RESUMO
Although organic solvents have been associated with CNS toxicity, neurotoxicity testing is rarely a regulatory requirement. We propose a strategy to assess the potential neurotoxicity of organic solvents and predict solvent air concentrations that will not likely produce neurotoxicity in exposed individuals. The strategy integrated an in vitro neurotoxicity, an in vitro blood-brain barrier (BBB), and an in silico toxicokinetic (TK) model. We illustrated the concept with propylene glycol methyl ether (PGME), widely used in industrial and consumer products. The positive control was ethylene glycol methyl ether (EGME) and negative control propylene glycol butyl ether (PGBE), a supposedly non-neurotoxic glycol ether. PGME, PGBE, and EGME had high passive permeation across the BBB (permeability coefficients (Pe) 11.0 × 10-3, 9.0 × 10-3, and 6.0 × 10-3 cm/min, respectively). PGBE was the most potent in in vitro repeated neurotoxicity assays. EGME's main metabolite, methoxyacetic acid (MAA) may be responsible for the neurotoxic effects reported in humans. No-observed adverse effect concentrations (NOAECs) for the neuronal biomarker were for PGME, PGBE, and EGME 10.2, 0.07, and 79.2 mM, respectively. All tested substances elicited a concentration-dependent increase in pro-inflammatory cytokine expressions. The TK model was used for in vitro-to-in vivo extrapolation from PGME NOAEC to corresponding air concentrations (684 ppm). In conclusion, we were able to predict air concentrations that would not likely result in neurotoxicity using our strategy. We confirmed that the Swiss PGME occupational exposure limit (100 ppm) will not likely produce immediate adverse effects on brain cells. However, we cannot exclude possible long-term neurodegenerative effects because inflammation was observed in vitro. Our simple TK model can be parameterized for other glycol ethers and used in parallel with in vitro data for systematically screening for neurotoxicity. If further developed, this approach could be adapted to predict brain neurotoxicity from exposure to organic solvents.
Assuntos
Éter , Propilenoglicóis , Humanos , Toxicocinética , Propilenoglicóis/metabolismo , Propilenoglicóis/toxicidade , Éteres/toxicidade , Etilenoglicóis/toxicidade , Etilenoglicóis/metabolismo , SolventesRESUMO
Glycol ethers are solvents used in a plethora of occupational and household products exposing the users to potential toxic effects. Several glycol ethers derived from ethylene glycol induce hematological toxicity, such as anemia in workers. The exposure effects on blood cells of glycol ethers derived from propylene glycol are unknown in humans. The aim of our study was to evaluate blood parameters indicative of red blood cell (RBC) hemolysis and oxidative stress in participants exposed to propylene glycol (propylene glycol monobutyl ether (PGBE) and propylene glycol monomethyl ether (PGME)), two extensively used propylene glycol derivatives worldwide. Seventeen participants were exposed 2 h in a control inhalation exposure chamber to low PGME (35 ppm) and PGBE (15 ppm) air concentrations. Blood was regularly collected before, during (15, 30, 60, and 120 min), and 60 min after exposure for RBC and oxidative stress analyses. Urine was also collected for clinical effects related to hemolysis. Under the study conditions, our results showed that the blood parameters such as RBCs, hemoglobin concentration, and white blood cells tended to increase in response to PGME and PGBE exposures. These results raise questions about the possible effects in people regularly exposed to higher concentrations, such as workers.
