A Systematic Review of the Toxicokinetics of Micro- and Nanoplastics in Mammals Following Digestive Exposure

Abstract

The high production of plastic, along with its biostability and poorly managed recycling, has led to its widespread presence in the environment. Pollution from microplastics (particles smaller than 5 mm) and nanoplastics (particles smaller than 1 μm) poses a serious environmental problem, with long-term negative impacts on human and animal health. The goal of this systematic review is to identify the toxicokinetics of microplastics and nanoplastics after they are ingested by mammals. A total of 1057 articles were identified in the PubMed database, Web of Science, and Google Scholar through a manual search. After removing duplicates, 560 articles remained. Upon reviewing the titles and abstracts, 500 articles were excluded. Out of the remaining 60 articles, 43 were excluded, and 17 were included in the study. The current clinical evidence indicates that plastics can enter the body in the form of microplastics and nanoplastics. The digestive system is a significant pathway for absorption, and the resulting changes are influenced by factors such as the type of plastic, the duration of exposure, the particle size, and the individual’s clinical condition. Once absorbed, plastic particles can enter the body and cause significant changes in intestinal barrier function, hepatic metabolic changes, oxidative stress, and nephrotoxicity.

1. Introduction

High plastic production of more than 381 million tons/year [1], coupled with the biostability of plastics and poorly managed recycling, leads to the ubiquity of plastic in the environment and widespread exposure to animals and humans [2,3].

According to National Geographic, Washington, DC, USA, over 5 trillion tons of plastic debris are present in the ocean, of which 300,000 tons are floating on the surface of the ocean and 4 billion plastics per km² are located in the deep ocean. Each year, the production of plastics increases to 320 million tons/year globally [4]. By the year 2050, the plastic waste entering landfills or the environment is expected to reach 12 billion metric tons of waste, compared to 2015, when it weighed 4.9 billion metric tons [5].

Plastic is a highly versatile material that finds use in a wide range of industries, such as food, cosmetics, textiles, fishing, tourism, construction, transportation, renewable energy, and scientific and medical equipment. Despite the global efforts to restrict its production, plastic remains a preferred choice due to its advantageous properties, such as high stability, flexibility, and light resistance, so it is a material with wide use in a wide variety of fields [6,7,8].

Plastic pollution is a global concern because macroplastics, microplastics, and nanoplastics are found in soils, waterways, marine life, and the human body. While scientists have conducted research to measure the amount of plastic in the environment, they have come to the expected conclusion that plastic is ubiquitous. It is not surprising to find a large number of macroplastics, but the presence of microplastics and nanoplastics is concerning. Although there has been no measurement of nanoplastic particles in the environment, there are concerns that microplastics are more widespread and pose a greater danger than larger plastics [9].

1.1. Sources of Microplastic (MP) and Nanoplastic (NP) Pollution

A 2018 study to identify plastic contamination in bottled water sampled plastic water bottles from 9 different countries, 19 different locations, and 11 different brands of water. This study identified 93% microplastic contamination in 259 samples. The fragments obtained were analyzed by spectrophotometry, and it was identified that the microplastic identified was a polymer, i.e., polypropylene (54%), which is used to manufacture glass caps, and 4% of the particles were industrial lubricants. The information provided in this study suggests that the contamination of bottled water comes from the packaging and bottling process. Nonetheless, water is one of the most frequently consumed products by the general populace, and it is crucial to ascertain the potential health consequences of plastic pollution [10]. The highest concentrations of micro- and nanoplastics have been detected in water (94.37 MPs/L), followed by alcohol (32.27 MPs/L), air (9.80 MPs/m³), seafood (1.48 MPs/g), sugar (0.44 MPs/g), and honey (0.10 MPs). However, the greatest risk to an adult’s health is the inhalation of nanoplastics; for children, it is drinking water. Moreover, inhaled nanoplastic particles can cross the placenta and then translocate to the human fetal organs during gestation [11].

Comprehensive analyses of environmental pollution need to consider the adverse health effects of nano- and microparticulate plastics, including particles from emerging sources that have not received much attention, such as tire wear particles and particles from carpets and synthetic clothing [12]. Plastic particles are an emerging health concern and are a component of the suspended particles in the environment [13,14].

