Cytotoxicity of nanoparticles of welding aerosols (data from literature and own research)

  • Authors: O.B. Leonenko, N.S. Leonenko, V.А. Movchan, A.O. Lukianenko
  • UDC: 546.3-168:615.9
  • DOI: 10.33273/2663-4570-2018-81-1-25-38
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O. Leonenko1, N. Leonenko1, V. Movchan1, A. Lukianenko2

1State Institution "Kundiiev Institute of Occupational Health of the National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
2 E.O. Paton Electric Welding Institute of the National Academy of Sciences of Ukraine, Kyiv, Ukraine

Abstract. The data of literature and own researches concerning features of toxic action of welding aerosols are generalized. Which have a different chemical composition and dimensions. Their damaging effect depends on many factors. Prolonged exposure may occur in low concentrations. Most of the negative effects are determined by oxidative stress and DNA damage. There are the most dangerous components of welding electrodes are chromium and nickel.
Key words: welding aerosol, nanoparticles, cytotoxicity, damaging effect.

The modern period of scientific progress is related to the development of the latest nanotechnologies, leading to the improvement and appearance of new consumer qualities and properties of products that are many times higher than the existing level. At the same time, the production of nanomaterials, as well as traditional technologies (electric welding, diesel fuel combustion, industrial production, processing of plant raw materials) are accompanied by the emission of nanoparticles (NPs) into the environment. Natural processes like forest fires, volcanic emissions, etc. can also be sources of ultrafine aerosols with the particle size of up to 100 nm. [1,2].

The peculiarity of NP toxic effect formed during welding works may be that fact there are NPs of certain chemical elements of different sizes at the same time in the air of the working area. Thus, in assessing NP exposure levels in the workplace of the electric welder, the maximum concentration of NPs from 1 to 100 nm during ANO-4 electrode welding was about 42,473 particles/cm³, which exceeded the “test” exposure levels, while the background concentration of particles from 1 to 100 nm was 8,484 particles/cm³, and therefore, it corresponded to the recommended levels [3]. In turn, eight metals (Al, Mg, K, Mn, Zn, Fe, Cu, Ni) were detected by atomic emission spectrometry in the air of the working zone, in which the concentrations of aluminium, magnesium, manganese, zinc, nickel and chromium exceeded the estimated values of the safe exposure levels (SEL) of these metals for nanosized particles. So, both before and after welding works, there was an increased concentration of nickel (84.00–1,000.00 times), chromium (10.00–225.00 times), magnesium (2.62–197.00 times), manganese (2.10–4.50 times), and after welding there was an increase in the concentration of nanosized aluminium (15.64 times) and zinc (4.10 times) [3]. In general, after welding, the total concentration of particles from 1 to 100 nm in the air of the working zone may exceed the background values 2–10 times [4].

In the process of arc welding, there is the interaction of the molten metal with slag and gases, with the formation of a welding aerosol (WA), consisting of solid particles (WASC) and gas phase (WAGC). Factors influencing WASC release: electrode coating composition, cored wire filler, flux; welding mode (current and voltage); composition of the main and electrode metal; thickness of electrode coating; electrode diameter [5]. In the process of welding, the components of welding materials (Fe, Mn, Si, Ca, Mg, K, Na, Ti, Al, Cr, Ni, Cu, F, etc.) can pass in WASC. Its oxidation and condensation result in solid oxides of the above-mentioned elements [6].

Increasing the basicity of the slag phase contributes to the intense evaporation of potassium, sodium, magnesium and calcium, and the beginning of this process is shifted towards lower temperatures. The type of their binding properties and the content in the electrode coating determine to a large extent the rate of aerosol formation [5].

Welding rate with coated electrodes practically does not affect the formation of an aerosol. The sizes of individual WASC particles vary from a few nanometers to tens of micrometres [7,8,9,10]: primary particles (<100 nm), accumulative range particles (100 nm ... 1 μm) and large particles (> 1 μm). It is noted that most of the primary particles have a size of 5–40 nm [11]. Larger particles accumulate in clusters, and small ones tend to form chains. WASC consists of particles and agglomerates of spherical and non-spherical forms [12]. The nucleus of particles with a heterogeneous structure is enriched with iron and manganese compounds, and the shell contains silicon, potassium, and sodium compounds. Such heterogeneity of WASC particle structure is due to the selectivity of the process of evaporation and condensation, with some constituents condensing at different temperatures. First, there is condensation of elements with lower vapour pressure (manganese, iron), and the elements with higher vapour pressure (sodium, potassium, etc.). [5].

