Alcohol and breast cancer.

Breast cancer is one of the main causes of death in women worldwide. In women, breast cancer includes over half of all tumours caused by alcohol. This paper discusses both ethanol metabolism and the mechanisms of mammary tumourigenesis caused by alcohol. Numerous signalling pathways in neoplastic transformation following alcohol consumption in women have been presented. In addition, primary and secondary prevention, phytochemicals, synthetic chemicals, specific inhibitors of enzymes and selective receptor modulators have been described.

Endogenous estrogens-breast cancer and chemoprevention.

Breast cancer is the most common female malignancy and the second leading cause of cancer related deaths. It is estimated that about 40% of all cancer in women is hormonally mediated. Both estrogens and androgens play critical roles in the initiation and development of breast cancer. Estrogens influence normal physiological growth, proliferation, and differentiation of breast tissues, as well as the development and progression of breast malignancy. Breast cancer is caused by numerous endo- and exogenous risk factors. The paper presents estrogen metabolism, in particular 17ß-estradiol and related hormones. The mechanisms of estrogen carcinogenesis include the participation of estrogen receptors, the genotoxic effect of the estrogen metabolites, and epigenetic processes that are also presented. The role of reactive oxygen species in breast cancer has been described. It called attention to a role of numerous signaling pathways in neoplastic transformation. Chemoprotective agents, besides other phytoestrogens, classical antioxidants, synthetic compounds, and their mechanisms of action have been shown.

Hexachlorobenzene as a persistent organic pollutant: Toxicity and molecular mechanism of action.

Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. Chronic exposure of humans to HCB leads to a number of effects, such as triggering of porphyria, microsomal enzyme induction, thyroid dysfunctions, neurological symptoms, and immunological disorders. In animals, HCB induced hepatic porphyria, neurotoxic effects, and toxic effects on the thyroid function, reproductive system, and immune system. HCB as a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR) is a hormonal disruptor. HCB is also known to cause tumors of the liver, thyroid and mammary gland in laboratory animals. This review presents HCB toxicity in humans and laboratory animals. The main attention was focused on the mechanisms of HCB toxicity, especially at the molecular level.

[Ethylene glycol and propylene glycol ethers - Reproductive and developmental toxicity]. / Etery glikolu etylenowego i glikolu propylenowego - toksycznosc reprodukcyjna i rozwojowa.

Both ethylene and propylene glycol alkyl ethers (EGAEs and PGAEs, respectively) are widely used, mainly as solvents, in industrial and household products. Some EGAEs demonstrate gonadotoxic, embriotoxic, fetotoxic and teratogenic effects in both humans and experimental animals. Due to the noxious impact of these ethers on reproduction and development of organisms EGAEs are replaced for considerably less toxic PGAEs. The data on the mechanisms of testicular, embriotoxic, fetotoxic and teratogenic effects of EGAEs are presented in this paper. Our particular attention was focused on the metabolism of some EGAEs and their organ-specific toxicities, apoptosis of spermatocytes associated with changes in the expression of various genes that code for oxidative stress factors, protein kinases and nuclear hormone receptors.

The effects of 2-methoxyethanol and 2-ethoxyethanol on hematological changes induced by 2-butoxyethanol.

BACKGROUND: Alkoxyethanols (ethylene glycol alkyl ethers) are used as mixtures in a variety of industrial and household products. The aim of this study has been to evaluate the effects of 2-methoxyethanol (ME) and 2-ethoxyethanol (EE) on hematological changes induced by 2-butoxyethanol (BE) in rats. MATERIAL AND METHODS: Experiments were performed on male Wistar rats treated subcutaneously with BE, ME, and EE alone (in the dose of 0.75 mM/kg/day and 1.25 mM/kg/day) and their mixtures with the molar ratio 1:1, for 4 weeks. Hematological analyses were performed on the day 0, 4, 11, 18, and 29. Hemoglobin (HGB) concentration in the urine was also determined in the rats treated with BE alone and co-exposed to BE and ME and also BE and EE. RESULTS: The rats co-exposed to BE and ME or BE and EE demonstrated significantly less pronounced hematological changes in comparison with animals treated with BE alone at the beginning of exposure. At the later period the hematological alterations in the same animals were markedly pronounced and progressing with exposure time. The rats co-exposed to BE and ME or BE and EE did not demonstrate hemoglobinuria. CONCLUSIONS: ME or EE co-administered to rats with BE lead to the amelioration in the majority of the hematological parameters at the beginning of the exposure. The hematological changes at the end of the co-exposure to BE and ME or BE and EE were markedly pronounced. The effects observed in this study appear to be related with metabolic interactions of the examined ether. Med Pr 2015;66(3):303-315.