Nano- and microplastic particles that reach the air from seawater and polluted soil are by-products of industrial activities and domestic air pollution from synthetic carpets and clothing. It is anticipated that the solid particles from these sources will contribute to increased environmental pollution in the future if their production rises for commercial and research purposes before being disposed of and released into the environment. The nanometric database created by the Technical University of Denmark (Konges Lyngby, Denmark) comprises data on more than 4000 nanomaterial-based products currently available [15].

At the same time, research should include an analysis of microplastics in groundwater from a hydrogeological point of view. Plastic can pollute groundwater, and this pollution can be represented by the following sources: the atmosphere, the interaction between plastic bodies and water, soils from agriculture, and urban infrastructure [16].

1.2. Plastic Types, Sizes, and Additives

Plastics are man-made materials created through the polymerization process of monomers derived from oil or gas [17]. It is estimated that there are approximately 45 different types of plastics that exist worldwide. The most commonly used organic polymers include polyethylene terephthalate (PET), polyethylene high-density (PEHD), polyvinyl chloride (PVC), polypropylene (PP), polystyrene (PS), and polyurethane (PU). Plastics such as PS, polypropylene (PP), polyethylene (PE), and expandable polystyrene (EPS) are commonly found in oceans and river sediments and on beaches. At ground level, PE and PP are the most common polymers, followed by PET and PVC. Polyesters, polyurethane, and polystyrene are detected less frequently in unperturbed sea surface samples [18,19]. Figure 1 represents the main types of plastics and the products obtained from them.

They are classified according to their size distribution [20]. Thus, plastics can be macroplastics (>25 mm), mesoplastics (5–25 mm), microplastics (1 µm–5000 μm), or nanoplastics (<1 µm) [21,22,23,24]. Depending on the reaction of plastics to heat, they can be classified into two types: thermoplastics and thermosets. Thermoplastics can be reshaped when heated, while thermoset plastics cannot be reshaped because they are cross-linked [25].

Table 1. Plastic classification by measurement.

Type of Plastic	Size	References
Macroplastic	≥25 mm	[23,26,27,28]
Mesoplastic	5–25 mm	[23,27,28]
Microplastic	1 μm–5000 μm	[21,22,23,29,30,31,32,33,34]
	0.1 μm–5 mm	[19,24,32,35]
	0.1 μm–5000 μm	[36]
Nanoplastic	<1 μm	[21,37,38]
	0.001 μm–1 μm	[22,23,31]
	0.001–0.1 μm	[35,36]
	<0.1 μm	[32,39,40,41]

shows the classification of plastics by their sizes, according to different authors.

Plastics contain various additives, such as polybrominated diphenyl ethers, bisphenol A, polycyclic aromatic hydrocarbons, and metals/metalloids, which are carcinogens and are used to improve the quality of plastics. It is noteworthy that up to 50% of the mass of produced plastic comprises chemical additives, such as phthalates, bisphenols, flame retardants, per- and polyfluoroalkyl substances, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and heavy metals. These substances are incorporated into plastics to impart particular characteristics, including hue, flexibility, flame retardance, and moisture resistance [15].

1.3. Presence and Degradation of Plastics in the Environment

In addition, microplastics tend to act as vectors for other contaminants, such as pathogens, organic pollutants, and heavy metals, due to their strong dispersion and diffusion mechanisms. Most ongoing research on microplastics has focused primarily on marine systems, but the contamination of land surfaces may also be important due to the observed release rate, which is approximately 20 times higher compared to the oceans [42].

The issue with plastics lies in the fact that nearly half of their production is in the form of single-use items, which are often improperly disposed of and end up polluting aquatic ecosystems [43]. Research indicates that less than 10% of industrially produced plastic is recycled, leading to its ubiquity [44]. A negative aspect of plastic in the marine environment is the economic damage to the fishing industry and tourism [45]. Plastic waste is harming and killing birds, mammals, fish, and marine reptiles through ingestion and entanglement, causing injuries and infections [46,47].

Microplastics in the environment can result from the degradation of larger plastics by biological, photochemical, and mechanical processes [48].

