Changes in the Dose-Response Relationship of One Toxicant Under Simultaneous Exposure to Another Toxicant.

We considered, in general form for a 22 full factorial experiment, linear approximations of the organism's dose-response relationship for some factors operating alone and modification of this relationship by another factor operating in the background. A typological classification of such modifications is suggested. An analysis of the outcomes obtained in a number of subchronic animal experiments on rats in which this response was assessed by changes in a large number of biomedical indices revealed that all theoretically possible variants (types) of the modification under consideration are actually observed depending on a specific index and specific harmful exposure. Statistical significance estimation procedures are formulated for each of them.

On the contribution of the phagocytosis and the solubilization to the iron oxide nanoparticles retention in and elimination from lungs under long-term inhalation exposure.

The aim of our study was to test a hypothesis according to which the pulmonary clearance vs. retention of metal oxide nanoparticles (NPs) is controlled not only by physiological mechanisms but also by their solubilization which in some cases may even prevail. Airborne Fe2O3 NPs with the mean diameter of 14±4nm produced by sparking from 99.99% pure iron rods were fed into a nose-only exposure tower. Rats were exposed to these NPs for 4h a day, 5days a week during 3, 6 or 10 months at the mean concentration of 1.14±0.01mg/m(3). NPs collected from the air exhausted from the exposure tower proved insoluble in water but dissolved markedly in the cell free broncho-alveolar lavage fluid supernatant and in the sterile bovine blood serum. The Fe2O3 content of the lungs and lung-associated lymph nodes was measured by the Electron Paramagnetic Resonance (EPR) spectroscopy. We found a relatively low but significant pulmonary accumulation of Fe2O3, gradually increasing with time. Besides, we obtained TEM-images of nanoparticles within alveolocytes and the myelin sheaths of brain fibers associated with ultrastructural damage. We have developed a multicompartmental system model describing the toxicokinetics of inhaled nanoparticles after their deposition in the lower airways as a process controlled by their (a) high ability to penetrate through the alveolar membrane; (b) active endocytosis; (c) in vivo dissolution. To conclude, both experimental data and the identification of the system model confirmed our initial hypothesis and demonstrated that, as concerns iron oxide NPs of the dimensions used, the dissolution-depending mechanisms proved to be dominant.

Applying theoretical premises of binary toxicity mathematical modeling to combined impacts of chemical plus physical agents (A case study of moderate subchronic exposures to fluoride and static magnetic field).

Sodium fluoride solution was injected i.p. to rats at a dose equivalent to 0.1 LD50 three times a week up to 18 injections. Two thirds of these rats and of the sham-injected ones were exposed to the whole body impact of a 25 mT static magnetic field for 2 or 4 h a day, 5 times a week. For mathematical analysis of the effects they produced in combination, we used a response surface model. This analysis demonstrated that (like in combined toxicity) the combined adverse action of a chemical plus a physical agent was characterized by a diversity of types depending not only on particular effects these types were assessed for but on their level as well. From this point of view, the indices for which at least one statistically significant effect was observed could be classified as identifying (1) single-factor action; (2) additivity; (3) synergism; (4) antagonism (both subadditive unidirectional action and all variants of contradirectional action). Although the classes (2) and (3) taken together encompass a smaller part of the indices, the biological importance of some of them renders the combination of agents studied as posing a higher health risk than that associated with each them acting alone.

[Combined subchronic toxicity of nickel and manganese oxides nanoparticles, and its decrease due to bioprotectors complex].

Stable suspensions of NiO and/or Mn304 nanoparticles with average diameter 16,7?8,2 nm and 18,4?5,4 nm respectively, obtained via laser ablation of the metals with 99,99% purification in deionized water, were injected intraperitoneally into rats in dose of 0,5 mg or 0,25 mg three times per week up to 18 times separately or in various dose combinations. A group of rats received combined injections of nanoparticles in the highest dose or merely water with oral <> containing pectin, vitamins A, C and E, glutamate, glycine, N-acetylcysteine, selenium, iodine and polyunsaturated fatty acids of omega-3 class. Intoxication development was assessed through multiple functional parameters and histologic changes in liver, spleen, kidneys and brain. Nickel and manganese accumulation in these organs was measured-via various methods. Both types of metallic oxide nanoparticles appeared to be hazardous for body, but Mn304 caused more harm according to major nonspecific toxicity manifestations. Moreover, they caused more intense injury to caudate nucleus and hippocamp neurons - that can be considered as an experimental model of manganese parkinsonism. Mathematic analysis based on response pattern revealed ambiguity of the combined toxicity type, depending on the effects assessed and on its level. Due to the bioprotector complex, organic and systemic toxicity and genotoxicity of Mn304 and NiO nanoparticles combined were diminished.

[Increasing resistance against hazardous effects of metals-containing nanoparticles as a prospective approach to health risks management].

