According to the World Health Organization (WHO), allergic diseases are the third most common after cardiovascular and oncological pathologies. Approximately 40% of the world population is allergic to drugs, household and industrial allergens, insect bites, food ingredients, etc. According to WHO forecasts, by the end of the 21st century, every second person will suffer from some form of allergy (1).

Allergic diseases are one of the most common somatic diseases of childhood. In recent years, the prevalence of allergic diseases in schoolchildren has increased, reaching 20% (2, 3). The formation of allergies in children is characterized by the stages of development of sensitization and the transformation of clinical manifestations, depending on the child’s age. In children with atopy, the allergy generally manifests in food allergies and atopic dermatitis already in early childhood. Later, 10-15% of children develop allergic rhinitis, and 40-43% develop bronchial asthma. The severe course of atopic dermatitis and atopic rhinitis is a risk factor for the subsequent development of bronchial asthma (2–5). Since this process is often triggered by early childhood food allergies, therapeutic and preventive measures aimed at timely detection and compensation of allergic manifestations in children caused by food components are relevant.

The increasing prevalence of allergic diseases among schoolchildren and the high prevalence of food allergies in early childhood are complex issues influenced by a combination of genetic, environmental, and lifestyle factors. While the exact causes are not fully understood, several potential contributing factors are discussed (2–5): 1) Allergies often have a genetic component. Children with a family history of allergies are at a higher risk of developing allergic diseases. 2) The hygiene hypothesis suggests that reduced exposure to infections and certain microbes in early childhood due to increased hygiene and reduced family size may lead to an improperly developed immune system resulting in allergies. 3) Changes in diet, such as increased consumption of processed foods and a decrease in the consumption of fresh fruits and vegetables, may influence the development of allergies. 4) Exposure to environmental factors like pollution and a lack of contact with animals and rural environments may impact immune system development and contribute to the rise in allergies. 5) Early life events, including the mode of birth (cesarean section vs. vaginal birth) and breastfeeding practices, can influence a child’s susceptibility to allergens. 6) The composition of the gut microbiota in early life can play a crucial role in immune system development. Changes in the gut microbiota due to factors like antibiotic use, diet, and hygiene practices may impact the risk of allergies. 7) Psychological stress and lifestyle factors, such as lack of physical activity or excessive screen time, may also influence immune system function and contribute to the development of allergies. 9) Vaccination practices and antibiotic use in early childhood may influence allergy development.

It’s important to note that these factors likely interact with each other, and the specific combination of influences can vary from one individual to another.

Food allergy is one of the types of allergic reactions that develops when eating certain foods that contain an allergen, which in turn causes an aggressive pathological response of the immune system, which manifests, in most cases in an immediate type I reaction, due to hypersynthesis and critical participation of IgE (4–6). Food allergy occupies a special place among allergic manifestations in terms of prevalence and peculiarities of its etiology, prevention, and treatment. It is one of the main reasons for developing allergic diseases in children (5, 7–10). Medical observations suggest that food allergy occurs in 6-8% of children under two years of age (60-94% of those cases occur in the first year of life), with a subsequent decrease in its prevalence to 2% among the adult population (4, 5, 10).

Food allergy symptoms are often presented through itching in the mouth and larynx, laryngeal edema, coughing for no reason, wheezing and shortness of breath, and pain during a conversation. Nausea, vomiting, and diarrhea may meanwhile occur in more acute cases. With food allergies, hives may appear due to a sharp influx of blood to the face. Urticaria, in turn, can provoke bronchial spasms, laryngeal edema, and arterial hypertension, leading to severe consequences, even death. Most patients have a combination of several symptom complexes (7–10). Prevalence of food allergies varies widely and ranges from 0.9 to 13% of all allergic reactions (8, 10).

One of the causes of allergic diseases is considered to be a sizable antigenic load on the body due to combined effects of natural and anthropogenic factors, in particular artificial pollutants, which also include bio-pollutants. In addition to exogenous factors, there are also endogenous factors, primarily burdened heredity. It has been established that 40% of people have a hereditary tendency to atopy and that this population is susceptible to adverse environmental conditions (1, 8, 10). Over time, these individuals develop immediate-type allergic hypersensitivity with elevated levels of IgE, i.e., atopic allergic diseases type I (1, 3, 11). Often there is a combined effect of several factors: an unfavorable environmental situation, occupational hazards, social conditions, etc., that primarily affect patients with a hereditary predisposition (1–3, 12).

Of the endogenous factors, concomitant diseases of liver, kidneys, alimentary canal, respiratory system, and skin also play an essential role in allergy formation. Analysis of physical status of allergic patients showed a high percentage (67.5%) of concomitant pathology, especially liver pathology (chronic hepatocholecystitis, cholelithiasis, biliary dyskinesia), the alimentary canal (intestinal dysbiosis, enterocolitis, helminthic invasion, etc.), kidneys, etc. (3–6, 10). These diseases play an essential role in pathogenesis of allergic disease relapses.