Biodegradation is the action of living organisms—frequently microbes. Plastics can be degraded via biotic and abiotic pathways [49]. Biotic degradation can be subdivided into aerobic and anaerobic degradation and occurs mainly when particles are small enough to pass through microbial membranes [49,50]. While anaerobic degradation occurs in the absence of oxygen, such as in sediments and landfills, aerobic degradation happens in the presence of oxygen. Abiotic degradation can occur through photodegradation and hydrolysis, which involve initiation, propagation, and termination steps [49]. However, when it comes to plastic polymers with a heteroatomic backbone, the degradation process is different [51]. The durability of the polymer also depends on the additives used during the treatment of the polymers. For example, the stability and durability of PE can be increased significantly by using specific additives such as UV absorbers and quenchers [52,53].

Photodegradation refers to the action of UV rays in the degradation of the plastic matrix. Thermoxidative degradation is a slow process of oxidative degradation that occurs at moderate temperatures and breaks down plastic over time. Thermal degradation is achieved by the action of high temperatures, and hydrolysis occurs via the action of water on the plastic [53].

Due to their small size and unique shapes, which increase the surface-to-volume ratio of MP/NP, they can easily penetrate cell membranes and harm biota [54]. A particle tracking analysis revealed that polystyrene nanoplastic particles were formed after 56 days and polyethylene particles were formed after 8 weeks of exposure to artificial seawater [55].

Micro- and nanoplastics are present in a wide range of foods, such as salt, honey, tea bags, drinks, and bottled water, as well as in the air that we breathe [56,57].

Therefore, there is a need for scientific research to understand their distribution in the environment and their negative impacts on health.

1.4. Identification and Toxicological Risk of Plastics

The identification of plastic particles can be performed by visual microscopic identification (partly after staining), micro-Fourier transform infrared spectroscopy (μ-FTIR), or micro-Raman spectroscopy [58]. Both μ-FTIR and micro-Raman spectroscopy are effective in identifying polymers. While μ-FTIR can identify particles larger than 10 μm, micro-Raman spectroscopy can analyze particles as small as 1 μm [59]. However, due to the considerable variability in the absence of a generally accepted standard, the use of diverse techniques can significantly influence study outcomes and affect the overall understanding of both plastic pollution and its toxicological profile.

The toxicological risks of plastics are due to plastic particles, polymer additives, and adsorbed contaminants [60,61]. Plastic particles have been found to cause internal abrasion or blockages in the gastrointestinal systems of animals. Smaller particles may even cause injury as they can translocate into body tissue [62]. In addition, particles smaller than 1.5 μm in size can penetrate deeply into organs, as per the European Food Safety Authority (EFSA, Parma, Italy) [36,63].

In addition, an increasing number of studies on the toxicological impacts of MP/NP refer to the induction of oxidative stress, inflammation, DNA damage, neurotoxicity, reproductive and developmental abnormalities, changes in lipid/energy metabolism, and other pathophysiological abnormalities observed in various in vivo and in vitro test models [64,65].

There has been a rise in tumor diseases in wild species, like fibropapillomatosis in sea turtles and genital carcinoma in sea lions, which were previously non-existent. Researchers have found a correlation between the increased frequency of tumors in marine animals and the increased number of synthetic monomers [66,67].

2. Microplastic and Nanoplastic Uptake

2.1. MP and NP Ingestion

Oral ingestion is one of the main ways in which organisms are exposed to MP and NP. This is because microplastics can be found in drinking water, fish and fish food, mussels, and salts from lakes and oceans, and even in bottled water [68,69,70,71,72,73]. According to Danopoulos et al. (2020), the most commonly found polymers in bottled water are PET and PP [74]. Meanwhile, Kosuth et al. (2018) discovered that 88% of tap water samples from both developed and developing countries contained MP and NP [57]. Moreover, Kutralam-Muniasamy et al. (2020) found MP in milk in Mexico, with concentrations ranging from 1 to 14 particles/L and sizes varying from 0.1 to 5 mm [75]. Philipp et al. (2020) also reported finding microplastic particles in the intestines of harbor seals (Phoca vitulina) and grey seals (Halichoerus grypus) [76].

2.2. Intestinal Absorbtion

Many studies have shown that plastics can be absorbed in the intestines—either in the small or large intestine. The uptake of plastic particles in the gut is influenced by their size, shape, concentration, charge, and chemical composition.

