On the Mechanisms of the Cardiotoxic Effect of Lead Oxide Nanoparticles.

Lead compounds are one of the most common pollutants of the workplace air and the environment. In the occupational setting, the sources of their emission, including in nanoscale form, are various technological processes associated with lead smelting and handling of non-ferrous metals and their alloys, the production of copper and batteries. Both lead poisoning and lead exposure without obvious signs of poisoning have a detrimental effect on the cardiovascular system. The purpose of this research was to investigate the mechanisms of the cardiotoxic effect of lead oxide nanoparticles (PbO NPs). The toxicological experiment involved male albino rats subchronically exposed to PbO NPs (49.6 ± 16.0 nm in size) instilled intraperitoneally in a suspension. We then assessed post-exposure hematological and biochemical parameters of blood and urine, histological and ultrastructural changes in cardiomyocytes, and non-invasively recorded electrocardiograms and blood pressure parameters in the rodents. Myocardial contractility was studied on isolated preparations of cardiac muscles. We established that PbO NPs induced oxidative stress and damage to the ultrastructure of cardiomyocytes, and decreased efficiency of the contractile function of the myocardium and blood pressure parameters. We also revealed such specific changes in the organism of the exposed rats as anemia, hypoxia, and hypocalcemia.

An overview of experiments with lead-containing nanoparticles performed by the Ekaterinburg nanotoxicological research team.

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.

Some patterns of metallic nanoparticles' combined subchronic toxicity as exemplified by a combination of nickel and manganese oxide nanoparticles.

Stable suspensions of NiO and/or Mn3O4 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 Mn3O4 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.

Further development of the theory and mathematical description of combined toxicity: An approach to classifying types of action of three-factorial combinations (a case study of manganese-chromium-nickel subchronic intoxication).

For characterizing the three-factorial toxicity, we proposed a new health risk-oriented approach, the gist of which is a classification of effects depending on whether a binary combined toxicity's type remains virtually the same or appears to be either more or less adverse when modeled against the background of a third toxic. To explore possibilities of this approach, we used results of an experiment in which rats had been injected ip 3 times a week (up to 20 injections) with a water solution of either one of the toxics (Mn, Ni or Cr-VI salts) in a dose equivalent to 0.05 LD50, or any two of them, or all the three in the same doses, the controls receiving injections of the same volume of distilled water (4mL per rat). Judging by more than 30 indices for the organism's status, all exposures caused subchronic intoxication of mild to moderate strength. For each two-factorial exposure, we found by mathematical modeling based on the isobolograms that the binary combined subchronic toxicity either was of additive type or departed from it (predominantly toward subadditivity) depending on the effect assessed, dose, and effect level. For the three-factorial combination, different classes of effects were observed rather consistently: class A - those regarding which the third toxic's addition made the binary toxicity type more unfavorable for the organism, class B - those regarding which the result was opposite, and class C - those regarding which the type of binary combined toxicity on the background of a third toxic virtually remained the same as in its absence. We found a complicated reciprocal influence of combined metals on their retention in kidneys, liver, spleen and brain which might presumably be one of the possible mechanisms of combined toxicity, but the lack of an explicit correspondence between the above influence and the influence on toxicity effects suggests that this mechanism is not always the most important one. The relevance of the proposed classification to health risk analysis and management is briefly discussed.

Toxicodynamic and toxicokinetic descriptors of combined chromium (VI) and nickel toxicity.

After repeated intraperitoneal injections of nickel and chromium (VI) salts to rats, we found, and confirmed by mathematical modeling, that their combined subchronic toxicity can either be of additive type or depart from it (predominantly toward subadditivity) depending on the effect assessed. Against the background of moderate systemic toxicity, the combination under study proved to possess a marked additive genotoxicity assessed by means of the random amplification of polymorphic DNA test. We also demonstrated that chromium and nickel reciprocally influenced the retention of these metals in some organs (especially in the spleen) but not their urinary excretion in this study.

Does a concomitant exposure to lead influence unfavorably the naphthalene subchronic toxicity and toxicokinetics?

Rats were given 20 times during 40 d either naphthalene per gavage or the same and lead acetate intraperitoneally in single doses corresponding to 5% of the respective 50% lethal doses. The concomitant exposure to lead not only added some typical indicators of lead toxicity to the moderate naphthalene intoxication picture but also exaggerated some less specific indices for intoxication. However, a number of such indices testified to attenuation of naphthalene's adverse effects under the impact of lead. Lead also lowered urinary excretion of both total and conjugated naphthalene, while the free- to total naphthalene ratio in urine sharply increased. These results corroborate implicitly the initial hypothesis that lead, being an inhibitor of cytochrome P450, hinders phase I of the naphthalene biotransformation and, thus, the formation of derivates which can be more toxic but are capable of entering into reactions of conjugation with resulting detoxication and elimination of naphthalene from the body.

Attenuation of subchronic formaldehyde inhalation toxicity with oral administration of glutamate, glycine and methionine.

Inhalation exposure of outbred female white rats (initial age about 4 months) to formaldehyde vapours (12.8 ± 0.69 mg/m(3)) 4h per day, 5 days per week during 10 weeks induced statistically significant changes in some indices characterizing differential WBC count, functional status of the central nervous system and liver, redox and porphyrin metabolisms, bone marrow micronuclei count as well as free amino acid spectrum of the blood serum. The development of intoxication was accompanied by increased urinary excretion of formaldehyde, formic acid and methanol. Daily oral administration of glutamate (150-180 mg), glycine (12 mg) and methionine (50mg) in combination rendered all of the formaldehyde's toxic effects reduced. This administration also caused a significant increase in the ratio between the rates of excretion of formic acid and non-metabolized formaldehyde. This shift supposedly reflects activation of oxidative detoxifying biotransformation of formaldehyde. Taking into consideration that the combination of amino acids used in this study proved innocuous in protectively effective doses, the administration in this combination may be recommended to humans exposed to high levels of formaldehyde in workplace or ambient air.