Impairment of barrier function of internal organs in chronic diseases facilitates entry of various exoallergens (drugs, dust, food components, etc.) and xenobiotics of industrial origin into the body and also deteriorates detoxification and elimination of these foreign substances from the body. As a result of significant antigenic stimulation of immunocompetent cells, hyperproduction of IgE occurs (primarily in individuals with hereditary atopy), increased synthesis of immune complexes with damage to the membrane of mast cells (blood basophils), and release of biologically active substances from them into bloodstream - histamine, serotonin, acetylcholine, etc. Accumulation of these substances in the body leads to development of endotoxicosis and aggravates the patient’s condition (3, 10–15).

Endotoxicosis is understood to be a multifactorial pathological process based on systemic tissue hypoxia with all its complex metabolic consequences. With endogenous intoxication, catabolism processes intensify, tissue alteration, liver and kidney failure, microcirculation disorders, and metabolic disorders occur. Exposure of cells to xenobiotics leads to changes in the properties of their membranes and disruption of intracellular homeostasis and metabolism. As a result of these pathological processes, toxins penetrate intercellular space and enter bloodstream. Regardless of how exoallergens enter the body, biologically active substances enter bloodstream and are distributed throughout organs and tissues affecting them either at the site of penetration or at the level of organs and systems. Toxic products of allergic reactions and various ecopathogens (in a native or transformed form) enter through liver, pancreas, and intestinal mucous secretions, into the digestive canal’s lumen, from where they can be reabsorbed into the blood. Having passed phases of biotransformation, xenobiotics as endogenous toxic substances are thus distributed between the blood, tissues, and enteric system (15–22).

Given the mechanisms of pathogenesis and toxic manifestations of allergic reactions, it is advisable to use detoxification methods in the complex treatment of patients with allergic diseases. From this point of view, enterosorbents, and in particular, enterosorbents based on silicon dioxide, which have been available in the Ukrainian and other post-Soviet markets for over 30 years, have proven themselves as safe and effective. These are affordable nutritional supplements and medicines that have universal sorption and detoxifying properties to address a variety of pathogenic intestinal microorganisms, food, helminthic, household and industrial toxins and allergens, circulating immune complexes, and inflammatory mediators (23–35) – all factors that play a critical role in sensitization and development of allergic reactions of various origins. These nonspecific properties of enterosorbents make it possible to be considered reasonable components in complex therapy of allergic diseases, which can significantly alleviate the course of these diseases and improve the life quality of sensitized patients.

Many external agents, including allergens, enter the digestive system. Due to unique properties of the mucosa of the digestive canal, a barrier exists in the intestine that serves to prevent penetration of allergens into the blood, including dangerous microorganisms, viruses, and toxins. Low acidity (pH) of gastric juices and presence of proteolytic enzymes both contribute to destruction of protein allergens, which in turn leads to loss of their allergenic properties (7–9, 19, 50, 73). Immune cells meanwhile protect the body from foreign agents and increase barrier properties of the intestine. Failure of the immunological defense program in the intestine’s immune system leads to increased permeability of the digestive canal mucosa for allergens and food allergies. This failure often manifests itself in overproduction of IgE antibodies and inability of the body to defend against invasion of antigens (4, 8, 10, 74). The antigen thus causes an alternating sequence of reactions: burning in the mouth, vomiting, abdominal pain, diarrhea, etc. When it enters the bloodstream, the allergen can cause drop in pressure, rash or eczema on skin, and bronchospasm in lungs (7–10). Almost any food product can become an allergen and cause development of food allergies. Protein products containing animal and vegetable proteins have more pronounced sensitizing properties, although there is no direct relationship between protein content and allergenicity of products (10, 75).

Of the endogenous factors, a significant role in formation of allergies is concomitant diseases of the liver (chronic hepatocholecystitis, cholelithiasis, biliary dyskinesia), the digestive canal (intestinal dysbiosis, enterocolitis, helminthic infestations, etc.), kidneys, respiratory system and skin. These diseases play an essential role in pathogenesis of relapses of hypersensitivity, both with and without an immunological mechanism of development (9, 16, 51). Presence of intestinal dysbiosis, even in subcompensated forms, often results in presence of products of incomplete digestion in the intestine. These, in turn, support clinical manifestations of food allergies since they can be allergens and, at the same time, enhance inflammatory changes in the digestive canal mucosa due to direct irritating effects (9, 54, 58, 72, 74).

Functional immaturity of the immune and digestive systems, insufficient production of digestive enzymes, deficiency of beneficial microflora, and intestinal infections, all play an essential role in formation of food allergies in children. The risk of a food allergy developing in a child may increase in presence of toxicosis, allergy, infection (helminthic, bacterial, fungal), and associated diseases, as well as being the result of an unbalanced diet during the mother’s pregnancy and during breastfeeding. Allergic sensitization of a child may be influenced by the nature of feeding (natural or artificial), types and timing of introduction of complementary foods, drug therapy, and allergens that enter the body from the environment. In addition, genetic predisposition to food allergies is of great importance. If neither parent has an allergy, then allergies are likely to occur in 4-10% of children; if one of the parents has allergies, then this probability increases to 25-50%; if both parents have allergies, then the probability of the child having an allergy increases to 40-80% (6, 8–10). A special low-allergenic diet currently is however not recommended for healthy people and pregnant and lactating women with a hereditary predisposition to atopy. On the contrary, it is believed that presence of allergens in the blood and milk of the mother contributes to development of tolerance to these food allergens in the child (76–78). However, exposure to epigenetic factors during fetal development and the first thousand days of life after birth remains a high-risk factor for child sensitization (79).