Plastic particles need to pass through the mucus layer in order to reach the epithelium of the intestine. The intestinal epithelium is composed of enterocytes, mucus-producing goblet cells, and microfold (M) cells [77,78]. Different mechanisms can cause the absorption of plastic particles, and it can be based on the size of the particles. These mechanisms include endocytosis mediated by enterocytes and transcytosis via microfold cells, also known as M cells, found in a subset of intestinal epithelial cells in gut-associated lymphoid (GALT) tissue, known as Peyer’s patches. Persorption is the passage through gaps at the tips of the villi following the loss of enterocytes and paracellular uptake [79,80].

Because Peyer’s patches have a high proportion of M cells, they are the main sites of microplastic absorption. Furthermore, the intestinal absorption of particles can lead to toxicologically relevant systemic exposure. Due to the small size of nanoplastics, they can penetrate deeply into organs [81]. M cells are specialized epithelial cells that are missing the microvilli found on other intestinal epithelial cells.

Conversely, they possess broader (micro-)folds and a more delicate luminal surface, facilitating the rapid absorption of particles within the intestine [82]. Figure 2 shows the pathologic pathways through which MPs enter the gut.

The gastrointestinal mucosal layer serves as the primary barrier against foodborne pathogens, toxins, and antigens. Celiac disease, colon cancer, and inflammatory bowel disease are all examples of diseases that can result from barrier defects caused by GI mucosal damage [83]. The gut microbiome is an essential element for gut health. It plays a vital role in supporting digestion, nutrient absorption, barrier function, and immunity [84]. The gut microbiome is sensitive to diet, drugs, and pollutants. Changes in it are linked to many diseases, including cancer, autoimmune diseases, diabetes, obesity, and cognitive dysfunction [85,86]. Malnutrition and diets high in saturated fat and high-fructose carbohydrates can lead to increased gastrointestinal permeability in the mucosa [87]. During inflammation, epithelial barriers become more permeable, leading to increased translocation [88].

Peda et al. (2016) conducted a study on European sea bass (Dicentrarchus labrax, body size = 140 ± 8.42 g) that were fed feed containing 0.3 mm PVC plastic particles for 30, 60, and 90 days. Observations of histological sections of the intestinal segments revealed several pathological lesions. These lesions were associated with inflammatory, circulatory, and structural changes, indicating that PVC had translocated into the intestine and caused harmful effects on the mucosal and submucosal musculature of the three sections of the intestine [89]. Another study was performed on zebrafish, Danio rerio, by Lu et al. (2016), who monitored the effects of the absorption and accumulation of PS in the gut, gills, and liver. The researchers noted that PS particles with a size of 5 µm were found to accumulate in the gut, gills, and liver, whereas PS particles of 20 µm were found to accumulate only in the gills and gut. The team conducted a histological analysis of the liver and found 5 µm and 70 nm PS particles in the tissue, along with some pathological lesions, inflammation, lipid accumulation, and alterations in oxidative stress proteins [90].

MPs/NPs accumulate in various organs, including the gastrointestinal tract, respiratory system, reproductive system, nervous system, hemolymph, embryos, liver, kidneys, and spleen [91,92].

A team of researchers led by Regusa recently found microplastic particles in the placentas of six consenting volunteers. The particles were present on the fetal side and maternal side and in the chorioamniotic membrane, indicating that they can cross tissue membranes and enter the bloodstream, allowing them to travel to various parts of the body [93]. This discovery suggests that microplastics or nanoplastics can reach the human placenta. The presence of microplastics in human stool samples, reported by Schwabl et al. in 2019, further supports this conclusion [94]. MPs/NPs are able to cross membrane and tissue epithelial barriers (transmucosal passage), reaching the lymphatic and circulatory systems, where they can be transported to the liver, brain, reproductive tissue, embryos, and other sensitive tissue types in the body [93,95,96].

It has been discovered that microplastics present in the air can harm the digestive tract and immune system. Airborne particles that are small in size can be absorbed into the lung epithelium and then reach the systemic circulation [97,98]. The stimulation of the immune system occurs through the gut–lung axis [99]. The larger particles in the respiratory tract are transported to the digestive tract via the mucociliary tract. Therefore, the fate of plastic particles is determined by their size. Those that are small enough can enter the bloodstream and trigger an immune response after being ingested or inhaled. The intestinal mucus layer retains microplastics exceeding 150 μm, which directly come into contact with intestinal epithelial cells. Consequently, intestinal inflammation may arise, impacting the immune system. Particles smaller than 150 μm can traverse the mucus barrier [39].