Assuntos
Éteres , Hemólise , Humanos , Éteres/toxicidade , Voluntários Saudáveis , Propilenoglicóis/toxicidade , Propilenoglicol/toxicidadeRESUMO
BACKGROUND: The ecigarette has become increasingly popular in recent years. However, the question of toxicity is not yet clear and there is global uncertainty regarding the use of ecigarettes. This is intensified by the fact that there is a lack of declaration of the liquid ingredients. OBJECTIVE: The present paper investigates propylene glycol, a major component of the liquids, for possible acute inflammatory reactions as well as cytotoxic and genotoxic effects on human nasal mucosa cells. MATERIALS AND METHODS: The nasal mucosa cells from 10 volunteers were cultivated at the air-liquid interface and then exposed to different concentrations of propylene glycol. The analysis was carried out using the trypan blue test, comet assay, micronucleus test, and interleukin (IL)-6 and IL8 sandwich ELISA. RESULTS: The trypan blue test showed no reduction in vitality. No increase in IL6 and IL8 concentrations were detected in the sandwich ELISA. In the comet assay, the Olive tail moment showed a dose-dependent increase in DNA fragmentation compared to the negative control at all examined concentrations. A difference between the pure substance and the negative control was shown in the micronucleus test. CONCLUSION: Possibly repairable dose-dependent DNA fragmentation and profound DNA alterations at high concentrations of propylene glycol warrant enhanced genotoxicological studies. These should include long-term exposure studies and assessment of further ingredients of the liquids. Consequently, the manufacturers need to be forced to declare the latter.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Mucosa Nasal/efeitos dos fármacos , Propilenoglicóis/toxicidade , Vaping/efeitos adversos , Células Cultivadas , Ensaio Cometa , Humanos , Inflamação , Testes para Micronúcleos , Mucosa Nasal/citologiaRESUMO
Skin exposure to cleaning products in the general and occupational population are a public health concern. Among the most frequently identified amphiphilic organic solvents in cleaning products are propylene glycol monomethyl ether (PGME) and propylene glycol n-butyl ether (PGBE). Internal dose from skin exposure may be efficiently evaluated using in vitro flow-through diffusion cells with excised human skin. Our aim in this study was two-fold; 1) characterize the permeation rates (J), time lag (Tlag), and permeation coefficients (Kp) of PGME and PGBE in human ex-vivo skin permeation assays, and 2) determine a possible mixture effect on skin permeation characteristics when applied together. Our results showed a short Tlag for PGME and was reduced further depending on the amount of PGBE in the mixture (Tlag was reduced from 2 h to 1-1.7 h) for fresh skin. PGBE Tlag slightly increased when mixed with 50 % or more PGME. Permeation rate decreased to half for both PGME and PGBE in mixture at any concentration. This substantial permeation was greater with previously frozen skin. This mixture effect could favor permeation of other compounds through human skin.
Assuntos
Modelos Biológicos , Propilenoglicóis/farmacocinética , Absorção Cutânea , Pele/metabolismo , Administração Cutânea , Humanos , Técnicas In Vitro , Cinética , Propilenoglicóis/química , Propilenoglicóis/toxicidade , Pele/efeitos dos fármacos , Testes de Irritação da PeleRESUMO
Regulations that are indirectly driving the substitution of hazardous chemicals, such as the EU REACH regulation, necessitate improvements in chemical alternatives assessment frameworks. In those frameworks, life cycle thinking lacks some important aspects such as systematic and quantitative occupational safety methods and risks from intermediate chemicals that are not released to the environment under normal operating conditions. Concerns of companies about regulatory drivers regarding substances of very high concern often lead to inadequate evaluation of the baseline situation; an issue also overlooked by the frameworks. Moreover, life cycle assessment is optional for assessors with limited resources, such as small and medium enterprises. However, the success of substitution should not be evaluated without life cycle concerns. An environmental impact assessment model has been suggested to overcome these shortcomings of the chemical alternatives assessment frameworks. The model was applied to a case study of primed metal sheet production, where the company was driven to substitute reprotoxic 2-methoxypropanol used in their formulations. The results show that the proposed model is promising for solving the mentioned shortcomings, informing the assessor about substances of very high concern along the life cycle, and it has the potential to be further improved with the help of supporting software and databases. Particularly, in the occupational safety area that concerns risks of accidents at work, improvements to the EU occupational health database can drastically increase the accuracy of the assessments. Besides, the development of methodologies for the quantification of the impacts of reprotoxic, bioaccumulative and endocrine disruptor substances is necessary.
Assuntos
Disruptores Endócrinos/toxicidade , Meio Ambiente , Substâncias Perigosas/toxicidade , Modelos Teóricos , Medição de Risco/métodos , Humanos , Saúde Ocupacional , Propilenoglicóis/toxicidadeRESUMO
Vanillin propylene glycol acetal (VPGA) has been used as a flavoring agent. Here, we performed a 13-week subchronic toxicity study of VPGA in F344 rats with oral administration by gavage at doses of 0, 100, 300, and 1000â¯mg/kg body weight (BW)/day. In the 1000â¯mg/kg BW group, loss of vigorous activity and listlessness immediately after administration were observed for both sexes throughout the experimental period. Reduction of body weight gain was noted in both sexes at 1000â¯mg/kg BW. Serum biochemistry demonstrated significant increases in total protein, albumin, total cholesterol, calcium, inorganic phosphorus, and γ-glutamyl transpeptidase in both sexes at 1000â¯mg/kg BW and increases in the albumin/globulin ratio and urea nitrogen in the male 1000â¯mg/kg BW group. A significant increase in relative liver weight was detected in both sexes at 1000â¯mg/kg BW. Histopathologically, centrilobular hepatocellular hypertrophy in the liver was observed in both sexes at 1000â¯mg/kg BW. In addition, the incidence of fatty changes in hepatocytes in the male 1000â¯mg/kg BW group was decreased compared with that in the control. Based on these results, the no-observed-adverse-effect level for VPGA was evaluated to be 300â¯mg/kg BW/day for both sexes in the current study.