With regard to allergic reactions to food components, it is important to distinguish between two main types of food allergy: true food allergy and pseudoallergy (non-allergic hypersensitivity). Non-allergic food hypersensitivity is clinically similar to an immediate type allergic reaction but it develops without participation of basic immunological mechanisms, such as IgE sensitization and Th2 response. Pseudoallergy differs from other reactions associated with food intolerance (defects or absence of digestive enzymes, psychoemotional intolerance) in that the same mediators are involved in its manifestation as in true food allergies (histamine, leukotrienes, prostaglandins, cytokines) albeit they are released from allergy target cells in a nonspecific way, that is, without the participation of IgE or other allergic antibodies. In this way, pseudoallergy is a result of the direct impact of food substrate antigens on target cells, in particular, mast cells, and, indirectly, with the activation of several biological systems by the antigen, such as the kinin system, the complement system, etc. in the absence of the immunological link of allergic sensitization (4, 8–10, 70).

Among the mediators of pseudoallergy, histamine plays a unique role. Many factors provoke development of food pseudoallergy: excessive intake of histamine into the body with foods rich in histamine, tyramine, and histamine liberators; excessive formation of histamine from food substrates; increased absorption of histamine with functional insufficiency of the digestive system mucosa; increased release of histamine from target cells; violation of the synthesis of prostaglandins, and leukotrienes (8, 9, 80).

Diagnosis of non-allergic hypersensitivity is based on the clinical pattern, dynamics of the course, and response to the elimination of pseudoallergy causes (80–83). True allergic reactions to food allergens are detected in approximately 35% of cases and pseudoallergic in 65% (9, 10, 12, 70).

Development of food allergies or pseudoallergies provokes disorders common to adults and children. It results in an increase in the permeability of the intestinal mucosa, pancreatic insufficiency, enzymopathy, inflammation of the biliary tract, intestinal dyskinesia, etc. Disorderly eating and rare or frequent meals meanwhile lead to impaired stomach secretion, gastritis, mucus hypersecretion, and other disorders contributing to development of food allergies or pseudoallergies (9, 10, 81, 84, 85). When digestive and hepatobiliary systems function correctly, food products supplied through the enteral route do not result in sensitization. Often the reason for pseudoallergies in food is not the foods themselves but various chemical additives introduced to improve taste, smell, and color and ensure shelf life (83).

Polymorphism of pseudoallergic skin rashes to food varies from urticaria (10–20% of the examined persons), papular eruption (20–30%), erythematous, and macular (15–30%) to hemorrhagic and bullous rashes (18, 19, 80, 82, 83). However, dividing food allergies into true and pseudoallergy is somewhat arbitrary. The same patient may develop hypersensitivity reactions to foods due to involvement of specific immune mechanisms and non-immune reactions. In addition, with a true food allergy, the patient may develop pseudo-allergic reactions to food over time, which aggravates the severity of the disease, making diagnosis difficult, and reducing the effectiveness of treatment.

Main principles of treating food allergies are an integrated approach with phased-in therapy aimed at elimination of allergy symptoms and prevention of exacerbations. To reach optimal results, the treatment should include drug therapy, elimination therapy, environmental control, allergen-specific immunotherapy (3, 6, 8–10, 93–95), and nonspecific approaches, such as enterosorption (24, 27, 32, 33). The most promising treatment method being studied is allergen-specific immunotherapy (AIT), which primarily includes oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) approaches (96–103). Additionally, there are currently actively studied adjunct and alternative treatment methods, such as use of IgE inhibitors, probiotics, and early introduction of allergenic foods in infancy (93–95, 97, 104–106). However, typical treatments still include food allergen elimination and AIT (96, 97, 107).

An effective measure to detoxify the body is an efferent (sorption) therapy aimed at accelerated removal from the body of xenobiotics, harmful metabolites, circulating immune complexes, mediators of allergic reactions, inflammatory cytokines, food and industrial toxins, decay products of helminths, and other toxic substances. Experience with this type of treatment, mainly in post-Soviet countries, has shown the feasibility of its use in the acute period of allergic diseases and to prevent recurrence of the disease. Today, enterosorption is a component of complex therapy for various types of intoxication, including allergic, with a scientifically based and clinically proven efficacy (23–35, 111–125).