2.3. MP and NP Internalization at the Molecular Level

The internalization mechanisms vary across different cell types and are influenced by factors such as the particle size, morphology, and chemical composition, all of which can affect particle uptake and toxicity [100,101,102,103,104]. There are two types of internalization pathways—energy-dependent and non-energy-dependent transport. Energy-dependent transport can be further divided into phagocytosis and pinocytosis. Phagocytosis is primarily employed by specialized cells, including macrophages, neutrophils, and monocytes [105,106]. Nanoparticles can be absorbed through phagocytosis and pinocytic mechanisms, including macropinocytosis, caveolin- and clathrin-mediated endocytosis, and dynamin-independent endocytosis [107].

The actin cytoskeleton and Rho family GTPases play a role in the processes of macropinocytosis and phagocytosis. Large vacuoles known as phagosomes are produced by phagocytosis, whereas macropinosomes are produced by macropinocytosis. These processes are distinguished by the fact that macropinocytosis generates macropinosomes by fusing endocytic vesicles with the plasma membrane, whereas phagocytosis generates phagosomes [108].

These processes are facilitated by receptors and dependent on dynamin.

They rely on invagination into the plasma membrane and the formation of clathrin-coated vesicles and caveolar vesicles, which are then transported within the cell [105,107,109]; see Figure 3.

Understanding the uptake pathways of nanoparticles is important in mediating both their intracellular fates and the biological response.

Within some cell types, clathrin-mediated endocytosis is the main pathway of internalization, while caveolin-mediated endocytosis occurs mainly in endothelial cells [109].

In previous research, clathrin-mediated endocytosis was found to play a role in nanoparticle absorption. NPs enter the cell through similar internalization mechanisms. In addition, renal epithelial cells (293T), bone marrow-derived macrophages (BMDM), and fibroblasts (L929) can be accessed by NPs through macropinocytosis and phagocytosis [107].

According to some research, the uptake of nanoparticles in particular cell types may not be dependent on energy or receptors.

This has led researchers to conclude that particle uptake can occur through epithelial barriers such as tight junctions between cells [100,110].

The process of particle internalization takes their size into account, but there is debate regarding the minimum size required for absorption. Some researchers suggest that clathrin-mediated endocytosis is only possible for clathrin-coated pit sizes of about 120 nm. However, others claim that typical clathrin-coated pit sizes range from 60 to 200 nm [101,106,111]. Caveolae-mediated particle uptake can occur for particles ranging in size from 200 nm to less than 1 μm [101,112]. On the other hand, macropinocytosis-derived particles should have a size greater than 150 nm [113].

In the case of PS particles, the optimal size for phagocytosis is 88 nm to 2.68 µm. However, smaller particles accumulate more rapidly and are more efficient. At tight junctions, nanoparticles can be internalized through paracellular transport if their size is less than 10 nm [100,114].

Internalization is also conditioned by the change in the surface area of the particles. Another non-endocytic internalization pathway is interaction with the lipid bilayers of plasma membranes and the higher uptake of positively charged PS NPs relative to negatively charged particles [113]. Positively charged PS NPs are absorbed through clathrin-mediated endocytosis, as described by Jiang et al., whereas experiments with single PS NPs showed internalization via micropinocytosis [115,116].

In a study conducted by Hillery et al. in 1994, female rats were given 60 nm polystyrene particles for 5 consecutive days. The study revealed that the absorption of plastic particles was more prominent in the lymphoid tissue of both the small and large intestines [117].

Studies show that absorbed nanoplastics can be distributed to various organs, including the liver, spleen, heart, lungs, thymus, reproductive organs, kidneys, and even the brain, crossing the blood–brain barrier [36,118].

Due to the fact that small NPs possess a large surface area relative to their total mass, they are more likely to interact with surrounding biomolecules and trigger adverse responses. Therefore, smaller NPs are more toxic than larger ones.

The toxicity of nanoparticles is affected by their size, but other factors can also play a significant role, such as surface functionalization. For example, cationic nanoparticles are more toxic than neutral or anionic nanoparticles due to their high affinity for negatively charged elements of the plasma membrane [119].

3. Methodology

This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.

3.1. Search Strategy

A systematic literature search was performed in Web of Science, PubMed, and Google Scholar.

The search terms used were “microplastic”, “microsize”, “nanoplastic”, “nano-size”, “plastic”, “oral”, “toxicokinetic”, “digestive exposure”, and “mammals”. Search terms were combined using AND, OR to refine the query and ensure the complete retrieval of relevant studies.