Testicular effect of a mixture of 2-methoxyethanol and 2-ethoxyethanol in rats.

BACKGROUND: 2-Methoxyethanol (ME) and 2-ethoxyethanol (EE) represent a large group of chemicals which are used separately or as mixtures. These compounds exert multidirectional toxic effects. The present studies aimed to demonstrate the effects of ME and EE alone and their mixture on the reproductive organs in the rats. METHODS: Male Wistar rats were treated subcutaneously with ME and EE alone (1.25-5.0mM/kg/day) or with their mixture (1:1) for 4 weeks. After completion of the experiment, the testes, epididymides, and prostate were weighed. In post-mitochondrial supernatant of the testes, the level of total protein, non-protein and protein sulfhydryl groups, malondialdehyde, total antioxidant status, and glutathione peroxidase and glutathione reductase activities were determined. RESULTS: Exposure to ME alone resulted in a dose-dependent decrease in the organ weights, the total protein, non-protein and protein sulfhydryl groups. EE alone led to less marked alterations. Co-exposure to ME and EE caused alterations similar as in the rats treated with ME alone. CONCLUSIONS: Marked testicular atrophy, decrease in epididymis and prostate weights are predominant effects of the repeated exposure to relatively low doses of ME and EE. A decrease in the total protein level, and protein sulfhydryl groups may be responsible for testicular atrophy. A significant depletion of non-protein sulfhydryl groups and occasionally elevated glutathione peroxidase activity may indicate that ME and EE resulted in disturbances of pro-oxidant/antioxidant balance. The study suggests that testicular toxicity in male rats co-exposed to ME and EE is mainly caused by the former compound.

Diacetyl exposure as a pneumotoxic factor: a review.

Diacetyl (2,3-butanedione) is a natural ingredient in foodstuffs which is not generally regarded health risk to consumers. Nevertheless, when manufactured for use as a synthetic flavouring/additive in processed foods (e.g. microwave popcorn), it poses a human health threat at the workplace. Its pneumotoxic action consists of inflammation, obstruction and restriction in the distal respiratory tract. One of the factors causing bronchiolitis obliterans is also recognised to be diacetyl. The scientific literature mostly describes human exposure to diacetyl in factory settings where functional disorders and structural changes of the respiratory system have been recorded, particularly bronchiolitis obliterans. Moreover, differential diagnosis shows pathological changes in the distal respiratory tract and in the pneumotoxic actions of diacetyl.

Potential neurotoxic effect of ethylene glycol ethers mixtures.

BACKGROUND: Ethylene glycol ethers (EGEs) are widely used as mixtures in various industrial processes and in many household products. 2-Methoxyethanol and 2-ethoxyethanol primarily exert gonadotoxic effect, while 2-butoxyethanol and 2-isopropoxyethanol have potent hemolytic activity. EGEs can cross the blood-brain barrier, but their potential neurodegenerative action in vivo has not been investigated, yet. In the present work, we examined potential adverse effects of EGEs on some selected brain structures. METHODS: A mixture of two compounds: one with stronger hydrophilic properties (2-methoxyethanol or 2-ethoxyethanol) and the second more lipophilic (2-butoxyethanol or 2-isopropoxyethanol) were administered sc for 4 weeks. Total antioxidant capacity, lipid peroxidation and caspase-3 activity were determined in the frontal cortex and hippocampus. RESULTS: It has been found that 4-week administration of a mixture of two EGEs, with various intensity, decreased total antioxidant capacity, enhanced lipid peroxidation and increased caspase-3 activity in the frontal cortex and hippocampus of Wistar rat. CONCLUSION: The obtained results suggested that EGEs exerted adverse effects on the CNS cells and may contribute in pathogenesis of neurodegenerative disorders.