Sorbents are used to fix and remove food allergens from the digestive canal, in addition to products of incomplete enzymatic cleavage (medium molecular weight toxic metabolites) released as a result of allergic or eosinophilic inflammation, biologically active substances (serotonin, histamine, bradykinin, neuropeptides, prostaglandins, leukotrienes, etc.), pathogenic, opportunistic microorganisms and viruses, bacterial endotoxins associated with impaired intestinal microbiota. Binding of these substances in the intestinal lumen prevents their absorption, promotes their rapid and safe excretion, and improves conditions of the digestive system (23, 25–30, 34, 35). Indirect effects of sorbents are elimination or weakening of toxic-allergic reactions, prevention of endotoxicosis, reduction of the metabolic load on organs of excretion and detoxification, restoration of the integrity and permeability of the intestinal mucosa, stimulation of intestinal motility, and improvement of blood supply (24, 27–33, 120, 121, 124, 125). Figure 3 summarizes clinically significant effects of enterosorbents application. The main advantage of enterosorption is its non-invasiveness, a small number of contraindications, the absence of complications, and changes in the biochemical composition of the blood through a sustained course of treatment (26, 30, 32, 116–118, 120, 121, 123). Enterosorbents are successfully used not only as a pathogenetic but also as an etiotropic mono- and combined therapy for intestinal infections and other infectious diseases (23, 26, 29, 30, 35). The clinical efficacy of some enterosorbents in mild and moderate forms of intestinal infections is not inferior to antibiotics (32). Effectiveness of enterosorption is comparable to the use of probiotics (120, 121).

There are several sorption methods using different physiological mechanisms. In practice of allergists, the most acceptable method is enterosorption, based on binding and removal of toxic substances and metabolites from the digestive canal (33, 111, 112). The gastroenterosorption detoxification involves the possibility of reverse passage of toxic substances from the blood into the intestine with their further binding by enterosorbents (9, 24, 30) The use of enterosorbents is applicable both in acute periods of allergic diseases and in inter-recurrent periods. Since the barrier function of the gastrointestinal canal mucosa is impaired, many toxic substances can be absorbed and lead to endotoxicosis, which is often found in patients with urticaria, atopic dermatitis, and other allergic reactions (24, 32, 33).

Enterosorption, as an effective detoxification method, is used for treatment of urticaria, psoriasis, atopic dermatitis, eczema, lupus erythematosus, dermorespiratory and dermointestinal syndromes, bronchial asthma, and other diseases (23–28, 32, 33, 114, 115, 119). With food and drug allergies and atopic dermatitis, using sorbents in complex therapy leads to more rapid regression of skin rashes and subjective sensations, as well as normalization of the gastrointestinal canal function. There is a positive effect in terms of laboratory parameters such as the decreasing number of eosinophils and level of total IgE in blood (28, 32, 119), increasing in cellular and humoral immunity, in particular, the number of T lymphocytes increases, eosinophilia decreases, level of circulating immune complexes decreases, while content of immunoglobulins class M and E stabilizes, itching reduces, and edema phenomena and hives decrease (24, 28, 33, 34, 113–119, 122). It is significant that at the same time, enterosorbents increase sensitivity to hormones, making it possible to reduce the amount of glucocorticosteroid therapy by 50 percent on average and, in some patients, complete withdrawal of hormonal therapy (32).

In patients with bronchial asthma, enterosorption has demonstrated positive results when combined with unloading and dietary therapy: signs of intoxication, intensity of concomitant skin-allergic manifestations, hormone dependence, drug intolerance, frequency and severity of bronchospasm attacks decrease (24, 33). The use of enterosorbents is effective in metabolic disorders in allergic patients and in detoxification of organs. Function of internal organs is improved with concomitant pathology of the hepatobiliary system, kidneys, cardiovascular vascular diseases, and diabetes. The ability of enterosorbents to reduce antigenic load on the body makes them suitable as a preventative measure for persons who come into contact with a large number of harmful substances in manufacturing and everyday life, as well as those living in industrial regions (23–35, 113, 115).

Development of intestinal dysbiosis plays an important role in formation of allergic reactions, in particular in food allergies. Dysbiosis contributes to increasing the permeability of the intestinal wall for products with sensitizing activity. Also, metabolic products of microorganisms themselves can be allergens. Therefore, normalizing intestinal microbiota, including the use of enterosorbents, is the fundamental principle of food allergies treatment (9, 29, 33). When the intestinal barrier function is intact, with typical microflora composition, endotoxins penetrate bloodstream in small amounts and are detoxified in liver hepatocytes. Conversely, with dysbiosis development, endogenous intoxication is maintained, resulting in increased permeability of the intestinal wall and weakening of adaptive and protective mechanisms. At the same time, some pathological processes in the body can cause intestinal dysbiosis and formation of endogenous intoxication by themselves, thus creating a vicious circle. These are diseases of the gastrointestinal canal with impaired motor evacuation and secretory functions (chronic pancreatitis, cholelithiasis, chronic gastritis, liver steatosis, hepatitis, etc.), resection of the stomach, small or large intestine, diverticular disease, past intestinal infections, helminthic infestations, giardiasis, or taking certain medications, including antibiotics, as well as chronic diseases of other organs and systems. In all these cases it is also advisable to prescribe enterosorption therapy (23–29, 35, 84, 100–105, 113–115).

Enterosorbents should be included in complex therapy in the first days or hours of exacerbation of an allergic disease or an acute allergic reaction. They are introduced into the gastrointestinal cavity orally. Usually, sorbents are prescribed 1.5-2 hours before meals. This period is needed for the enterosorbent to react with the stomach content and to be partially evacuated to the intestine, where its interaction with components of the intestinal contentcontinues. Sorbents and other drugs should not be applied simultaneously; there should be 2-3 hours between respective intakes. For most sorbents, the daily therapeutic dose is 0.2-1 g/kg of body weight, and maximal doses - are up to 2 g/kg of body weight. At the same time, the daily dose of enterosorbents is evenly distributed into 3-4 doses between breakfast, lunch, and dinner. The course of treatment is 6-8 days (no more than 14 days) with a gradual dose reduction over the last 2-3 days (23–30, 113, 115, 119, 120, 123).

