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Our studies of exposure to binary mixtures of nanoparticles (TiO 2 + SiO 2 ; TiO 2 + Al 2 O 3 and SiO 2 + Al 2 O 3 ) 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.

Moderate subchronic intoxication was induced in rats by repeated intraperitoneal injections of PbO (49.6 ± 16.0 nm) and/or CdO (57.0 ± 13.0 nm) nanoparticles (NP) three times a week during 6 weeks. In particular, there was a reduction in arterial blood pressure and in blood concentrations of a number of factors controlling vasoconstriction and vasodilation, particularly of endothelin 1 (ET-1). This toxic effect was attenuated with a bioprotective complex administered in the background. The study confirmed as well that the combined binary action typology varies depending on which effect it is estimated by.

The authors propose to consider as hormesis phenomenon not only a realization of the Arndt-Schulze rule but any non-monotonic dose-response relationship for a certain outcome that is characterized by changing direction of a response between adjacent ranges of doses of an initiator of this response, the number of such ranges being two or more. This approach is illustrated with results of several in vitro experiments on different established cell lines exposed to CdS or PbS nanoparticles., (Copyright © 2020. Published by Elsevier B.V.)

Rats were exposed to nickel oxide nano-aerosol at a concentration of 2.4 ± 0.4 µg/m 3 in a "nose only" inhalation setup for 4 h at a time, 5 times a week, during an overall period of 2 weeks to 6 months. Based on the majority of the effects assessed, this kind of exposure may be considered as close to LOAEL (lowest observed adverse effect level), or even to NOAEL (no observed adverse effect level). At the same time, the experiment revealed genotoxic and allergic effects as early as in the first weeks of exposure, suggesting that these effects may have no threshold at all.

Over the past few years, the Ekaterinburg (Russia) interdisciplinary nanotoxicological research team has carried out a series of investigations using different in vivo and in vitro experimental models in order to elucidate the cytotoxicity and organ-systemic and organism-level toxicity of lead-containing nanoparticles (NP) acting separately or in combinations with some other metallic NPs. The authors claim that their many-sided experience in this field is unique and that some of their important results have been obtained for the first time. This paper is an overview of the team's previous publications in different journals. It is suggested to be used as a compact scientific base for assessing health risks associated not only with the production and usage of engineered lead-containing NPs but also with their inevitable by-production as toxic air pollutants in the metallurgy of lead, copper or their alloys and in soldering operations.

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.

We had previously demonstrated on various stable cell cultures exposed to chemically different nanoparticles when assessing their cytotoxicity by different outcomes, dose-response relationships may be either monotonic or non-monotonic falling within an extended understanding of the hormesis paradigm. Presently, on human fibroblasts exposed to the copper-oxide and/or selenium-oxide nanoparticles, we assessed their cytotoxic effect by the inhibition of oxygen uptake against modulating the respiratory function of mitochondria (oligomycin, followed by carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone, and, finally, rotenone with antimycin A). It is hypothesized that a given type of this relationship is closely associated with the mitochondrial respiratory function. However, in only one case, this hypothesis was confirmed by finding that the monotonic dose-response relationship transformed into a non-monotonic one of the hormesis type under exposure to SeO-NP with the mitochondrial respiratory function fully inhibited by the effect of rotenone + antimycin А. In all other variants of the experiment, the shape of this relationship did not depend on the addition of the above agents to the cell culture. Neither did the effect of these modulators change the pattern of combined action of CuO-NP and SeO-NP, which was additive in all cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Subchronic intoxication was induced in outbred male rats by repeated intraperitoneal injections with lead oxide (PbO) and/or cadmium oxide (CdO) nanoparticles (NPs) 3 times a week during 6 weeks for the purpose of examining its effects on the contractile characteristics of isolated right ventricle trabeculae and papillary muscles in isometric and afterload contractions. Isolated and combined intoxication with these NPs was observed to reduce the mechanical work produced by both types of myocardial preparation. Using the in vitro motility assay, we showed that the sliding velocity of regulated thin filaments drops under both isolated and combined intoxication with CdO–NP and PbO–NP. These results correlate with a shift in the expression of myosin heavy chain (MHC) isoforms towards slowly cycling β–MHC. The type of CdO–NP + PbO–NP combined cardiotoxicity depends on the effect of the toxic impact, the extent of this effect, the ratio of toxicant doses, and the degree of stretching of cardiomyocytes and muscle type studied. Some indices of combined Pb–NP and CdO–NP cardiotoxicity and general toxicity (genotoxicity included) became fully or partly normalized if intoxication developed against background administration of a bioprotective complex. [ABSTRACT FROM AUTHOR]

In vitro toxicological experiments were performed on an endothelial cell line exposed to different doses of spherical nanoparticles of cadmium and/or of lead sulfides with mean diameter 37 ± 5 nm and 24 ± 4 nm, respectively. Toxic effects were estimated by Luminescent Cell Viability Assay, endothelin-1 concentration and cell size determination. Some dose-response relationships were typically monotonic (well approximated with hyperbolic function) while others were bi- or even 3-phasic and could be described within the expanded hormesis paradigm. The combined toxicity type variated depending on the effect it was assessed by. [ABSTRACT FROM AUTHOR]

Stable suspensions of NiO and/or Mn 3 O 4 nanoparticles with a mean diameter of 16.7 ± 8.2 nm and 18.4 ± 5.4 nm, respectively, prepared by laser ablation of 99.99% pure metals in de-ionized water were repeatedly injected IP to rats at a dose of 0.50 mg or 0.25 mg 3 times a week up to 18 injections, either separately or in different combinations. Many functional indices as well as histological features of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The accumulation of Ni and Mn in these organs was measured with the help of AES and EPR methods. Both metallic nanoparticles proved adversely bio-active, but those of Mn 3 O 4 were found to be more noxious in most of the non-specific toxicity manifestations. Moreover, they induced a more marked damaging effect in the neurons of the caudate nucleus and hippocampus which may be considered an experimental correlate of manganese-induced parkinsonism. Mathematical analysis based on the Response Surface Methodology (RSM) revealed a diversity of combined toxicity types depending not only on particular effects these types are assessed for but on their level as well. The prognostic power of the RSM model proved satisfactory. [ABSTRACT FROM AUTHOR]