Attenuation of Combined Nickel(II) Oxide and Manganese(II, III) Oxide Nanoparticles' Adverse Effects with a Complex of Bioprotectors

Stable suspensions of NiO and Mn3O4 nanoparticles (NPs) with a mean (±s.d.) diameter of 16.7 ± 8.2 and 18.4 ± 5.4 nm, respectively, purposefully prepared by laser ablation of 99.99% pure nickel or manganese in de-ionized water, were repeatedly injected intraperitoneally (IP) to rats at a dose of 2.5 mg/kg 3 times a week up to 18 injections, either alone or in combination. A group of rats was injected with this combination with the background oral administration of a “bio-protective complex” (BPC) comprising pectin, vitamins A, C, E, glutamate, glycine, N-acetylcysteine, selenium, iodide and omega-3 PUFA, this composition having been chosen based on mechanistic considerations and previous experience. After the termination of injections, many functional and biochemical indices and histopathological features (with morphometric assessment) of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The Ni and Mn content of these organs was measured with the help of the atomic emission and electron paramagnetic resonance spectroscopies. We obtained blood leukocytes for performing the RAPD (Random Amplified Polymorphic DNA) test. Although both metallic NPs proved adversely bio-active in many respects considered in this study, Mn3O4-NPs were somewhat more noxious than NiO-NPs as concerns most of the non-specific toxicity manifestations and they induced more marked damage to neurons in the striatum and the hippocampus, which may be considered an experimental correlate of the manganese-induced Parkinsonism. The comparative solubility of the Mn3O4-NPs and NiO-NPs in a biological medium is discussed as one of the factors underlying the difference in their toxicokinetics and toxicities. The BPC has attenuated both the organ-systemic toxicity and the genotoxicity of Mn3O4-NPs in combination with NiO-NPs

Combined Subchronic Toxicity of Aluminum (III), Titanium (IV) and Silicon (IV) Oxide Nanoparticles and Its Alleviation with a Complex of Bioprotectors

Stable suspensions of metal/metalloid oxide nanoparticles (MeO-NPs) obtained by laser ablation of 99.99% pure elemental aluminum, titanium or silicon under a layer of deionized water were used separately, or in three binary combinations, or in a ternary combination to induce subchronic intoxications in rats. To this end, the MeO-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks before measuring a large number of functional, biochemical, morphological and cytological indices for the organism’s status. In many respects, the Al2O3-NP was found to be the most toxic species alone and the most dangerous component of the combinations studied. Mathematical modeling with the help of the Response Surface Methodology showed that, as well as in the case of any other binary toxic combinations previously investigated by us, the organism’s response to a simultaneous exposure to any two of the MeO-NP species under study was characterized by a complex interaction between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which outcome this type was estimated for and on effect and dose levels. With any third MeO-NP species acting in the background, the type of combined toxicity displayed by the other two remained virtually the same or changed significantly, becoming either more or less unfavorable. Various harmful effects produced by the (Al2O3-NP + TiO2-NP + SiO2-NP)-combination, including its genotoxicity, were substantially attenuated by giving the rats per os during the entire exposure period a complex of innocuous bioactive substances expected to increase the organism’s antitoxic resistance

Using Various Nonlinear Response Surfaces for Mathematical Description of the Type of Combined Toxicity

The article considers the problem of characterizing the type of combined action produced by a mixture of toxic substances with the help of nonlinear response functions. Most attention is given to second-order models: the linear model with a cross-term and the quadratic model. General propositions are formulated based on the data on combined toxicity patterns previously obtained by the Ekaterinburg nanotoxicology team in animal experiments and analyzed with the help of the linear model with a cross-term. It is shown now that the quadratic model features these general characteristics in full measure, but interpretation of combined toxicity types based on isobolograms obtained by the quadratic model is more difficult. This suggests that where both models ensure a comparable quality of combined toxicity type identification, it would be enough to use the linear model with a cross-term

The most important inferences from the Ekaterinburg nanotoxicology team’s animal experiments assessing adverse health effects of metallic and metal oxide nanoparticles