The eligibility criteria included publications in English, peer-reviewed journals, in vivo mammalian studies, and research demonstrating alterations following the administration of microplastics (MPs) and nanoplastics (NPs).

3.2. Study Selection

Searches were limited to works published before 30 April 2024. The selection process used the PRISMA 2020 guidelines with the following steps (Figure 4):

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a total of 500 duplicate articles were removed (557 remained);

-

after reading the titles and abstracts, 500 were eliminated (60 articles were evaluated in full-text form);

-

seven articles were deleted due to a lack of irrelevant information and data (53);

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reports were excluded if the research was performed in vitro (15) or not on mammals (11);

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finally, 17 articles were included in the review.

In vitro studies and non-animal research were omitted from the search because they were not relevant to this study.

Only in vivo studies were selected in order to observe more clearly the absorption of these particles in the digestive tract and the factors influencing their absorption, as well as the toxic effects produced.

4. Results

Inclusion and Exclusion Criteria

This review includes studies on mammals that presented the digestive uptake of microplastics and the associated changes. A total of 17 studies out of 1057 were included in this analysis. We include a description of the characteristics of all studies in

Table 2. Studies identified in the literature that investigated digestive exposure to different types of plastics.

Reference	Species	Type, Size, and Period of Exposure to Plastic	Mode of Exposure and Dose	Results
[120]	Rats and guinea pigs	Polystyrene latex microspheres, 2 μm	Oral gavage 1.42 to 1.95 × 109 particles in 0.25 mL dose	Particle absorption varied with age. Young adult males (7 weeks) were more affected than younger (3 weeks) and older (17 and 52 weeks) age groups.
	Mice	Polystyrene latex microspheres, 2 μm	Oral gavage 6.84 × 108 in 0.1 mL
[121]	Mice	Polystyrene (PS) MPs of 5 μm, 20 μm; Periods studied: 1, 2, 4, 7, 14, 21, and 28 days after exposure to MPs.	Oral gavage	MPs accumulated in the liver, kidneys, and intestine, and the distribution depended on the size of the PS particles. Disruption of energy and lipid metabolism induced oxidative stress and negative neurotoxic responses. Lipid droplets and hepatic inflammation were found in mice treated with PS MPs.
[122]	Mice, male	Polyethylene (PE) and PS+ co-exposure organophosphorus flame retardant (OPERs) beads, 0.5–1.0 μm; for 90 days	Drinking water	Inflammation and lipid droplet formation in mouse liver and gut. Oxidative stress and neurotoxicity. Disruption of amino acid metabolism and energy metabolism.
[123]	Mice, male	Polystyrene MPs, 0.5, 50 μm, for 5 wk	Drinking water: - 1.456 × 1010 particles/L for 0.5 μm; - 1.456 × 104 particles/L for 50 μm	Reduced mucus secretion in the colon caused by intestinal microbiota dysbiosis.
[85]	Mice, female F0, F1	Polystyrene pristine MPs, size 5 μm, during pregnancy and lactation (~6 weeks)	Drinking water: 100 and 1000 μg/L	Maternal metabolic disorders were linked to imbalances in gut microbiota and impaired gut barrier function. The F1 and F2 generations experienced intergenerational changes that had long-lasting metabolic effects.
[124]	Mice, male	PS pristine fluorescent MPs, size 5 μm, for 6 wk	Drinking water: 100 (1.456 × 106 particles/L) and 1000 μg/L (1.456 × 107 particles/L)	MP exposure caused intestinal barrier dysfunction, gut microbiota dysbiosis, and bile acid metabolism disorder.
[125]	Mouse	Polyethylene (PE) MPs + contaminated PAEs (phthalate esters), size 45–53 µm, for 30 days	Oral gavage 100 mg/kg/day, about 5.25 × 104 particles/day	Symptoms of inflammation and metabolic disorder in the gut including increased intestinal permeability, heightened inflammation, and altered gut microbiota.
[126]	Mice C57BL/6	Polyethylene MPs, size 10–150 μm, for 5 consecutive weeks	Feed: 6, 60, and 600 μg/day	Gut bacterial overgrowth. Dysbiosis and inflammation in the small intestine.