Extremely high toxicity of metal-containing nanoparticles necessitates search of methods to increase body resistance against its harmful effects. The authors' experiments summarized in the article demonstrated that some combinations of certain biologically active substances selected according to sound theoretic background and prescribed in harmless doses can significantly decrease integral and specific manifestations of organ and system toxicity and even genotoxicity of such nanoparticles. Further development of this research direction should be recommended for practical implementation.

[APPROACHES TO ENHANCING THE ORGANISM'S RESISTANCE TO THE ADVERSE EFFECTS OF NANOMATERIALS AS EXAMPLIFIED BY NANOSILVER AND NANOCOPPER OXIDE].

Subchronic intoxications in rats induced by repeated intraperitoneal injections of stable water suspensions of silver or copper oxide nanoparticles in low dosage were manifested by adverse shifts in some functional and biochemical indices, by development of histo-structural changes in different tissues and by poly-organ fragmentation of DNA. All these manifestations of toxicity were substantially attenuated against the background of parallel oral administration of bioprotective complexes comprising vitamins, trace elements, pectin, some amino acids and a fish oil preparation rich in omega-3 fee fatty acids, this composition has been adjusted to mechanisms of action of this or that nanomaterial.

Interaction of iron oxide Fe3O4 nanoparticles and alveolar macrophages in vivo.

Aqueous suspension of magnetite nanoparticles with primary diameter of 10 nm were intratracheally administered into rat lungs. In 24 h, cells were isolated from bronchoalveolar lavage and examined under a transmission electron microscope. Alveolar macrophages demonstrated ability to actively uptake single nanoparticles and small aggregates composed of such particles, which then formed larger conglomerates inside fused phagosomes. Some of these mature phagosomes shed the membrane and free nanoparticles closely interacted with nuclear membrane and with cristae and mitochondrial membranes thereby inflicting pronounced damage to these intracellular structures. The loss of primary lysosomes can be viewed as indirect evidence attesting to the role played by diffusion of lysosomal hydrolytic enzymes in the final destruction of the alveolar macrophages provoked by nanoparticles.

Combined subchronic fluoride-lead intoxication and its attenuation with the help of a complex of bioprotectors.

BACKGROUND: Combined toxicity of lead and fluoride has been studied insufficiently, and there is no known information about attempts to inhibit it with any bioprotectors. METHODS: Lead acetate and sodium fluoride, administered separately or in combination, were injected i.p. to rats at isoeffective sublethal doses 3 times a week for 6 weeks. Some of the rats were exposed to the same combination against the background of oral administration of a bioprotector complex (BPC) comprising pectin, glutamate, and multivitamin/multimineral preparations. Following exposure, functional and biochemical indices and histopathological examinations of the femur of exposed and control rats were evaluated for signs of toxicity. RESULTS: We have shown that with regard to a number of effects on the organism level the combined toxicity of lead and fluoride may be evaluated as additive or even superadditive, but lead reduces fluoride accumulation in the bone, and pathological changes in the bone tissue proved to be less marked for combined exposure compared with separate exposures. The BPC has been demonstrated to attenuate a range of the combined harmful effects of lead and fluoride, including those on the bone tissue. CONCLUSIONS: In spite of the fact that fluoride and lead may reciprocally attenuate their harmful effects on the bone tissue in case of combined exposure, they prove to be more toxic for soft tissues just in combination than when administered separately. The development of combined intoxication may be substantially inhibited by means of the tested set of innocuous biologically active agents.

[Comparative experimental assessment of the impact of gold and silver nanoparticles on the phagocyting cells of the lower airways].

Judging by the cytological characteristics of the free cell population of the lower airways obtained with assistance of the bronchoalveolar lavage in 24 hours after the intratracheal instillation of equal doses of equidimensional gold or silver nanoparticles, both metals result in active recruitment of phagocytes with domination of neutrophile leukocytes, especially marked after the instillation of the nanosilver. The higher ratio of these cells count to that of alveolar macrophages gives evidence for the significantly higher cytotoxicity of the nanosilver comparing with both nanogold and even the smallest silver particles in the micrometric range. Transmission electron microscopy demonstrates similar pictures of intracellular distribution and ultra-structural damages caused by internalized nanoparticles in both types of phagocytes, while there are significant differences between cells under impact of nanosilver vs. those under impact of nanogold. The highest importance is higher propensity of the nanosilver particles to aggregation and to ingression into mitochondria with damaging these organelles.

[Comparative evaluation of alveolar phagocytosis response to intratracheally applied magnetite (Fe3O4) in nano- and micrometer ranges].

The authors compared cytotoxicity of magnetite (Fe3O4) particles in nanometric ranges (10 nm and 50 nm) and micrometer range (1 microm), analyzing changes in cellular subunits of bronchoalveolar lavage in 24 hours after intratracheal application of the particles. Findings are that the nanoparticles are more biologically aggressive than the micrometric particles, but induce more active and effective defensive reaction of alveolar fagocytosis.