It is established that particles of different sizes affect the welder’s body in different ways. Particles with a diameter of fewer than 20 μm can remain weighed in the air [7], particles of more than a few micrometres in size settle on the walls of the body airways and are excreted together with mucus. About 30 % of particles of 0.1–1 μm in size, as well as of less than 0.1 μm (100 nm) in size settle in the lungs. Almost 100 % of particles with a diameter of fewer than 1 μm enter the body through the respiratory tract [10]. Nanosized particles may penetrate through the skin [13], also in the brain through the olfactory nerve (nervus olfactorius), bypassing the blood-brain barrier [14].

The key factors that determine the harmful effects of WA on the welder’s health, along with dispersion of particles, include the chemical composition of welding materials, mode of welding, levels of substances released into the air [6]. Mainly WA contains aerosols of metals and their oxides (iron, manganese, chromium, vanadium, tungsten, aluminium, titanium, zinc, copper, nickel, etc.), gaseous fluoride compounds and many other elements. In addition to aerosols, WA may contain harmful gases: carbon oxides, nitrogen oxides, ozone and others.

Since welding works are accompanied with a significant emission of nanoparticles into the working zone air, which has a higher biological activity and a damaging effect compared to macroparticulate particles of similar substances, determining regularities of mechanisms of biological action of WA nanosized fractions will promote safer use of welding technologies.

Across the globe, despite numerous studies, there is no unambiguous answer on NPs risk, since there is no complete understanding of their physical and chemical properties, effects on the body and its remote effects. For the vast majority of nanomaterials (NM), mechanisms of penetration in the body, biocompatibility, biotransformation, translocations in organs and tissues, elimination from the body and, most importantly, their toxicity [15, 16] are not fully elucidated.

Metal NPs, including those formed during the welding process, begin to react intensely with the surrounding medium, which leads to their oxidation and agglomeration. Because of its very small size, NPs can penetrate through biological membranes and get to cells, tissues and organs easier than larger particles.

The most common way of getting nanosubstances to the body is inhalation [17]. It is connected with production processes, including electric welding works, as well as penetration from the environment as a result of emissions from industrial facilities, transport, use of aerosols of NPs in everyday life, natural processes (volcanic eruptions, dust storms, etc.). When inhaled, NPs can settle in the nasopharynx, tracheobronchial region and in the alveoli. The most vulnerable organ for NPs is the lungs. The airways are well protected from penetration of large particles due to the active epithelium and mucous layer on their surface [18]. There are sensitive endings of olfactory and trigeminal nerves in the nasal and tracheobronchial parts of the respiratory tract. The olfactory nerve can be the way of NPs penetration to the central nervous system (CNS) of a person.

Regardless of the pathway to the body, NPs enter the circulatory system, spread throughout the body and can accumulate in the bone marrow, central and peripheral nervous systems, organs of the gastrointestinal tract, lungs, liver, kidneys, lymph nodes, have a long half-life [19,20,21]. Direct contact of metal NPs with biological membranes often ends with the capture of the former inside the cell with a number of mechanisms.

An important role in interaction with the biomembrane, along with the hydrophobic effect, belongs to the size of the particles [22], which determines the high penetration capacity. They are capable of both intracellular and intercellular passage of the main cellular barriers.

The mechanism of influence of nanoobjects on living structures may be due to the formation of reactive forms of oxygen (singlet oxygen, superoxide anion) in their presence [23,24,25], as well as complexes of NPs with proteins, nucleic acids [26, 27]. Formation of reactive oxygen intermediates (ROI) is a normal cellular process that participates in a variety of cellular reactions, as well as in the protective mechanism of the immune system. However, excessive ROI causes serious damage to cellular macromolecules such as proteins, lipids and DNA, which leads to harmful effects on cells.

According to current data, NPs toxicity is due to surface properties, size, shape, the chemical composition of NPs, the toxicity of decomposition products, development of apoptosis or cell necrosis or cellular membrane lysis caused by them [22, 28].

NMs, which cause free-radical oxidation, include quantum dots, carbon nanotubes, NPs of silver, titanium dioxide, iron oxide, quartz, some organic polymers [29, 30, 31], and others.