Preventive (anti-relapse) dose of enterosorbents is 0.2-0.5 g/kg of body weight. Sorbents should be used for a 7-10-day period, during which it is possible to take them both in the morning and in the evening, 1.5-2 hours after dinner. A prophylactic course for allergic patients should be carried out monthly (in the first three months), then once a quarter during a year. Frequency of prophylactic enterosorption treatment is decided individually for each patient, taking into account the severity of both underlying and concomitant pathologies (24–27, 29).

Clinical effect of enterosorbents depends on timelines of their prescription - the earlier the drug is administered, the higher the sorption coefficient and clinical effect. A negative factor of several sorbents is, however, the sorption of vitamins, mineral salts, and other valuable substances, as well as the nonspecific sorption of enzymes (pepsin, trypsin, amylase), which in some cases requires correction by enzyme replacement therapy (26, 27, 32, 123).

General contraindications for the use of enterosorbents are erosive gastritis, peptic ulcer of the stomach and duodenum, ulcerative lesions of the intestine, and its atony. Cautious use of enterosorbents is recommended for patients with reduced intestinal peristaltic activity. A relative contraindication is a tendency to constipation. Excretion during the process of enterosorption should be daily; if necessary, laxatives are prescribed. While taking enterosorbents, increasing the drinking regimen and consuming foods with a high fiber content are recommended. Vitamin preparations are also recommended (24, 26–29, 32, 33, 35, 113–115, 119–121).

Sorption therapy of persons with allergic diseases should be individualized for each patient, considering comorbidity and tolerance to the sorption preparation. Mandatory indications for including enterosorbents in the complex of rehabilitation measures are acute allergic reactions of any etiology. Enterosorbents are indicated for prophylactic purposes for people with hereditary atopy and for patients receiving long-term corticosteroid therapy with concomitant liver, kidneys, and intestines pathology that slows down the detoxification of xenobiotics. Sorption methods for treating allergic diseases and concomitant pathological conditions are highly effective and practice safe methods of endogenous detoxification. They are recommended for widespread introduction into clinical practice in inpatient and outpatient settings for different age groups of patients (9, 24, 33, 113–119, 123). In post-Soviet countries, enterosorbents are included in the protocols for treatment of various manifestations of food allergy in children, along with an elimination diet and systemic treatment, depending on clinical symptoms of the disease (24–26, 29, 32, 33).

For enterosorbents, the main considerations that should be taken into account, especially for enterosorbents used in pediatric practice are the following:

Many enterosorbents that meet the above requirements already exist in the arsenal of therapies available to pediatricians. These methods have been used in clinical practice for over 30 years and are used globally (23–33, 111, 112, 128–132).

All of them have certain advantages and can be prescribed to allergic patients depending on individual indications, including such characteristics as tolerability, efficacy, features of the course of the underlying disease, and presence of concomitant diseases. This review is limited to detailed consideration of enterosorbents based on silicon dioxide, particularly a drug known under the trade name “White Coal” (Carbowhite) produced by the Ukrainian company OminiFarma ( Figure 4 ).

Silicon (Si) is one of the chemical elements found in the Earth’s crust, and it ranks second in abundance after oxygen (125, 133). The oxide forms of silicon are silicate (SiO4) and silica (silicon dioxide, SiO2), which are also present in various plants, organs, and tissues of humans and animals, and enter the human body with food, being physiological components of the body (125, 133). Silicon is widely used in industry, and its oxide forms are often used in biomedical applications. Silica nanoparticles have several rare properties, such as ease of synthesis, modifiable surface, strong mechanical properties, and relatively inert chemical composition, which ensure the durability of biomaterials based on them (134–137).

There are two primary states of silica - crystalline and amorphous ( Figure 4 ). Both conditions have the same molecular formula but differ in structural arrangement (133, 134). The lattices of crystalline silica are arranged regularly, while the lattices of amorphous silica are arranged irregularly (121–139).

Crystalline silica has several forms. A well-known form is α-quartz, which can be converted to β-quartz, tridymite, and cristobalite when heated. There is also porous crystalline silica called porosil; all porosils are synthetic. Terms nanoporous, mesoporous, and microporous refer to the pore diameter. “Nanoporous” refers to materials with pore diameters less than 2 nm, “microporous” refers to materials with pore diameters greater than 100 nm, and “mesoporous” refers to materials with pore diameters between 2 and 100 nm (133, 134, 136, 140). Mesoporous silicon and silica particles are ideal candidates for controlled drug release due to their rare properties, such as high surface area, large pore volumes, controlled pore sizes, and good chemical and thermal stability (135, 136, 141).

Amorphous silica can be divided into three groups: natural form (rare), a by-product of power plants and metallurgical production, and synthetically created silica (133, 134). Amorphous synthetic silica is a promising candidate for gene carrier and molecular imaging, mainly due to its highly tunable biocompatibility and stability (126, 127). In addition, it is also used in dietary supplements (142), catheters, implants, and dental fillers (143).