Assuntos
Acetais/toxicidade , Aromatizantes/toxicidade , Propilenoglicóis/toxicidade , Acetais/administração & dosagem , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Aromatizantes/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Propilenoglicóis/administração & dosagem , Ratos Endogâmicos F344RESUMO
Nowadays scientific achievements in various areas of lives have caused the creation of more and more «foreign body substances¼ known as xenobiotics. As it is widely accepted that human health is a product of both genetics and the environment; and premise that also holds true for the immune system with unclear morphogenetic aspect, so we selected the purpose of our work as detection of ultrastructural changes in the spleen and thymus under the influence of tryglycidyl ether of polyoxypropylenetriol (TEPPT) and propylene glycol (PP). Subacute experiment has been performed on the matured male rat's with administration of 1/10 LD50 and 1/100 LD50 of TEPPT and PP during 7 days, 15 days, 30 days and 45 days. Obtained materials of spleen and thymus have been investigated with ultramicroscopic and histological examination. Detection of cellular density has been performed. On the base of obtained results we can conclude that structure of spleen and thymus is susceptible to influence of TEPPT and PP. Ultrastructural changes in those organs of the immune system are characterized by margination of chromatin in nuclei, appearance of pronounced invaginations of karyolemma till fragmentation of nuclei; condensed, wrinkled cytoplasm, dilatation of mitochondria, vacuolization of cytoplasm. Such changes are manifestation of hydropic dystrophy and apoptosis development with resulting in reducing of cellular density in 45 days more pronounced under TEPPT influence with 1/10 LD50 dose: in mantle zone of spleen follicle from 171.1±4.1to 123.7±10.8 cells/104 µm2, in marginal zone of spleen follicle from 104.6±3.8 to 79.4±9.7, in cortical zone of thymus from 180.1±3.9 to 128.3±9.1, in medullar zone of thymus from 137.4±3.7 to 98.6±8.3.
Assuntos
Compostos de Epóxi/toxicidade , Polímeros/toxicidade , Propilenoglicóis/toxicidade , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos , Xenobióticos/toxicidade , Animais , Feminino , Ratos , Baço/ultraestrutura , Timo/ultraestrutura , Testes de Toxicidade SubagudaRESUMO
It is challenging but imperative to merge imaging agents and small molecule therapeutics into one nanoentity for diagnosis and treatment. Herein, we constructed polymeric nanoparticles for targeted delivery and combination chemotherapy, which formed through host-guest interactions among three elements: 1)â ß-cyclodextrin polymer (poly-ß-CD), as the backbone of nanoparticles; 2)â two antitumor drugs-doxorubicin (DOX) and docetaxel (DTX); and 3)â aptamers labeled with adamantane and fluorescein (Ad-aptamer-FAM), as recognition elements. First, polymeric nanoparticles, termed self-assembled supramolecular nanoparticles (SSNPs), were formulated by combining hydrophobic DTX and DOX with poly-ß-CD via host-guest interactions. Then, the surface of SSNPs modified the aptamer to acquire targeting ability; such nanoparticles were termed targeted self-assembled supramolecular nanoparticles (T-SSNPs). As evidenced by MTS assay data, T-SSNPs exhibited significant selective cytotoxicity toward target cells. The results also indicated that combination drugs achieved a good synergistic effect with a combination index of 0.43. Thus, an effective and simple drug delivery system was constructed for targeted delivery and combination chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Propilenoglicóis/química , beta-Ciclodextrinas/química , Aptâmeros de Nucleotídeos/química , Sequência de Bases , Linhagem Celular Tumoral , DNA/química , Portadores de Fármacos/toxicidade , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Nanopartículas/toxicidade , Propilenoglicóis/toxicidade , Nanomedicina Teranóstica/métodos , beta-Ciclodextrinas/toxicidadeRESUMO