Any chemical compound in the nanoscale has a large number of active centres. It is traced on the example of fullerenes, distinguished from the number of all alkenes by the number of double bonds in hexagonal rings. Such bonds provide high reactivity of NPs in reactions with proteins and nucleic acids [22]. The presence of a large number of active centres is characteristic of almost all NPs: fullerenes, titanium oxide nanosized, carbon nanotubes, quantum dots, promoting the generation of reactive oxygen intermediates as well as lipid and protein peroxide oxidation in the body. As a result, there is disruption of the membrane structures and their functions with the subsequent increase in the permeability of biomembranes for other toxicants, development of inflammation [15, 32].

The participation of NPs in the process of formation of oxygen radicals depends on the surface properties of NPs (photochemical, electric field, charge density and electron conductivity). Increased levels of free radicals result in the destruction of macromolecules (e.g. phospholipids, nucleic acids and proteins), impaired cellular processes (obtaining energy in mitochondria, etc.).

It is impossible to exclude the presence of other mechanisms of NPs toxicity associated, in particular with their harmful effects on cellular membranes and organelles, increased transport of potentially toxic components through the barriers of the body, as well as possible genotoxicity and allergic action [33].

One of NPs peculiarities is their high specific surface, which increases the adsorption capacity. This property causes NPs ability to adsorb various contaminants on their surface and facilitate their transport inside the cell, which dramatically increases the toxicity of the latter [22, 34, 35].

There are certain electrophysical properties that contribute to the change in the structural and energy states of intracellular fluids due to donor-acceptor interaction, which increases the energy capacity of intercellular and membrane exchange, on the one hand, and the state of clusters formed on the surface of NPs, on the other. With an increase in the volume of a cluster above a critical size, it breaks up with the formation of free radicals and singlet oxygen [35].

The above properties of NPs to the induction of free radicals, damage to the cytoskeleton, high permeability and ability to be located in the nucleus of the cell [36], DNA damage suggest their genotoxic action, which, according to the investigation data, may cause a higher carcinogenic risk compared with the effect of microparticles of the same compounds [22, 37]. Due to their small size, NPs can be embedded in the membrane, penetrate into cell organelles, bind to proteins, nucleic acids, and thereby change the functions of biostructures.

The combination of the above factors suggests that NPs can have completely different physical and chemical properties and a biological (including toxic) action compared with the substances in a usual physical and chemical state, therefore, they relate to new types of materials and products, thus characteristics and consideration of their potential risk to human health and environment in all cases is mandatory.

From a theoretical point of view, NPs potential toxicity cannot be predicted based on the toxicity of bulk materials of the same chemical nature. According to the literature, in NPs it is almost always greater, especially with long-term penetration to the body. Most of the results for assessing the toxicity of NPs were obtained by their single or short-term administration to laboratory animals. Many of the studied materials were found not to have acute toxicity. Instead, the effects of chronic exposure to NPs have not been sufficiently studied so far, although they may be more significant, especially for species with a long life cycle, including for humans. Nowadays, almost nothing is known about the accumulation of NPs in various organs and tissues, especially in case of chronic exposure [38]. In addition, it is impossible to exclude the possibility of transformation of NPs themselves during their migration to the body.

The main problems of assessing the toxicity of NPs include the following. First, the toxicity of NPs cannot be a derivative of the toxicity of analogues in the macro-dispersed phase or in the form of a continuous phase. Secondly, available toxicological methodologies are based on determining the toxicity of a substance in accordance with mass concentration, not acceptable for NPs, for which the size of the surface area or the number of NPs may be limiting, but not the mass concentration as such. In addition, the toxicological properties of NPs are the result not only of their chemical composition, but also the diversity of other peculiarities, in particular, surface characteristics, size, shape, composition, chemical reactivity, etc.

Nanoparticles by their nature exhibit physical and chemical properties that depend not only on the size but also on quantum mechanical, adhesive, catalytic, optical, electrical properties, and geometric characteristics. Moreover, chemicals that do not exhibit toxicity in the usual (non-nanosized) form, can exhibit it in the form of NPs.

The fundamental non-stationary and non-homogeneity of the nano-bio interface is determined by the complex structure of the protein-carbohydrate-lipid matrix of the membrane and the constantly changing cellular secretion [33]. These changes can modify the properties of the NP surface, which in turn can potentially reduce or vice versa increase the toxicity of particles [39]. As a result, we are dealing with a virtually infinite number of varieties of “interfaces” between NPs and biological objects.