Nanoparticles are one of the most general terms for designating isolated ultradispersed objects, duplicating previously known terms (colloidal particles, ultradispersed particles) but differing from them in clearly defined dimensional boundaries. Solid particles less than 1 nm in size are usually referred to as clusters and more than 100 nm - to submicron particles. A nanoparticle is an isolated solid-phase object, the dimensions of which in all three sizes range from 1 to 100 nm. At the same time, in some fields of knowledge, in particular, in biomedical nanotechnologies, nanoparticles are often conventionally referred to as objects with a diameter of up to several hundred nanometers, the small size of which also plays a significant role in their properties and application, in particular, providing increased mucosal absorption during oral administration. At present, it is generally accepted by the world scientific community that nanoparticles of synthetic amorphous silica and, especially, submicron particles do not have toxic side effects when used in sufficiently high doses and are almost eliminated from the gastrointestinal canal physiologically without entering into biological fluids (23–30, 32, 33, 91, 92, 114, 133–136, 138, 144–151). Moreover, the use of amorphous silica nanoparticles (Aerosil 380 and Aerosil 200) has been approved in the European Union as a safe food additive E551, and Aerosil 300 is widely used in pharmaceutical and cosmetic industries (135, 144, 145, 151–153).

The Manufacturers Association of amorphous silica and independent studies have verified the safety of synthetic amorphous silica. In particular, in several works, based on a comparison of numerous clinical and laboratory studies, it was shown that none of the forms of silica, including colloidal nanoparticles, bioaccumulates. All of them are eliminated from living organisms within a short time using physiological mechanisms (150, 151). Research centers and individual experts in the European Union and the USA have evaluated the daily dosage limits of synthetic amorphous silica, which would lead to undesirable toxicological effects. A brief review of animal studies on the oral safety of amorphous silica has been published by the Organization for Economic Co-operation and Development (OECD) (152) and the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) (153).

Silicon dioxide-based enterosorbents are produced from high-quality patented raw materials from Evonik (Germany), obtained using a unique technology that allows the creation of soluble porous and non-porous materials from the lightest fraction of silicon dioxide (nanoparticles 7-40 nm in size), which include Aerosil Ox50, Aerosil 130, Aerosil 150, Aerosil 200, Aerosil 300, Aerosil 380 (135–137, 144, 152, 153). They have a high degree of dispersion and a large sorption surface area. Therefore, the daily dose of silica preparations is only 2-4 g, almost ten times less than that of activated carbon (29). Silica preparations are prescribed for adults and children over three years old, 3-4 tablets up to 4 times daily. With prolonged administration in therapeutic doses, silicon dioxide preparations do not cause noticeable changes in the activity of enzymes of the intestinal mucosa; they differ in lower (compared to other sorbents) excretion of vitamins and microelements and their rapid recovery to normal levels without additional drug load (30, 32, 34, 35, 116, 118), which is typical, in particular, for the enterosorbent White Coal (Carbowhite).

The active substance of the enterosorbent White Coal is a highly dispersed, non-porous colloidal anhydrous silicon dioxide (silica, SiO2). The drug is manufactured using modern, highly dispersed technology from patented raw materials, silicon dioxide Aerosil 300 from Evonik ( Figure 4 ). The safe dosage range of Aerosil 300, used in the drug White Coal varies from 100 to 300 mg/kg of body weight/day, with short-term use - up to 1000 mg/kg per day (23).

The production technology guarantees that the White Coal tablet will disintegrate in the body in a few minutes, turning into a highly dispersed suspension, while 1 g covers 380-400 m². The product was introduced to the Ukrainian market in 2008. To date, the clinical evaluation of the efficacy and safety of the product has been shown by multiple studies, which also showed the absence of any undesirable side effects of treatment (23, 35, 115–118, 154–160). White Coal is registered as a drug in Ukraine, Georgia, and Uzbekistan.