During 2009–2017 we have studied nanoparticles of elemental silver or gold and of iron, copper, nickel, manganese, lead, zinc, aluminium and titanium oxides (Me-NPs) using, in most cases, a single low-dose intratracheal instillation 24 h before the bronchoalveolar lavage to obtain a fluid for cytological and biochemical assessment and, in all cases, repeated intraperitoneal injections in non-lethal doses to induce subchronic intoxications assessed by a lot of toxicodynamic and toxicokinetic features. We have also studied the same effects for a number of relevant combinations of these Me-NPs and have revealed some important patterns of their combined toxicity. Besides, we have carried out long-term inhalation experiments with Fe2O3, NiO and amorphous SiO2 nano-aerosols. We have demonstrated that Me-NPs are much more noxious as compared with their fine micrometric counterparts although the physiological mechanisms of their elimination from the lungs proved to be highly active. Even if water-insoluble, Me-NPs are significantly solubilized in some biological milieus in vitro and in vivo, which may explain some important peculiarities of their toxicity. At the same time, the in situ cytotoxicity, organ-systemic toxicity and in vivo genotoxicity of Me-NPs strongly depends on specific mechanisms characteristic of a particular metal. For some of the Me-NPs studied, we have proposed standards of presumably safe concentrations in workplace air. Along with this, we have proved that the adverse effects of Me-NPs could be significantly alleviated by background or preliminary administration of adequately composed combinations of some bioprotectors. Keywords: Metallic nanoparticles, Toxicity, Genotoxicity, Combined nano-impacts, Permissible exposure levels, Bioprotectio

Experimental Testing of an Approach to Establishing Combined Toxicity of Ternary Nanoparticle Mixtures

Our studies of exposure to binary mixtures of nanoparticles (TiO2 + SiO2; TiO2 + Al2O3 and SiO2 + Al2O3) based on mathematical modelling show that their combined subchronic toxicity can either be of an additive type or deviate from it depending on the outcome, dose ratio, and levels of effect. To characterize the type of toxicity of ternary mixtures of nanoparticles, we successfully tested a previously developed approach for assessing the combined toxicity of metal ions. In this approach, the effects are classified by a null, positive, or negative change in the toxicity of binary nanoparticle mixtures when modeled against the toxicity of the third agent added

Experimental study and mathematical modeling of toxic metals combined action as a scientific foundation for occupational and environmental health risk assessment. A summary of results obtained by the Ekaterinburg research team (Russia)

Assessment of cumulative health risks associated with the widely observed combined effects of two or more metals and their compounds on the organism has the toxicology of mixtures as its scientific basis although there is no full match between such assessment and this basis while some of the contradictions between them are of a fundamental nature. This state of things may be explained not only by simplifications characteristic of the generally recognized methodology of risk assessment but also by extreme complexity of the theory of combined toxicity, the most essential issues of which are considered by authors on the basis of literary and, mostly, their own previously published data. Keywords: Toxic metals, Typology of combined toxicity, Mathematical modeling, Health risk assessmen

Further development of mathematical description for combined toxicity: A case study of lead–fluoride combination

In this article, we check and develop further some postulates of the theory and mathematical modeling of combined toxic effect that we proposed earlier [1]. To this end, we have analyzed the results of an experiment on rats exposed during 6 weeks to repeated intraperitoneal injections of lead acetate, sodium fluoride or both. The development of intoxication was estimated quantitatively with 54 functional, biochemical and morphometric indices. For mathematical description of the effect that lead and fluorine doses produced alone or in combination, we used a response surface regression model containing linear and cross terms (hyperbolic paraboloid). It is shown that the combination of lead and fluoride features the same 10 types of combined effect that we found previously for the lead and cadmium combination. Special attention is given to indices on which lead and fluorine produce an opposite effect

Low-Frequency Content of THz Emission from Two-Color Femtosecond Filament

We experimentally investigate the low-frequency (below 1 THz) spectral content of broadband terahertz (THz) emission from two-color femtosecond filament formed by the 2.7-mJ, 40-fs, 800+400-nm pulse focused into air. For incoherent detection, we screened the Golay cell by the bandpass filters and measured the THz angular distributions at the selected frequencies ν=0.5, 1, 2 and 3 THz. The measured distributions of THz fluence were integrated over the forward hemisphere taking into account the transmittance of the filters, thus providing the estimation of spectral power at the frequencies studied. The spectral power decreases monotonically with the frequency increasing from 0.5 to 3 THz, thus showing that the maximum of THz spectrum is attained at ν≤0.5 THz. The THz waveform measured by electro-optical sampling (EOS) based on ZnTe crystal and transformed into the spectral domain shows that there exists the local maximum of the THz spectral power at ν≈1 THz. This disagrees with monotonic decrease of THz spectral power obtained from the filter-based measurements. We have introduced the correction to the spectral power reconstructed from EOS measurements. This correction takes into account different focal spot size for different THz frequencies contained in the broadband electromagnetic pulse. The corrected EOS spectral power is in semi-quantitative agreement with the one measured by a set of filters