Hematological effects of exposure to mixtures of selected ethylene glycol alkyl ethers in rats.

Exposure to various ethylene glycol monoalkyl ethers (EGAEs) is known to result in hemolytic effect caused by their metabolites, appropriate alkoxyacetic acids, generated via both alcohol dehydrogenase and aldehyde dehydrogenase. It has been shown in many studies that administration of single doses of EGAEs to rats lead to dose- and time-dependent hemolytic anemia. The repeated exposure to isopropoxyethanol (IPE), and butoxyethanol (BE), contrary to methoxyethanol (ME) and ethoxyethanol (EE), resulted in significantly less pronounced hematological changes. While the majority of hematological effects were dramatic at the beginning of the exposure, later these changes clearly regressed despite continued weekly exposure to these ethers. The gradual recovery from the hemolytic anemia may be associated with tolerance development to the hemolytic effect of IPE and BE. ME demonstrated high hematotoxicity, which increased progressively and reached a maximum at the end of 4 week exposure, whereas EE revealed moderate hematological effects. It might be suspected that ME and EE may modified of IPE hemolytic activity in rats simultaneously treated with these compounds. In the rats co-exposed to IPE and ME subcutaneously at a relatively low doses of 0.75 mM + 0.75 mM for 4 weeks, a significantly less pronounced hematological changes at the beginning of the exposure in comparison with animals treated with IPE (0.75 mM) alone were observed. At the later period, i.e., at the end of 4 weeks exposure, the hematological alterations in the same animals were markedly pronounced and progressively elevated with exposure time, except for mean corpuscular volume (MCV) values, which were significantly lower in comparison with IPE group. ME at the higher dose of 1.25 mM/kg and EE at both doses of 0.75 and 1.25 mM/kg did not modify the hematotoxicity of IPE (at doses of 0.75 mM and 1.25 mM) at the beginning of the exposure, whereas increased its harmful effects at the end of the treatment. The amelioration in the majority of the hematological parameters at the beginning of the exposure may be caused by inhibitory effect of ME on IPE metabolism. On the contrary, an accumulation of the methoxyacetic acid and ethoxyacetic acid, toxic metabolites of ME and EE, respectively, and no tolerance development to the hemolytic effect of these two chemicals may be responsible for elevated hematological alterations at the end of the exposure.

Effects of ethylene glycol ethers on cell viability in the human neuroblastoma SH-SY5Y cell line.

Ethylene glycol ethers (EGEs) are a class of chemicals used extensively in the manufacture of a wide range of domestic and industrial products, which may result in human exposure and toxicity. Hematologic and reproductive toxicity of EGEs are well known whereas their action on neuronal cell viability has not been studied so far. In the present study, we investigated the effects of some EGEs on cell viability and on the hydrogen peroxide-induced damage in the human neuroblastoma (SH-SY5Y) cells. It has been found that 2-phenoxyethanol in a concentration-dependent manner (5-25 mM, 24 h) increased the basal and H(2)O(2)-induced lactate dehydrogenase (LDH) release and 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT) reduction. 2-Butoxyethanol given alone did not affect LDH release and MTT reduction but concentration-dependently enhanced the cytotoxic effect of H(2)O(2). 2-Isopropoxyethanol significantly and concentration-dependently (1-25 mM) increased the basal LDH release and attenuated MTT reduction, but did not potentiate the cytotoxic effect of H(2)O(2). Contrary to this, 2-methoxyethanol did not show a cytotoxic effect while 2-ethoxyethanol at high concentrations intensified the hydrogen peroxide action. This study demonstrated that among the EGEs studied, 2-phenoxyethanol showed the most consistent cytotoxic effect on neurons in in vitro conditions and enhanced the hydrogen peroxide action. 2-Isopropoxyethanol had also a potent cytotoxic effect, but it did not enhance the hydrogen peroxide action, whereas 2-butoxyethanol only potentiated cytotoxic effect of H(2)O(2). It is concluded that the results of the present study should be confirmed in in vivo conditions and that some EGEs, especially 2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol, may be responsible for initiation or exacerbation of neuronal cell damage.