According to the manufacturing specification, the particles of silicon dioxide in feedstock used for production of the White Coal have a size of 7 nm, which during the production process under the influence of high temperature, form submicron agglomerates with a size of more than 100 nm (137, 160). It is essential that during the production of the White Coal, silicon dioxide Aerosil 300 is subjected to the process of further additional coarsening of agglomerated particles according to the patented wet granulation technology of the Omnifarma company, that is, the White Coal is not a nanoproduct and does not carry the risks associated with possible systemic toxicity or toxicity to the immune system when taking therapeutic doses of silicon dioxide nanoproducts (146–153, 161). No evidence exists of natural mechanisms for the degradation of Aerosil 300 agglomerates to their original nanoparticles in the human body. Such deagglomeration can only be achieved by ultrasonic irradiation (138) or by passage through the gastrointestinal canal with pH > 12 (151), which is not possible in the human body (162). Therefore, amorphous silicon dioxide used in White Coal is a structurally stable submicron agglomerate of nanoparticles that remain intact in the gastrointestinal canal. Moreover, these agglomerates cannot pass through the intestinal epithelial barrier and thus do not circulate in the body fluids with the exception possible presence of a very limited number of free nanoparticles. This unique property of White Coal significantly contributes to its safety profile when used as the enterosorbent and reduces potential negative consequences associated with the possible presence of trace amounts of free amorphous silica nanoparticles in the product. Nevertheless, to clarify the safety profile of the White Coal drug, it is advisable to conduct further studies of its pharmacokinetic and pharmacodynamic properties. White Coal is produced as tablets containing 210 mg of the active substance. It is easily dispersed in the gastrointestinal canal, forming a large sorption surface. It is almost entirely (more than 99%) excreted from the intestine through feces, practically without entering the systemic circulation (less than 1%). From systemic circulation, the drug is excreted through the kidneys with urine. The enterosorbent is widely used as mono and complex therapy for acute intestinal diseases (salmonellosis, food poisoning), acute diarrhea of various etiologies, and exogenous intoxication with household and industrial toxins, drugs, alcohol, and food intoxications. It is also used as an adjuvant for viral hepatitis, allergic diseases, dermatitis, late gestosis of pregnant women, cirrhosis of the liver, chronic toxic hepatitis, chronic non-calculous cholecystitis, non-alcoholic fatty liver disease and other mono and complex pathologies ( Figure 4 ). At the same time, the enterosorbent does not cause constipation and absorbs toxic substances in the intestines selectively, without loss of beneficial trace elements. In addition, due to the formation of concentration and osmotic gradients, White Coal promotes the removal of various toxic products from the internal environment of the body (blood, lymph, interstitium), including medium molecules, oligopeptides, amines, and other substances, which are formed in a result of systemic inflammatory and allergic reactions (23, 35, 113, 115–118, 154–161). Figure 5 demonstrates the distribution and the mechanism of action and evacuation of the enterosorbent White Coal from the digestive system.

A remarkable feature of enterosorbent White Coal is the combined effect of silicon dioxide (Aerosil 300) and microcrystalline cellulose, which is part of its composition as an additional active substance. Microcrystalline cellulose positively impacts the tablet’s properties (163) and functions of the gastrointestinal canal (164). This food additive enhances the buffering effect of food, potentiates the hydrolysis of proteins in the stomach, modifies the secretion of gastrointestinal hormones, affects the transit and hydrolysis of nutrients in the small intestine, inhibits the absorption of monomers and bile acids, reduces intracavitary pressure in the colon, stimulates intestinal motility and growth of microflora, reduces the risk of gallstone formation, and has a hypoglycemic effect (29, 31, 164). Following a request from the European Commission, the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) delivered a scientific opinion re‐evaluating the safety of microcrystalline cellulose (E 460(i)) and modified variations. From the reported studies, the Expert Panel considered a safe application for the microcrystalline, powdered, or modified cellulose to be around 660–900 mg/kg body per day (165).

In 2016, a multicentre, randomized, double-blind, placebo-controlled study of the efficacy and safety of White Coal in acute diarrhea was conducted (level of evidence I (A) according to CEBM (35). Administration of White Coal to patients (children and adults) with acute diarrhea during 3-5 days in doses 1260, 1890, and 4200 mg daily (for different groups) resulted in the termination of diarrhea in an average of 1.7 days without any side effects (35). The clinical trial results were approved by the US FDA - available at the ClinicalTrials.gov web resource (166).

In 2009, the results of a clinical study on the use of the enterosorbent White Coal in the complex treatment of children with manifestations of food allergies were published (113). The study was conducted as an open randomized in the National Children’s Specialized Hospital “Okhmatdet” (Kyiv, Ukraine). Under observation were 46 children aged 1 to 15 years with manifestations of food allergies against the background of various allergic pathologies.

The studies were carried out in dynamics: in the acute period of the disease (before treatment), on the 7th and 14th days of complex therapy with the inclusion of the White Coal. The enterosorbent was administered orally in 3 doses at a total daily dose of 150 mg/kg, 1 - 1.5 hours before meals and between doses of other drugs for 14 days. The effectiveness of treatment was assessed according to the following criteria: SCORAD index, level of total and specific IgE, degree of dysbiosis, level of hematological activity, the full dose of systemic glucocorticosteroids, and duration of the acute period.

The treatment resulted in a reduction in duration of the acute period of atopic dermatitis, urticaria, and angioedema, a decrease in the level of specific IgE to cow’s milk proteins in children with atopic dermatitis, and an improvement in the state of the gastrointestinal canal with the decreasing of dysbiosis symptoms. The total dose of systemic glucocorticosteroids was reduced in children with an acute episode of urticaria and angioedema. These data indicate a relatively high clinical efficacy of the 14-day course of the enterosorbent White Coal in children aged 1 to 15 years with manifestations of food allergies against the background of various pathologies ( Figure 6 ).

The effects of silica exposure on the body, especially crystalline silica, have been studied extensively. Studies have shown that exposure to crystalline silica associated with the use or production of this material causes silicosis (fibrous lung disease) in workers and that this exposure is also associated with other lung diseases such as lung cancer, lung emphysema, pulmonary tuberculosis, autoimmune diseases (149, 166–169). The toxicity and pathogenicity profile of silica, and therefore the risk of silicosis, depends on the inhaled particles’ size and physical and chemical properties (167–171). It has long been thought that the crystal structure imparts silica toxicity. Still, recent studies show that the number and distribution of sialon and siloxane groups, rather than crystallinity, act as primary toxic factors (172, 173).