As is known, the effect of NPs on living organisms is that they, due to their small size and physical and chemical properties, can overcome tissue barriers, penetrate into the cells of all organs and tissues. Further, NPs can penetrate into cell structures, including the nucleus. The studies conducted to confirm the relationship between the occurrence of serious diseases (including cancer, cardiovascular, neurodegenerative) and prolonged exposure of the body to NPs. Most likely, there are no mechanisms for their active detoxification. NPs with a complex configuration are considered to be the most dangerous.

Thus, the toxic effects of NPs, including those formed during welding operations, depend on many initial conditions of NPs themselves (including their size and structural organisation, from the physical nature) [40, 41], and of the subsequent nano-bio interfaces after penetration into the tissues and blood, so they are not predictable, and target organs and mechanisms for development of toxic effects are extremely diverse.

In the course of the analysis of nanosized fractions formed during welding with experimental electrodes with a reduced content of chromium (VI), with a rutile-type of coating (14–25, 14–26, 14–27, 14–30, 14–32) and different types of bonding agents (K-Na, K-Na-Li, K-Na, Na-Li, Li respectively), the emission of NPs into the working zone air and chemical composition of nanosized fractions were evaluated [4]. It was established that the welding was accompanied with a significant emission into the working zone air of nanoparticles, which was characterised by temporal dynamics of the total concentration of NPs, their fractional distribution and content of nanosized metals. The following nanosized metals are detected in the process of welding with experimental electrodes in the working zone air: chrome, manganese, zinc, iron, cobalt, copper, silicon. The experimental electrodes at welding showed a tendency to reduce the emission of nanosized metals, in particular, chromium, into the working zone air which corresponded to a decrease in the content of this element in their composition [4].

The toxicity of NPs of oxides of several metals that may be present in welding aerosols (NiO + Mn3O4; CuO + PbO; CuO + ZnO; PbO + ZnO; PbO + CuO + ZnO) was studied in outbred female rats upon isolated and combined action using two experimental models: single intratracheal instillation in small doses in 24 hours and repeated intraperitoneal injections for 6 weeks with non-lethal dosing [42]. A variety of combinational toxicity types for the same NP pair was shown, depending on which specific effect it was evaluated for, and often also on the dose-dependent level of this effect. It is also shown that the risk-oriented approach to the classification of three-factor toxicity, previously developed for the combined action of metals in the ion-molecular form, is also adequate for the studied NPs. The author concluded that, given the composition of welding electrodes, the welder will be exposed simultaneously to the combined effect of several different types of NPs. However, it has long been known that persons occupied in the pyrometallurgical and welding industries almost inevitably undergo the inhalation effect of a combination of metal oxide NPs formed as by-products of the technology and polluting the working zone air and surrounding atmosphere, since the combined nature of such contamination is due to the composition of welding metals, electrode lubrication, fluxes, etc. Meanwhile, on the background of the active development of toxicology of nanomaterials that is a characteristic feature of the last decade, there is a lack of work on the comparative assessment of the toxicity of various nanosized metals and almost complete lack of attention to the analysis of the regularities of their combined action [42]. Although the general problem of the combined action of poisons and analysis of their regularities and practical aspects, in particular, the problem of combined toxicity of metals in the ion-molecular form – has for long attracted the attention of specialists and is widely evolving in toxicology.

The synthesis of the views prevailing in the scientific literature and the results of experiments involving binary (Pb-Cd, Pb-F, Cr-Ni, Cr-Mn, Ni-Mn) and triple (Cr-Ni-Mn) combinations upon intraperitoneal intoxication with the salts of these elements alone, or in combination, using mathematical planning of the experiment and a mathematical description of its results, prompted the authors to formulate several fundamental conclusions: In addition to the three main types of combined action (additivity, subadditivity and superadditivity, or synergism), complex variants of their combination may be noted, depending on which particular effect they are evaluated for, as well as the magnitude of this effect and the dose level of the combined factors.