[Tributyltin compounds--the substances noxious to health]. / Zwiazki tributylocyny (IV)--substancje szkodliwe dla zdrowia.

Tributylotin (TBT) compounds are lipophilic substances having low vapour pressure TBT have been used as an active ingredient in molluscicides, antifoulants and wood preservatives, disinfectants and as biocides used in cooling systems, pulp and paper mills, leather processing, and textile mills. TBT acute poisoning in humans were manifested by hepatic functional changes, hypoglycemia, glycosuria, and respiratory system disturbances, similar to asthma. In experimental animals these compounds exerted mainly immunosuppressive, endocrinopathic, neurotoxic, hepatotoxic, nephrotoxic, and skin and eye irritative effects. Mutagenic, genotoxic and carcinogenic activity of TBT have not been confirmed. However gonadotoxic, embryotoxic, fetotoxic, and developmental effects were observed. In this article the actual views on the mechanisms of TBT toxic effects have been described. In conclusion, TBT may be a potential hazardous to human health.

[Carcinogenic effect of tobacco smoke]. / Rakotwórcze dzialanie dymu tytoniowego.

Both epidemiological and experimental studies provide evidence of the dose-effect relationship between the number of cigarettes smoked and lung cancer risk, exposure to tar or tobacco smoke and skin cancers or squamous cell carcinoma of the trachea and lung. Polycyclic aromatic hydrocarbons (PAHs) and volatile N-nitrosamines, and also tobacco specific N-nitrosamines are considered to be the major carcinogens in tobacco smoke. To exert carcinogenic effect these compounds require previous metabolic activation by biotransformation enzymes. Individual susceptibility to chemical carcinogens is genotype and phenotype dependent. Machine-measured yields of tar, nicotine, carbon monoxide, benzo[a]pyrene and N-nitrosonornicotine in cigarette smoke are significantly lower than actual intake by smokers. The following features have significant influence on the tobacco smoke composition, cancer risk and other disease risks relative to cigarette smoking: tobacco type and its modifications and also nitrate content in tobacco. Tobacco additives, including ammonia releasing substances, do not contribute to cigarette smoke composition and its toxicity. Filters, paper porosity, cigarette length and circumference as well as the number of tobacco cuts per inch (whether it is coarse-cut or fine-cut tobacco) are of primary significance for the chemical composition of cigarette smoke and health risk.

Studies on the nature of hemolytic effect induced by ethylene glycol alkyl ethers.

The nature of hemolytic effect induced by ethylene glycol alkyl ethers was analyzed taking into account G-6-PDH activity, ATP, pyruvate and thiols levels in peripheral blood of rats treated with single doses of 2-ethoxyethanol and 2-butoxyethanol. In addition, the susceptibility to autoxidation of rat erythrocyte lipids was evaluated. A decrease of ATP level in a dose-dependent manner and an increase in protein- and nonprotein-bound sulfhydryl groups were observed. These results indicate that an acute hemolytic effect of ethylene glycol alkyl ethers is not associated with alterations in G-6-PDH activity and the susceptibility of erythrocyte lipids to autoxidation. Increases in protein- and nonprotein-bound sulfhydryl groups seem to indicate the selective hemolysis of the aged erythrocytes. The increase in pyruvate and thiol levels may protect erythrocytes against the appearance of oxidative stress.

Comparison of the in vitro hemolytic effects produced by alkoxyacetic acids on human and rat erythrocytes.