[127]	Mice, C57 male, with induced acute colitis	PS MPs, size 5 µm, for 28 days	Drinking water: 500 μg/L	Mice exhibited enhanced inflammation, increased hepatic lipid peroxidation, promoted adipocyte differentiation, and hepatic metabolic disorder.
[128]	Mice, male, C57/BL6	Pristine polystyrene (PS) negatively charged carboxylated (PS-COOH) and positively charged aminated polystyrene (PS-NH2), size 70 nm and 5 μm in diameter, for 28 days	Oral gavage 2 mg kg−1 0.2 mg kg−1 (for the carboxylated and aminated groups)	Marked dysbiosis of the gut microbiota. Decrease in body weight. The levels of serum ALP, AST, T-Bil, CK, r-glutamine transferase (r-GT), and creatinine (SCr) increased significantly after exposure to 2 mg kg−1 PS-NH2. Morphopathology of the stomach, duodenum, jejunum, and colon was significantly damaged after exposure to PS-NH2; crypts were damaged, intestinal villi disappeared, and the walls of the intestine and stomach became thin and showed obvious layers of inflammatory exudates after exposure to PS-NH2. Caused obvious injuries to the gut tract, leading to the decreased expression of tight junction proteins.
[129]	Mice, C57-BL/6, male	PS MPs, size 5 µm	Oral gavage 500 μg/L	Increased expression of inflammatory factors (TNF-α, IL-1 β, and IFN-γ) and intestinal immune imbalance. Exposure to PS MPs induced histopathological damage in colonic mucosa.
[130]	Mice, ICR	Polyethylene microplastics (PE MPs), size 10–50 μm 1. Single oral dose toxicity study, 14 days; 2. Repeated oral dose toxicity study, 28 days	Oral gavage 500, 1000, and 2000 mg/kg/day	In the toxicity experiments with a single oral dose, there were no changes. For the repeated oral dose toxicity study, the histopathological examination revealed granulomatous inflammation in the lungs and MPs in the lungs, stomach, duodenum, ileum, and serum.
[131]	Mice, C57BL/6	Polypropylene (PP) MPs, size 8 and 70 m, for 28 days	Oral gavage 1, 10, and 100 mg/kg/d	Damage to tight junctions of the colon and decreased expression of ion transporters, intestinal mucus, and secretion. Induced colonic apoptosis and damage to the intestinal barrier through oxidative stress and TLR4/NF-κB inflammation.
[132]	Rats (juvenile)	Polystyrene MPs, size 1 μm, for 28 days	Oral gavage 2.0 mg/kg/d	Decreased rate of body weight gain and organ indices of the kidney, heart, and ovaries. Nephrotoxicity caused by disturbances of serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1b, IL-6, and TNF-a.
[133]	Rats (Wistar, male)	Polyethylene terephthalate (PET MPs), size 85 μm, for 14 days	Oral gavage 1.4 mg/kg, 35 mg/kg, and 125 mg/kg	Lack of clinical signs of toxicity. Changes in specific markers of liver, cardiac, and renal function. Increased levels of oxidative stress indicators.
[134]	Pigs, 8 wk old	PET (maximum size 300 μm), 28 days	Oral feed 0.1 g/day, 1 g/day, 28 days	Alterations in the enteric nervous system and the histological structure of the duodenum. Changes were more pronounced in the group of animals receiving microplastics at a dose of 1 g/day than in the group receiving 0.1 g/day.
[135]	Mice, C57BL/6J, male	Polystyrene MPs, size 0.2, 1, or 5 μm, for 28 days	Oral gavage Dose: 1 mg/kg body weight daily	Oxidative stress and inflammatory cell infiltration in the colons of mice and increased expression of pro-inflammatory cytokines. Increased intestinal permeability and decreased mucus secretion. At 5 μm size, PS damage was more severe than at 0.2 and 1 μm.

.

5. Discussion

We reviewed 17 studies, most of which focused on mice and rats, with very few on guinea pigs and pigs. The primary plastic studied was polystyrene. One indicated that plastic absorption was influenced by the age of the individual. Individuals younger than 3 weeks old showed higher tissue absorption, despite having shorter and thinner intestines, resulting in a smaller surface area for plastic absorption. However, 7-week-old individuals showed similar tissue absorption to 3-week-old individuals, even with a longer and thicker gut. The mentioned study found that 7-week-old individuals absorbed the most plastic compared to 3- and 15-week-old individuals. Increasing age was linked to thinner intestinal segments and a decrease in the absorption rate [120].