This study investigated whether and how 3-chloro-1,2-propanediol (3-MCPD) fatty acid esters, a group of food contaminants formed during processing, might inhibit the immune system through suppressing T lymphocyte activation for the first time. Three 3-MCPD esters including 1-palmitoyl-3-chloropropanediol (1-pal), 2-palmitoyl-3-chloropropanediol (2-pal), and1,2-dipalmitoyl-3-chloropropanediol (dipal) were selected as the probe compounds to test the possible effects of fatty acid structure on their potential immune inhibitory effect. The results showed that 1-pal and 2-pal, but not dipal, significantly suppressed ConA-induced T lymphocyte proliferation, cell cycle activity, Th1 and Th2 cytokine secretion, CD4+ T cell populations, and the ratio of CD4+/CD8+ T cells under the experimental conditions. Moreover, Western blotting and immunofluorescence analyses revealed that 1-pal and 2-pal could inhibit the activation of ConA-stimulated mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. In addition, 1-pal significantly suppressed DNFB-induced delayed-type hyper sensitivity (DTH) reaction characterized by the increased ear thickness and IFN-γ production in mice. These observations indicated that 3-MCPD esters exerted a negative effect on T lymphocyte-mediated immunity, and the immunosuppressive activities of 3-MCPD monopalmitates were stronger than 3-MCPD dipalmitate.
Assuntos
Imunossupressores/toxicidade , Palmitatos/toxicidade , Propilenoglicóis/toxicidade , Linfócitos T/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/sangue , Citocinas/metabolismo , Dinitrofluorbenzeno , Ésteres , Feminino , Hipersensibilidade Tardia/sangue , Hipersensibilidade Tardia/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Baço/citologia , Linfócitos T/metabolismoRESUMO
Rapid technology growth and its implementation in all spheres of the people's lives dictates the necessity for thorough study of the influence of different chemicals on human's health. This study was undertaken to elucidate the structural changes that occur in the matured rats' spleen experimentally induced by selected xenobiotic, so, purpose of our work was detection of microscopic peculiarities of the spleen under the influence of laproxides. In subacute experiment were uncovered organometric alterations of the matured male rat's spleen after the administration of 1/10 LD50 of polyether-tryglycidyl ether of polyoxypropylene triol (TEPPT). The study was performed on 72 outbreed WAG male matured rats with the weight 200±10g. Histological slides were studied with performing morphometric and statistical methods. We revealed changes of morphologiÑ data in comparison to control data which shows reactivity of the spleen in response to the induced xenobiotic. The received and analyzed data demonstrate the morphological changes of the spleen, specifically changes of the linear dimensions and weight of the spleen due to the influence of the TEPPT. The spleen is very sensitive to the effects of xenobiotics, in particular, TEPPT that is even reflected in its grossly (weight and linear dimensions) and histological features (reliable changes of the of the white pulp area of the spleen from 17.87±1.04% to 27.37±1.71%, diameter of lymphatic follicles from 426.59±11.18 µm to 382.31±11.73 µm, width of the mantle zone from 45.73±1.08 µm to 37.18±2.29 µm, width of the marginal zone from 81.32±1.79 µm to 74.63±2.08 µm, width of the periarterial zone from 88.73±2.69 µm to 97.24±2.61 µm).
Assuntos
Poluentes Ambientais/toxicidade , Linfonodos/efeitos dos fármacos , Poliésteres/toxicidade , Propilenoglicóis/toxicidade , Baço/efeitos dos fármacos , Animais , Animais não Endogâmicos , Dose Letal Mediana , Linfonodos/patologia , Linfonodos/ultraestrutura , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Baço/patologia , Baço/ultraestruturaRESUMO
2-methyl 1,3-propandiol (MPD) is a low molecular weight, colorless glycol used in polymer and coating applications. The log Kow of -0.6 suggests partitioning to aqueous phases with a low concern for possible bioaccumulation. MPD was found to be inherently biodegradable. Ecotoxicological results in several aquatic and terrestrial species found no significant hazard potential. MPD is rapidly absorbed via the oral and dermal routes, metabolized to 3-hydroxybutyrate, and excreted in urine with a half-life of 3.6 h. Acute toxicity testing found low toxicity via all routes. Barely perceptible skin irritation was observed in human volunteers, whereas there was no evidence of irritation in rabbits. Skin sensitization in Guinea pigs was negative. Human skin patch results indicated minimal response in about 1% of individuals. There was no evidence of mutagenicity using bacterial and mammalian test systems. A 90-day oral study in rats found no adverse effects at any dose. Three developmental toxicity studies in rats and rabbits, found no treatment-related maternal toxicity, fetal toxicity or malformations. A two-generation reproduction study in rats found no consistent treatment-related adverse effects on reproduction in either generation. No carcinogenicity studies with MPD were identified. MPD presents a low degree of toxicological and ecotoxicological or environmental hazard.