When characterising the development of intoxication with a large number of effects there may be not only unidirectional action, but also explicit antagonism, and often one and the same pair of toxicants acts at one dose ratio unidirectionally, and at another — in opposite directions. When adding a third toxicant, the type of binary toxicity of the two other components of the triple combination may remain mostly the same as in its absence but may be changed both in the direction of increasing and in the direction of decreasing the effect [42, 43]. The validity of these conclusions was confirmed by the studies carried out on the same design in the subchronic experiment with parenteral intoxication, as well as upon a single intracutaneous administration of metal-oxide NPs alone and in combinations: NiO-NP+Mn3O4-NP; PbO-NP+CuONP, PbO-NP+ZnO-NP, ZnO-NP+CuO-NP; PbONP+ CuO-NP+ZnO-NP [44, 45]. The authors came to the conclusion that the effects of the combined action of metal-oxide NPs on the body are characterised by the same basic patterns as for the previously studied combined toxicity of metals and metalloids in the ion-molecular form.

Since the high specific surface area of free NPs increases their chemical reactivity, the catalytic and toxic properties of many NPs are not recognized by the protective systems of the body [1, 46, 47], and NPs are not biotransformed and excreted from the body. It is established that insoluble or poorly soluble NPs, when administered to laboratory animals, may cause inflammation of the lungs, fibrosis, pulmonary tumours, gene mutations; penetrate into the intercellular space, circulate in the bloodstream, move to other organs [51, 17, 20, 21].

Nano-dispersed oxides of manganese, chromium, and nickel in the form of an aerosol can be the most toxic elements during welding operations upon inhalation route of administration [52]. Manganese oxide NPs due to their small size and high penetrating ability may overcome the blood-brain barrier and cause morpho-functional dysfunctions of various parts of the central nervous system upon different ways of entering the body, even in small concentrations. Neurotoxicity of manganese oxide (IV) nanoparticles with the intracutaneous administration were shown at doses of 2.63 mg/kg and 5.26 mg/kg. When inhaled, manganese oxide (III, IV) particles, which did not exceed 30 nm, may penetrate into the brain directly along the olfactory nerve [53].

It is found that during the 4-hour exposure of rats to nanosized manganese, LC50 was 0.12 mg/dm3. The largest number of particles in the study of actual concentrations in 2 hours of the exposure corresponded to the size of 20 40 nm, and after 4 hours of the exposure — 30–50 nm, that is, the size of particles varied (increased) during the experiment. The clinical picture of acute intoxication was characterised by irritation, neurotoxic effects of the action, inhibition of respiration, a combination of which could cause the death of animals. Based on LC50 (more than 0.05–0.5 mg/dm3) for chemical compounds, the test substance may be classified as hazard class 2 (high hazardous substances) [54, 55], which according to the international classification of hazards of chemical compounds (GHS) allowed assuming the negative effects of such an impact.

Nickel oxide NPs is able to interact with cell membranes, proteins, DNA, to affect the proteomic and metabolic profile, accumulate in cells, organs and tissues, have cytotoxic action, have a transforming activity and carcinogenic effects [44,56]. Stable suspensions of NiO and Mn3O4 NPs with an average diameter of 16.7 ± 8.2 nm and 18.4 ± 5.4 nm were administered intraperitoneally to rats at a dose of 2.5 mg/kg 3 times a week up to 18 injections alone or in combination. At the end of the injection, numerous functional and biochemical parameters and histopathological peculiarities (with a morphometric evaluation) of the liver, spleen, kidneys and brain were evaluated on the basis of toxicity. Ni and Mn accumulation in these organs was measured using atomic emission and electron paramagnetic resonance spectroscopy.

It is established that despite the fact that both types of metal NPs showed an unfavourable bioreactivity, Mn3O4 NPs were somewhat more harmful than NiO [44]. In addition, they caused significant damage to the neurons in the caudate nucleus and hippocampus, which can be considered as an experimental indicator of manganese-induced parkinsonism. The combined toxicity of these NPs is complex (additivity, synergism or subdiaditation), depending on the estimated effect. The comparative solubility of Mn3O4 and NiO NPs in the biological environment was measured in vitro and considered to be one of the factors underlying the difference between their toxicokinetics and toxicity.

Subchronic administration of spherical NPs of nickel oxide and manganese oxide of similar sizes to rats resulted in the development of moderately expressed subchronic intoxication, which in both cases was characterised by damaging changes in functional parameters and microscopic structure of internal organs. However, most of the evidence showed that Mn3O4 NPs was more toxic than NiO NPs, despite the fact that the accumulation of manganese (both total, and especially in the form of NPs) in organs (liver and spleen) was much lower than the accumulation of nickel. It is possible that both high toxicity and lower retention of Mn3O4 NPs in the body are due to their high solubility in comparison with NiO nanoparticles.