OBJECTIVES: The alkoxyacetic acids (AAAs) are urinary metabolites of alkoxyethanol solvents. It is well documented that these chemicals can cause acute hemolytic anemia in humans and laboratory animals. There are scarce data on the relative hemolytic activity of these acids. Likewise, information is lacking on the relationship between their hemolytic activity and physicochemical properties. The aim of this study was to compare the hemolytic activity of five AAAs in red blood cells (RBCs) derived from donors' blood and male Wistar rats. Moreover, the possible relationship between lipophilic and hemolytic activity of AAAs was also investigated. MATERIALS AND METHODS: The RBCs washed in TRIS buffer, pH 7.4, were adjusted to a packed cell volume (PCV) of about 20% and incubated in a water bath at 37 degrees C for 0-3 h in the presence of different concentrations of AAAs. The hemolytic effects, in terms of the changes in RBCs, PCV, mean corpuscular volume (MCV) and free hemoglobin (HGBfree) in incubation medium, were evaluated. Based on the dose-response relationship for RBCs, PCV and MCV, the effective concentration values (EC50) and their 95% confidence intervals (95% CI) were calculated. The octanol-water partition coefficient (log P) and distribution coefficient (log D) of AAAs were computed using PALLAS software. The correlation between log P and log D values for AAAs at pH 7.4 and their EC50 was analyzed. RESULTS: Human RBCs were 1.9-3.1 times more resistant to the hemolytic activity of AAAs than rat erythrocytes. Also, the hemolytic activity of individual AAAs did not differ considerably; the maximum differences ranging from 2.0 to 3.3. The EC50 values of AAAs highly correlated with their log P and log D values. CONCLUSIONS: The relatively small differences between the hemolytic effects of AAAs on rat and human erythrocytes may be associated with the strong acidity and relatively similar lipophilicity of these chemicals.

[Ethylene glycol alkyl ethers--the substances noxious to health]. / Etery alkilowe glikolu etylenowego--substancje szkodliwe dla zdrowia.

Ethylene glycol alkyl ethers (EGAE), 2-methoxyethanol, 2-ethoxyethanol, 2-isopropoxyethanol, and 2-butoxyethanol, are widely used in a variety of industrial and household products. They are found in a number of paints, varnishes, engine fuels, hydraulic fluids, and also in many household products, including floor polishes and glass, leather, and upholstery cleaners. Human and animal studies have shown that EGAE can cause adverse reproductive, developmental, and hematological effects through inhalation, dermal absorption, and ingestion. The oxidation of these chemicals to appropriate aldehydes and alkoxyacetic acids is responsible for their toxic effects. The central nervous system, blood and blood-forming organs, and reproduction are the targets in acute and chronic intoxications with EGAE. Data on exposure, metabolism, biomonitoring, and toxic effects ofEGAE, especially those on hematological disorders in human and laboratory animals are presented in this paper.

Hematological effects of four ethylene glycol monoalkyl ethers in short-term repeated exposure in rats.

This study was carried out to compare the hematological effects of 2-methoxyethanol (ME), 2-ethoxyethanol (EE), 2-isopropoxyethanol (IPE), and 2-butoxyethanol (BE) in short-term studies in rats. Male rats were subcutaneously treated with ME or EE at a dosage of 0, 1.25, 2.5 and 5.0 mM/kg in saline, 5 days per week, for 4 weeks. Other rats were exposed to IPE or BE at doses of 0, 0.25, 0.5, 0.75 and 1.25 mM/kg in the same manner. Administration of each chemical, except of ME, resulted in a time- and dose-dependent swelling of erythrocytes as evidenced by an increase in mean corpuscular volume (MCV). Subsequently, red blood cells (RBC), packed cell volumes (PCV), hemoglobin concentration (HGB), and mean cell hemoglobin concentration (MCHC) decreased. Furthermore, an increase in mean cell hemoglobin (MCH) and reticulocyte counts was observed. The onset of hemolysis induced by EE, IPE or BE was faster than after ME administration. While in rats exposed to ME hematological changes were strongly pronounced and progressively increased with exposure time beginning from the day 11, those in animals treated with EE were rather persisted at low constant level for all exposure period. In contrast, the rats exposed to IPE and BE demonstrated the dramatic hematological changes more pronounced in case of BE than IPE at the beginning of exposure (on day 4). Despite of exposure duration, these changes were regressed, although the decrease in RBC and MCHC and the increase in MCV and MCH in rats treated with highest doses of both compound (0.5, 0.75, and 1.25 mM/kg) were more persistent, probably due to selective hemolysis of the aged erythrocytes. In addition, significant leukopenia due to reduction of lymphocytes in rats exposed to ME was observed. In summary, this study demonstrated no tolerance to ME- and EE-induced intravascular hemolysis developed under these experimental conditions. On the contrary, tolerance to IPE- and BE-induced hemolysis in rats exposed to these compounds was prompted.