Assuntos
Propilenoglicóis/toxicidade , Animais , Ecotoxicologia/métodos , Glicóis/toxicidade , Cobaias , Meia-Vida , Humanos , Coelhos , Ratos , Reprodução/efeitos dos fármacos , Pele/efeitos dos fármacosRESUMO
Functional gene fingerprinting of chemicals could be used to understand the direct gene-chemical interaction in the process of toxification from a genome-wide scale. 2, 2-bis (bromomethyl)-1, 3-propanediol (BMP) is a brominated flame retardant with widespread production but with very limited toxicological data. Here the cytotoxicity of BMP was assessed by Escherichia coli (E. coli) functional genome-wide knockout mutants screening and the underlying molecular mechanism was investigated. The median inhibition concentration (IC50) of BMP was 1.608 ± 0.078 mg/ml after 24 h exposure. 119 initial, including 66 sensitive and 53 resistant single gene mutants, were identified by a full library screening of BMP at the concentration of IC50. The resistant genes were significantly enriched in nucleobase-containing compound biosynthetic process (GO: 0034654) by gene ontology (GO) biological process analyses, which suggested that the pathway of DNA repair is a critical cellular process in the survival of cells exposed to BMP. Meanwhile, function annotation of all BMP responsive genes suggested the mechanism of BMP was associated with DNA damage, oxidative stress and cellular transmembrane transport process. Many genes were exclusively responsive to BMP comparing with other chemicals that has been assessed by E. coli mutant screening approach, which indicated that BMP has a distinct mode of toxic action. Overall, the functional genomic screening approach presented here provides a great tool to assess the cellular toxicological mechanism of environmental chemicals.
Assuntos
Escherichia coli/efeitos dos fármacos , Retardadores de Chama/toxicidade , Propilenoglicóis/toxicidade , Dano ao DNA , Escherichia coli/genética , Técnicas de Inativação de Genes , Genômica , Estresse Oxidativo , Propilenoglicol , Testes de ToxicidadeRESUMO
Thousands of gallons of industrial chemicals, crude 4-methylcyclohexanemethanol (MCHM) and propylene glycol phenyl ether (PPh), leaked from industrial tanks into the Elk River in Charleston, West Virginia, USA, on January 9, 2014. A considerable number of people were reported to exhibit symptoms of chemical exposure and an estimated 300,000 residents were advised not to use or drink tap water. At the time of the spill, the existing toxicological data of the chemicals were limited for a full evaluation of the health risks, resulting in concern among those in the impacted regions. In this preliminary study, we assessed cell viability and plasma membrane degradation following a 24-h exposure to varying concentrations (0-1000 µM) of the two compounds, alone and in combination. Evaluation of different cell lines, HEK-293 (kidney), HepG2 (liver), H9c2 (heart), and GT1-7 (brain), provided insight regarding altered cellular responses in varying organ systems. Single exposure to MCHM or PPh did not affect cell viability, except at doses much higher than the estimated exposure levels. Certain co-exposures significantly reduced metabolic activity and increased plasma membrane degradation in GT1-7, HepG2, and H9c2 cells. These findings highlight the importance of examining co-exposures to fully understand the potential toxic effects.
Assuntos
Cicloexanos/toxicidade , Éteres Fenílicos/toxicidade , Propilenoglicóis/toxicidade , Poluentes Químicos da Água/toxicidade , Linhagem Celular , Monitoramento Ambiental , Células HEK293 , Humanos , Rios/química , West VirginiaRESUMO
The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety.