At the same time, the exposure to Mn3O4 NPs increased the total amount of manganese in the brain, and the effect of damaging the caudate nucleus and hippocampus neurons caused by their action to a greater extent than the effect of NiO NPs, may be considered as toxicologically specific for manganese. The type of combined toxicity of Mn3O4 and NiO NPs differed according to different parameters (additivity, synergy and subdiaditation), and its identification deserves a special mathematical analysis. In general, it should be noted that such a combined effect caused a not less pronounced overall picture of intoxication, including damage to the brain structures than the exposure only to Mn3O4 NPs [44].

In our own studies to determine the cytotoxicity of WA samples, the procedure [55] was used, which includes WA sampling during welding by means of a special laboratory stand followed by extraction in distilled deionized water and determination of the toxicity index (It) equal to the ratio of the parameters of the mobility of indicator cells (bovine sperm) in a test sample to the parameters of their mobility in a control sample. The test solution is considered non-toxic with It values in the range of 70 %–120 %.

It is established that among the commercial trademarks of the used electrodes, the toxicity index for WA rutile electrode Cristal was at the level of 43.5–52.2 % (Table 1).

Table 1. Cytotoxicity of welding aerosols of experimental marks of electrodes

As for other classification of electrodes for welding high-alloy steels of rutile type of coating, it is found that all WA test electrodes (14–25, 14–26, 14–27, 14–30) exhibited a cytotoxic action, which was more pronounced in comparison with the first sample — It from 12.5 % to 31.3 %, and the value of the toxicity index for WA electrode 14–32 approached the limit values of the norm (It — 62.1–66.2 %), which may be due to the absence of toxic hexavalent chromium in its composition [4]. Instead, WA electrodes for welding carbon and low-alloy steels AHO-12 (rutile coating) and AHO-36 Monolith (rutile-cellulose coating) did not exhibit cytotoxic action (It — 74.4–108.2 %).

In another experiment among 9 WA test samples, the marked decrease of the toxicity index was observed in 5 samples (ЦЛ-11, ЭА-400/10у, ОЗЛ-6, АНВ-66, ОЗЛ-8 – It from 33.3 to 51 %, respectively) (Table 2)

Table 2. Cytotoxicity of welding aerosols of experimental marks of electrodes

There are no significant changes in УОНИ-13/55, АНО-13, АНО-36 Monolith — (It was 109.9 to 120.7 %, respectively) and a tendency to increase in МР-3 (It — 128,1 %).

The study results showed that the toxicity index of all WA electrodes with the main type of coating (ЦЛ-11, ЭА-400/10у, ОЗЛ-6, АНВ-66, ОЗЛ-8) for welding high-alloy steels was considerably lower than the electrodes with the main, rutile, rutile cellulose and rutile carbonate coatings respectively (УОНИ-13/55, АНО-13, АНО-36 Monolith and МР-3) for welding carbon and low-alloy steels. That is, the toxicity of WA electrodes for welding high-alloy steels is much higher than for carbon and low-alloy steels. This is due to the presence in these samples of compounds of extremely dangerous carcinogenic substances — hexavalent chromium and nickel, although the direct dependence of a damaging effect on their number is not observed.

According to the literature, other WA components are also dangerous. Thus, inhalation of iron oxide NPs of 22 and 280 nm in size to the body of rats at doses of 0.8 and 20.0 (mg/kg) induced reactive oxygen intermediates in the cells, hyperaemia, hyperplasia and fibrosis of the lung tissue, as well as blood coagulation system disorders [58,59]. Iron oxide NPs bioaccumulate in the liver and other organs of the reticuloendothelial system [60, 61]. Inhalation of copper NPs caused severe damage to the kidneys, liver and spleen in mice [62, 63]. Copper NPs of 50 nm in size is genotoxic and cytotoxic disturbing the integrity of cell membranes and inducing oxidative stress [58]. In addition to cytotoxicity, the genotoxic potential of zinc oxide NPs was observed both in in vivo and in vitro studies [64,65]. The ability of zinc oxide NPs to cause DNA damage is also established.

Aluminium oxide NPs affected the viability of cells, changed the mitochondrial function, increased oxidative stress [58, 66]. Aluminium NPs can suppress mRNA synthesis, cause cell proliferation, induce proatherogenic inflammation, and impairment of mitochondrial function.