Research conducted on mice for 28 days revealed that PS accumulated in the liver, kidneys, and intestines, leading to inflammation, increased hepatic lipid peroxidation, hepatic metabolic disorder, oxidative stress, neurotoxicity, the infiltration of inflammatory cells in the colon, and the increased expression of pro-inflammatory cytokines. Additionally, it was found that there was increased intestinal permeability and decreased mucus secretion [121,127,135].

Furthermore, administering PS over a longer period of time (5–6 weeks) resulted in gut microbiota dysbiosis, decreased mucus secretion in the colon, changes in bile acid metabolism, and gut barrier dysfunction. This was accompanied by the increased expression of inflammatory factors, intestinal immune imbalances, and histological lesions in the intestinal mucosa [123,124,129].

In juvenile rats, research identified a decreased rate of growth in body weight and in the organ indices of the kidneys, heart, and ovaries. It was also observed that there were changes at the serum level, with an increase in blood urea nitrogen, creatinine, and proinflammatory mediators IL-1b, IL-6, and TNF-a [132].

Pregnant and lactating females were involved in research with PS to show the long-term harmful effects of MPs. This study focused on the intestine, which experienced changes in intestinal barrier function and imbalances in gut microbiota. These changes affected the health of the mothers and, as a result, the health of the offspring [85].

The presence of negatively charged carboxylated and positively charged amine PS influenced the changes that occurred after intestinal absorption. These changes included marked dysbiosis of the gut microbiota, decreased body weight, and increased levels of ALP, AST, T-Bil, CK, r-glutamine transferase, and serum creatinine. Exposure to PS-NH2 amine PS also resulted in damage to intestinal crypts, the disappearance of intestinal villi, the thinning of the walls of the intestine and stomach, and the presence of obvious layers of inflammatory exudates [128].

The MP polyethylene can be toxic when combined with other substances, such as organophosphorus flame retardants. These interactions can disrupt amino acid and energy metabolism, leading to oxidative stress and neurotoxicity [122]. Additionally, PE contaminated with phthalate esters can cause intestinal inflammation, increased intestinal permeability, and an altered gut microbiota [125].

Microplastic modifications of polyethylene (PE-MP) appeared after repeated exposure to the toxicant, leading to granulomatous inflammation in the lungs and the presence of microplastics in the lungs, stomach, duodenum, ileum, and serum [130].

Polyethylene terephthalate (PET) was found to have no toxic effects on rats, as there were no clinical signs of toxicity or changes in specific markers of liver, cardiac, and renal function. However, there were increased levels of oxidative stress indicators. In pet pigs, the presence of microplastics led to changes in the enteric nervous system and in the histological structure of the duodenum. Notably, these changes were more significant in the group of animals receiving a dose of 1 g/day compared to those receiving 0.1 g/day [133,134].

Thus, absorbed nanoplastics can be distributed to various organs, including the liver, spleen, heart, lungs, thymus, reproductive organs, kidneys, and even the brain, crossing the blood–brain barrier. The observed changes include hepatic metabolic disorder, oxidative stress, neurotoxicity, changes in bile acid metabolism, the increased expression of pro-inflammatory cytokines, and nephrotoxicity with increased serum urea and creatinine. At the intestinal level, the main changes are intestinal microbiota dysbiosis, decreased mucus secretion in the colon, dysfunction of the intestinal barrier, and the infiltration of inflammatory cells in the colon. In addition, in young rats, a decrease in the rate of body weight gain was observed. The novelty of our review lies in its comprehensive focus on the toxicokinetic behavior of microplastics (MPs) and nanoplastics (NPs) following digestive exposure, emphasizing chronic and transgenerational effects, which are less explored in the existing literature.

6. Conclusions

Plastics are pervasive contaminants, particularly in water, posing a significant risk through oral exposure and necessitating further investigation into their biological effects. The gastrointestinal tract serves as a primary route for MP/NP absorption, with uptake influenced by the particle size, shape, concentration, charge, and composition. Once absorbed, plastic particles can compromise intestinal barrier integrity, induce oxidative stress, and cause hepatic and renal toxicity. Research on chronic exposure, particularly in pregnant women, and the impact of plastic additives is urgently needed.