Assuntos
Qualidade de Produtos para o Consumidor , Cosméticos , Éteres/toxicidade , Polietilenoglicóis/toxicidade , Propilenoglicóis/toxicidade , Alquilação , Animais , Fármacos Dermatológicos/química , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/toxicidade , Emulsificantes/química , Emulsificantes/farmacocinética , Emulsificantes/toxicidade , Éteres/química , Éteres/farmacocinética , Humanos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Propilenoglicóis/química , Propilenoglicóis/farmacocinética , Tensoativos/química , Tensoativos/farmacocinética , Tensoativos/toxicidade , Testes de ToxicidadeRESUMO
Two phase partitioning bioreactors (TPPBs) improve the efficiency of fermentative processes by limiting the exposure of microorganisms to toxic solutes by sequestering them into a non-aqueous phase (NAP). A potential limitation of this technology, when using immiscible organic solvents as the NAP, is the cytoxicity that these materials may exert on the microbes. An improved TPPB configuration is one in which polymeric NAPs are used to replace organic solvents in order to take advantage of their low cost, improved handling qualities, and biocompatibility. A recent study has shown that low molecular weight polymers may confer improved solute uptake relative to high molecular weight polymers (i.e., have higher partition coefficients), but it is unknown whether sufficiently low molecular weight polymers may inhibit cell growth. This study has investigated the biocompatibility of a range of low molecular weight polymers, and compared trends in biocompatibility to the well-established "critical log P" concept. This was achieved by determining the biocompatibility of polypropylene glycol polymers over a molecular weight (MW) range of 425-4,000 to Saccharomyces cerevisiae and Pseudomonas putida, two organisms which have been previously used in TPPB systems. The lower MW polymers were shown to have lower average log P values, and showed more cytotoxicity than polymers of the same structure but with higher molecular weight. Since polymers are generally polydisperse (i.e., polymer samples contain a distribution of MWs), removal of the lower MW fractions via water washing was found to result in improved polymer biocompatibility. These results suggest that the critical log P concept remains useful for describing the toxicity of polymeric substances of different MWs, although it is complicated by the presence of the low MW fractions in the polymers arising from polydispersity.
Assuntos
Reatores Biológicos/microbiologia , Polímeros/metabolismo , Polímeros/toxicidade , Propilenoglicóis/metabolismo , Propilenoglicóis/toxicidade , Pseudomonas putida/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Peso Molecular , Polímeros/química , Propilenoglicóis/química , Pseudomonas putida/crescimento & desenvolvimento , Pseudomonas putida/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismoRESUMO
The in vivo comet assay has been used for the evaluation of DNA damage and repair in various tissues of rodents. However, it can give false-positive results due to non-specific DNA damage associated with cell death. In this study, we examined whether the in vivo comet assay can distinguish between genotoxic and non-genotoxic DNA damage in urinary bladder cells, by using the following seven chemicals related to urinary bladder carcinogenesis in rodents: N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), glycidol, 2,2-bis(bromomethyl)-1,3-propanediol (BMP), 2-nitroanisole (2-NA), benzyl isothiocyanate (BITC), uracil, and melamine. BBN, glycidol, BMP, and 2-NA are known to be Ames test-positive and they are expected to produce DNA damage in the absence of cytotoxicity. BITC, uracil, and melamine are Ames test-negative with metabolic activation but have the potential to induce non-specific DNA damage due to cytotoxicity. The test chemicals were administered orally to male Sprague-Dawley rats (five per group) for each of two consecutive days. Urinary bladders were sampled 3h after the second administration and urothelial cells were analyzed by the comet assay and subjected to histopathological examination to evaluate cytotoxicity. In the urinary bladders of rats treated with BBN, glycidol, and BMP, DNA damage was detected. In contrast, 2-NA induced neither DNA damage nor cytotoxicity. The non-genotoxic chemicals (BITC, uracil, and melamine) did not induce DNA damage in the urinary bladders under conditions where some histopathological changes were observed. The results indicate that the comet assay could distinguish between genotoxic and non-genotoxic chemicals and that no false-positive responses were obtained.