Pyrazole and methylpyrazole for the treatment of 2-butoxyethanol poisoning.

2-Butoxyethanol (BE) is a one member of a family of ethylene glycol monoalkyl ethers that are used in a variety of industrial and household products. The clinical features of human and animal BE intoxications mainly include metabolic acidosis, CNS depression and coma, hemolytic anemia, hematuria, and renal injury. It is believed that metabolic activation of BE to butoxyacetic acid (BAA) is responsible for these pathologic changes. The treatment of BE poisoning have been based on an inhibition of the metabolic pathway enzymes which convert BE to toxic metabolites. Therefore, a comparison was made between antidotal properties of pyrazole (PY) and 4-methylpyrazole (MP) in rats subcutaneously intoxicated with BE. It was found that both antidotes effectively protected animals against appearance of hemolytic anemia signs induced by BE. MP appears to be more efficient than PY. These data confirm the beneficial role of alcohol dehydrogenase (ADH) inhibitors in BE intoxication.

The alkoxyacetic acids as calcium and magnesium chelating agents in vitro.

Alkoxyacetic acids (AAAs) are known urinary metabolites of the corresponding ethylene glycol monoalkyl ethers with a wide range of industrial and domestic applications. Hemolysis is the principal toxic effect of AAAs in humans and animals. The mechanism of red-cell damage is not known. It is suggested that some disturbances in ion balance, mainly related to calcium are one of the reasons of hemolysis. No comparative studies in the available literature on the chelating properties of numerous AAAs in respect to calcium were found. Therefore, a comparison was made between chelating effects of five AAAs on calcium and magnesium in vitro. It was demonstrated that calcium was bound at lower AAAs concentrations than magnesium. The chelating effect of AAAs expressed by EC50 values was positively correlated with both pKa values and Log P values of the examined acids. The obtained data indicate that the acidity and hydrophilic properties are responsible for the chelating effect of AAAs on calcium and magnesium in vitro. These data do not provide an explanation for differences in the hemolytic activity of the examined compounds.

[Health risk related to municipal waste incineration]. / Ryzyko zdrowotne zwiazane ze spalaniem odpadów komunalnych.

There are exposures to various organic and inorganic xenobiotics related to municipal waste incineration in work places and environment close to incinerators. Among others, these are polychlorinated biphenyls, dioxins, furans, chlorophenols, mono- and polycyclic aromatic hydrocarbons, toxic metals and irritation gases. Numerous studies revealed that these chemicals and their metabolites were generally not elevated in worker's blood and urine and in persons living near incinerators. The epidemiological studies indicate increased cancer risk and excess of ischemic heart disease in incinerator workers. In residents living in the vicinity of incinerators, a slightly increased cancer risk, respiratory symptoms, multiple pregnancy, congenital abnormalities, and disturbances in thyroid hormone levels were observed. However, these data do not provide univocal evidence that the cause-effect relationship between exposure and health risk does really exist.

[Health hazard for medical staff exposed to nitrous oxide]. / Zagrozenie zdrowia personelu medycznego narazonego na tlenek diazotu.

The paper briefly reviews available data on occupational exposure to nitrous oxide and health consequences in medical staff. Special attention is paid on causes of nitrous oxide contamination in occupational environment and monitoring its concentrations. On the basis of the epidemiological studies it was ascertained that nitrous oxide exerts multiple deleterious effects on human organism, especially on fertility, pregnancy, central nervous system and bone marrow.