Metal NPs, which are widely used both separately and in the composition of nm (as a coating of welding electrodes), include titanium oxide [27, 58]. It is a chemically inert compound, but studies have shown that its NPs have some toxic effects in experimental animals, including DNA damage, as well as genotoxicity and inflammation of the lungs [67, 68, 69]. In addition to genotoxicity, titanium dioxide NPs (5–200 nm) has a toxic effect on the immune function, liver, kidneys, spleen, myocardium, glucose and homoeostasis of lipids in experimental animals [27, 70].

TiO2 NPs can stimulate the production of free radicals and have a strong oxidative effect [22, 27]. Its inhalation leads to an increase in the number of neutrophils and phagocytes in the bronchoalveolar washings and distribution of nanoparticles in the lungs. Inhaled exposure to ultrathin TiO2 NPs (20 nm) showed their ability to penetrate and accumulate in the lymphoid tissue. Toxicity of TiО2 NPs is determined not only by their size but also by the form.

When inhaling TiO2 particles (12–250 nm), it was found that smaller particles were excreted more slowly and stayed longer in the body. Moreover, [71] the half-life of TiO2 from rat lungs was from 117 to 541 days depending on their size (250–25 nm, respectively), that is, the duration of preservation of particles in the body can be inversely proportional to their size. It was also established that exposure to TiO2 nanoparticles can lead to a carcinogenic action [72], whereas usual titanium oxide does not have such an effect.

Numerous studies show that the peculiarities of toxic effects of NPs, including those formed during welding, in contrast to the macroforms of substances depend on many factors: physical nature, surface properties, structure of nanoclusters and NPs, variety of sizes, forms, methods of obtaining and dispersing, concentration, composition, impurities, as well as the consequences of biomodification and biotransformation of the same material, biological model, based on which the test is conducted. Moreover, changes in these factors are not always linear [73,74], and substances in the nanoscale are characterised by greater biological activity and damaging effects [75,76,77] compared with macroforms.

Thus, the risk of nanosized WA fractions can be related to acute, subacute, chronic, and distant effects. The accumulated experimental data indicate low toxicity of the test samples following penetration of a single dose of NPs into the mammalian organism. The manifestation of subacute exposure to nanoobjects is somewhat remote in time from the beginning of the exposure, and their long-term chronic effects can be manifested at relatively low concentrations. Scientists assume the possibility of the presence of genotoxic and mutagenic action in NPs, due to their high permeability into cells and tissues, induction of free radicals, ability to penetrate into the nucleus of the cell and interact with DNA [78].

The realisation of toxic properties of NPs, including WA components, is determined by physical affinity for biological structures, for example, by means of electrostatic or hydrophobic interaction; and catalytic properties, with the activation of oxidative-reducing reactions. Target organs for NPs are lungs, liver, kidneys, brain, gastrointestinal tract. There is the dependence of target organs on the way of administration. Mechanisms of the development of the toxic effect under the influence of NPs and NMs are diverse. Due to its physical nature and chemical properties nanomaterials can induce ROI, pass through tissue barriers inside cells and interact with intracellular components. Most of the negative effects of NMs are determined by oxidative stress and DNA damage, which can lead to inflammatory reactions, apoptosis and cell necrosis. In addition, it is impossible to exclude the presence of other mechanisms associated, in particular, with the action of NMs on cell membranes and organelles, increased transport of toxic components through the barriers of the body, as well as possible neurotoxic effects, genotoxicity, hepatotoxicity, cardiotoxicity. No studies have been conducted to assess the hazard of most air suspensions formed during welding operations.

A considerable amount of metals (Mn, Zn, Fe, Co, Cu, Cr, Si, Al, Mg, K, Ni, Cr, Li, Na, K) is released, including in nanosized values during welding works in the working area. In real production conditions, the presence in the air of NPs containing only one single metal is a fairly rare exception, while the combined pollution with several metals and their oxides is a rule. Moreover, the quantitative correlations of both chemical elements and their particle values in the WA do not clearly depend on the composition of the welding electrode, welding conditions, etc. [79, 80].

By studying this problem and working out a considerable amount of publications on the experimental toxicology of metal and metal-oxide NPs, published recently in various literature sources and dealing with the study of the regularities of combined toxicity of NPs, we have come to some conclusion. Consequently, published works do not adequately cover the search for parallel experiments, which would compare the toxicity of different-sized metal NPs.

Therefore, the assessment results of WA biological effects, as well as other combinations of harmful production factors, require the development of original approaches for prediction of safety and reduction of occupational risk when used.



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