The safety of using amorphous silica and, mainly, silica nanoparticles, their systemic toxicity, and toxicity to the immune system are also discussed (133, 146–153, 161). Amorphous silica used to be considered less harmful than crystalline silica. However, recent studies have shown that amorphous silica nanoparticles may have the same potential toxicity as crystalline ones (146, 173). It is believed that the physicochemical properties of amorphous silica nanoparticles can have various toxic effects in vitro and in vivo. Several reviews have considered this issue in detail (134, 161, 173, 174).

The studies were mainly focused on the initial stages of the interaction of silica with cells located in the lungs and immunological modifications of the innate immune cellular response. Special attention was paid to the primary interaction of silica with alveolar macrophages. Usually, silica particles enter the alveolar space after inhalation and interact with macrophages, resulting in inhaled particles entering the phagosomes. The macrophage receptor MARCO has been described as the primary molecule responsible for silica recognition and uptake by macrophages (175). Other receptors from the group of recognition receptors (Pattern receptors) may also be involved in this process. In particular, it has been shown that CD204 can interact with silica and inhibit the activity of macrophages. In addition, significant downregulation of Toll-like receptor 2 (TLR2) after silica exposure may contribute to increased susceptibility to tuberculosis (176). Finally, the inability of macrophages to digest and remove phagocytosed silica particles leads to persistent inflammation and modification of the cellular response (177).

Some authors believe silica nanoparticles can interact with immunocompetent cells and cause immunotoxicity (146, 176, 177). The effect of silica nanoparticles on the immune system depends on the physicochemical properties of the nanoparticles and type of cells they affect and lead to different results (134, 138, 178, 179). The effector cells involved in these reactions are mainly tissue macrophages, peripheral blood monocytes, polymorphonuclear leukocytes, dendritic cells, lymphocytes, mast cells, and other cell types, modifying the immune response (34, 134, 146–149, 161, 178, 179).

Silica exposure can reduce cellular function and DCs’ activation, leading to a nonspecific attenuated inflammatory response disrupting antibacterial defense mechanisms and increasing susceptibility to bacterial infections, primarily Mycobacterium tuberculosis and other mycobacteria (176, 180, 181). However, the impact of silica on immune responses is complex and does not always result in increased susceptibility to bacterial infections; some effects promote the elimination of mycobacteria rather than their reproduction (161).

Potential toxicity of nanoparticles to immune cells is related to their ability to induce direct cell damage, such as apoptosis and necrosis. Functions of immune cells may change after interaction with nanoparticles, and this may affect immunospecific signaling pathways. Toxic effects can be assessed by functional activity of cells, development of pro-inflammatory reactions, generation of reactive oxygen species, cellular dysfunction, cytotoxicity, genotoxicity, and their underlying mechanisms (134, 182–191). Assessing the interaction between nanoparticles and cells of the immune system is critical in determining safety of silica nanoparticles, which are widely used in biomedical applications due to their unique chemical and physical properties (192, 193). In general, toxic effects of silica nanoparticles on the immune system in vivo are rare and occur only at oral doses significantly higher than the recommended allowable values (134, 170–174, 182–184, 194). Based on risk assessments of amorphous silica toxicity with known sources of silica, such as dietary supplement E551, a safe upper intake level has been estimated at 720 mg/day for a 60 kg adult, equivalent to 12 mg silica/kg body weight/day (133).

Considering the discussion regarding the possible toxicity and immunotoxicity of amorphous silica nanoparticles, the expert committee of the European Commission in 2018 revised the recommendations regarding the food additive E551. It concluded that, at the moment, there are no grounds for conclusions about the toxicity of this product for humans, and the recommendations of the European Commission made for it earlier, in 2009, remain valid (144, 145).

Amorphous silicon dioxide food supplements and drugs, particularly White Coal (Carbowhite), are safe at recommended doses because they are structurally stable submicron agglomerates of nanoparticles that do not disaggregate in the gastrointestinal canal and are hardly absorbed into body fluids. Given the composition and properties of White Coal, its usage scope can be extended to a wide range of allergic diseases, primarily food allergies. It is advisable to include White Coal in complex treatment of food allergies in adults and children over three years of age, as it contributes to faster relief of symptoms of damage to the gastrointestinal system, reduces endogenous intoxication, reduces drug load, and improves the patient’s quality of life. In addition, the high safety profile of White Coal and its unique sorption properties make it possible to recommend this enterosorbent to pregnant and breastfeeding women, especially during an exacerbation of allergic inflammation, to prevent allergic sensitization in hereditarily predisposed newborns.

VS collected and reviewed the literature, wrote and redacted the manuscript, and designed the illustrations. OK and EO redacted the manuscript and illustrations. VC and DD revised the manuscript and figures, contributed to rewriting Section 6 “Treatment of Food Allergy”, approved the final version of the revised manuscript, and agree to be accountable for all aspects of the work. All authors contributed to the article and approved the submitted version.