure | |||
Lysosomal disruption | Kidney toxicity | ||
Liver fibrosis | |||
Decreased locomotor activity | Decreased population growth rate | ||
Decrease in body weight | Decreased body weight | ||
Glutathione depletion | Impaired fertility | ||
Inflammation/Neuroinflammation | Learning and memory impairment | ||
Parkinsonian motor deficits | |||
Lung fibrosis/Bronchiolitis obliterans/Chronic obstructive pulmonary disease | |||
Cholestasis/Immune-mediated hepatitis/Increased liver steatosis | |||
Increase, papillomas/carcinomas | |||
Psoriatic skin disease | |||
Increased mortality | |||
Hyperinflammation | |||
Memory Loss | |||
Kidney failure | |||
Metabolically unhealthy obesity | |||
Increased mesotheliomas | |||
Breast cancer | |||
Pulmonary inflammation | Chronic obstructive pulmonary disease | ||
Respiratory dysfunction | |||
Increased mesotheliomas | |||
Increased mortality | |||
Hypersensitivity response | |||
Atherosclerosis | |||
Increased neutrophil activation | Increased thrombo-inflammation | ||
Mitochondrial dysfunction | Death/Failure, Colony | ||
Decreased population growth rate | |||
Heart failure/Increased mortality | |||
Kidney failure/Kidney toxicity | |||
Liver fibrosis/Liver injury | |||
Learning and memory impairment | |||
Parkinsonian motor deficits | |||
Breast cancer | |||
Apoptotic cell death | |||
Impaired IL-1R signalling | T-cell-dependent antibody response impairment | ||
Energy reserves depletion/Decreased fatty acid beta-oxidation | Decreased population growth rate | ||
Decreased body weight | |||
Blocked enzyme production (inhibition of aromatase/calcineurin activity) | T-cell-dependent antibody response impairment | ||
Metastasis, Breast Cancer | |||
Decreased fertility | |||
Decreased fecundity/fertility | Decreased fecundity/Decreased population growth rate/Decreased fertility | ||
Oxidation of iron in haemoglobin | Cyanosis | ||
Endoplasmic reticulum stress | Non-alcoholic fatty liver disease/Tumorigenesis | ||
Parkinsonian motor deficits | |||
Decreased cholesterol/altered cholesterol metabolism | Impaired fertility | ||
Decreased sperm quantity and/or quality in the adult testis | |||
Decreased cognitive function | |||
Altered lipid metabolism | Steatohepatitis | ||
Pancreatic acinar tumours | |||
Metabolic syndrome/stress | Metabolic syndrome/Insulin resistance | ||
Death/Failure, Colony | |||
Increased blood CCK level (satiety) | Pancreatic acinar cell tumours | ||
Cell injury | Learning and memory impairment | ||
Liver fibrosis/Liver injury/ | |||
Decreased growth | |||
Heart failure/Increased mortality | |||
Neurodegeneration | |||
Inhibition of digestive enzymatic activities (trypsin inhibition) | Pancreatic acinar cell tumours | ||
Alteration in intestinal microbiota | Gut dysbiosis | ||
Decrease in gene expression related to liver | Increased hepatocellular adenomas and carcinomas | ||
Covalent protein binding | Sensitisation of skin | ||
Increased allergic respiratory hypersensitivity response | |||
Meiotic spindle disorganisation | Increased aneuploid offspring | ||
Increased mortality | Increased mortality | ||
Decreased population growth rate | Decreased population growth rate |
AOP – adverse outcome pathway; KE – key event; MIE – molecular initiating event
The reviewed literature clearly evidences adverse health effects of PMNPs, even though they are not fully understood in humans. Many studies demonstrate that PMNPs can accumulate and cause inflammation in various tissues and organs or disrupt cellular processes.
It is important to consider all routes to determine aggregate exposure and include all routes in future studies of PMNP health effects. Risk assessment should also include interactions between PMNPs and other environmental pollutants that may act as a Trojan horse introducing hazardous substances into the body.
Research and action are needed to address all these issues and minimise the risks associated with the ever-increasing use of plastic materials. Further studies are needed to fully understand the mechanisms by which PMNPs affect human health and the extent of their toxicity at various exposure levels. Long-term studies are also needed to determine their chronic effects in order to develop effective risk assessment and management strategies and inform policy decisions aimed at minimising exposure to these particles and protecting human health.