Assuntos
Carcinógenos/toxicidade , Ensaio Cometa/métodos , Dano ao DNA/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Animais , Butilidroxibutilnitrosamina/toxicidade , Relação Dose-Resposta a Droga , Compostos de Epóxi/toxicidade , Isotiocianatos/toxicidade , Masculino , Propanóis/toxicidade , Propilenoglicóis/toxicidade , Ratos , Ratos Sprague-Dawley , Triazinas/toxicidade , Uracila/toxicidadeRESUMO
FTY720 (fingolimod), the sphingosine-1-phosphate (S1P) analogue, has been experimentally indicated to exert substantial ameliorating effects in animal models of Alzheimer's disease (AD). The present work aims to answer whether central S1P receptor 1 (S1P1) plays significant role in the impact of fingolimod in AD. To verify the prominence of central FTY720 phosphorylation, DMS (sphingosine kinase inhibitor) was infused intracerebrally in parallel with systemic FTY720 administration to prevent central formation of FTY720-P as the recognized active ligand for S1PRs. The corresponding S1P1 modulation was also investigated using the pharmacological blockage of central S1P1 by W123. Both DMS and W123 were efficiently capable of suppressing FTY720-ameliorating effects in AD animals, either on memory deficit or on COX-II and TNF-α expression. Our data conclude that experimental benefits of FTY720 in the context of AD depend on central S1P1 modulation, as well as on S1P kinase activity in the brain.
Assuntos
Doença de Alzheimer/metabolismo , Propilenoglicóis/toxicidade , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Doença de Alzheimer/etiologia , Doença de Alzheimer/fisiopatologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Cloridrato de Fingolimode , Masculino , Aprendizagem em Labirinto , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Ratos , Ratos Wistar , Esfingosina/farmacologia , Esfingosina/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Surface sealants have been successfully used in the prevention of erosive tooth wear. However, when multiple tooth surfaces should be sealed, the light-curing procedure is very time-consuming. Therefore, the aim of this study was to investigate whether reduced light-curing time (while maintaining similar energy density) has an influence on resin-based surface sealant cytotoxicity. METHODS: Bovine dentine discs were treated as follows: group 1: untreated, groups 2-5: Seal&Protect and groups 6-9: experimental sealer. Groups 2 and 6 were light-cured (VALO LED light-curing device) for 40 s (1000 mW/cm2), groups 3 and 7 for 10 s (1000 mW/cm2), groups 4 and 8 for 7 s (1400 mW/cm2) and groups 5 and 9 for 3 s (3200 mW/cm2). Later, materials were extracted in culture medium for 24 h, and released lactate dehydrogenase (LDH) activity as a measure of cytotoxicity was determined photometrically after cells (dental pulp cells and gingival fibroblasts) were exposed to the extracts for 24 h. Three independent experiments, for both sample preparation and cytotoxicity testing, were performed. RESULTS: Overall, lowest cytotoxicity was observed for the unsealed control group. No significant influence of light-curing settings on the cytotoxicity was observed (p = 0.537 and 0.838 for pulp cells and gingival fibroblasts, respectively). No significant difference in the cytotoxicity of the two sealants was observed after light-curing with same light-curing settings (group 2 vs. 6, 3 vs. 7, 4 vs. 8 and 5 vs. 9: p > 0.05, respectively). CONCLUSIONS: Shortening the light-curing time, while maintaining constant energy density, resulted in no higher cytotoxicity of the investigated sealants.
Assuntos
Materiais Dentários/toxicidade , Dentina/efeitos dos fármacos , Cura Luminosa de Adesivos Dentários/métodos , Selantes de Fossas e Fissuras/toxicidade , Cimentos de Resina/toxicidade , Animais , Bovinos , Técnicas de Cultura de Células , Células Cultivadas , Lâmpadas de Polimerização Dentária/classificação , Materiais Dentários/efeitos da radiação , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Gengiva/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/análise , L-Lactato Desidrogenase/efeitos dos fármacos , Cura Luminosa de Adesivos Dentários/instrumentação , Metacrilatos/toxicidade , Selantes de Fossas e Fissuras/efeitos da radiação , Propilenoglicóis/toxicidade , Cimentos de Resina/efeitos da radiação , Fatores de TempoRESUMO
The use of read-across of data within a group of structurally similar substances potentially allows one to characterise the hazards of a substance without resorting to additional animal studies. However the use of read-across is not without challenges, particularly when used to address the needs of a regulatory programme such as the EU REACH regulation. This paper presents a case study where a previously accepted read-across approach was used to address several data gaps in a REACH registration dossier but was subsequently rejected in part by the European Chemicals Agency (ECHA), resulting in the requirement to perform a developmental toxicity study in rodents. Using this case study, this paper illustrates some of the practical challenges faced when making use of read-across, particularly with respect to addressing the uncertainty associated with the use of read-across; showcasing the scientific justification and highlighting some of the potential implications/opportunities for future cases.