The Experts below are selected from a list of 6153 Experts worldwide ranked by ideXlab platform
Karl E. Gustavson - One of the best experts on this subject based on the ideXlab platform.
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comparisons of human cell based and Submitochondrial Particle bioassay responses to the meic compounds in reference to human toxicity data
Toxicology, 2002Co-Authors: Karl E. Gustavson, Harry W Read, John M HarkinAbstract:Abstract Toxicity results from Submitochondrial Particle (SMP) bioassays were compared to results from multiple human-cell-based assays to evaluate the SMP tests’ ability to indicate cellular toxicity. Correlation analyses between cell-based and SMP responses were conducted on a series of diverse chemicals of human toxicologic interest chosen in the Multicentre Evaluation of In vitro Cytotoxicity (MEIC) study and suggest a high degree of ordering. The r2 correlation coefficient obtained when comparing the log-transformed SMP results to the average cellular response for all compounds was 0.75 (n=42). When specific mitochondrial inhibitors (to which SMP arc extremely sensitive) and toxic metals (which SMP modeled poorly) were removed, the correlation improved to 0.91 (n=34). When the SMP assay of each individual cell-based assay was compared to the average toxic response of all the cell-based assays for these 34 compounds, the SMP r2 was greater than the median r2 of the cell-based assays, indicating its ability to predict cell-based toxic responses with a high degree of accuracy. Comparisons of the SMP data to the human toxicity data are similar to the cell line assays, where removal of the specific mitochondrial toxicants and metals greatly improves the relationship.
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Repeatability of the Submitochondrial Particle Assay
Ecotoxicology and environmental safety, 2002Co-Authors: Francis G. Doherty, Karl E. GustavsonAbstract:A study assessing the intralaboratory precision of the in vitro Submitochondrial Particle (SMP) electron transfer (ETr) and reverse electron transfer (RET) assays was undertaken using the standard reference toxicants, pentachlorophenol (PCP), sodium dodecyl sulfate (SDS), and zinc sulfate 7-hydrate (ZnSO4 7H2O). One to three trials of each assay were manually conducted daily for at least 5 days with each toxicant using commercially available sources of Particles and reagents. Composite coefficients of variation (CVs) for the ETr assay ranged from 20.6% for ZnSO4 to 29.3% for PCP (n > or = 15). Composite CVs for the RET assay ranged from 6.5% for SDS to 16.5% for PCP (n > or = 15). Comparison of intralaboratory results with in-house and published data demonstrates that the precision of both of these SMP assays is comparable to that of the more common in vivo, whole-organism bacterial, invertebrate, and fish toxicity tests.
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comparison of toxicities and mechanism of action of n alkanols in the Submitochondrial Particle and the vibrio fischeri bioluminescence microtox bioassay
Environmental Toxicology and Chemistry, 1998Co-Authors: Karl E. Gustavson, Anders Svenson, John M HarkinAbstract:Many studies on the toxicity of n-alkanols have been conducted and quantitative structure-activity relationships (QSARs) established comparing bioassay toxicity data to carbon number. The results typically indicate increasing toxicity with increasing n-alkanol chain length, but often higher homologues are not assessed, where toxicity no longer increases with carbon number—a phenomenon commonly called the cutoff effect. The mode of toxic action of these compounds has been designated narcosis I; however, the specific mechanism is unknown and widely debated. This study compares results for two commonly used bioassays, the Submitochondrial Particle (SMP) and the Microtox® bioassay, for the homologous series of n-alkanols ranging from methanol (C1-OH) to stearyl alcohol (C18-OH). Analysis of dose-response curve slopes indicates that the SMP assay exhibits a general mechanism of toxicity, whereas the Microtox assay exhibits this general mechanism to short-chain alkanols, but subsequently switches to specific interaction with the higher alkanols. This specific interaction is likely competitive inhibition of the bacterial luciferase. Comparison of the toxicities in these assays with octanol/water partition coeffients (Kow), the results of whole-organism tests, and a bacterial luciferase assay further substantiate this claim and indicate that the SMP is a better model of toxicity in whole organisms.
Emanuele Argese - One of the best experts on this subject based on the ideXlab platform.
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study on the toxicity of phenolic and phenoxy herbicides using the Submitochondrial Particle assay
Toxicology in Vitro, 2005Co-Authors: Emanuele Argese, Cinzia Bettiol, Alfonso Zambon, P Miana, Davide Marchetto, S De Vettori, Pier Francesco GhettiAbstract:Abstract A simple and rapid in vitro toxicological assay, utilizing Submitochondrial Particles (SMP), has been used to evaluate the toxic effects of fifteen herbicides belonging to the phenol and phenoxyalkanoic acid chemical classes. The SMP assay allows the quantitative evaluation of the toxicity of compounds with different mechanisms of action: uncouplers, inhibitors of the enzyme complexes involved in reverse electron transfer and in oxidative phosphorylation and chemicals that alter the membrane structure. The two groups of herbicides showed different levels of toxicity. For phenol derivatives, EC 50 values ranged from 0.16 μM (ioxynil) to 6.7 μM (2,4-dinitrophenol), whereas for phenoxy herbicides EC 50 values ranged from 21 μM (2,4,5-trichlorophenoxyacetic acid, 2,4,5-T) to 110 μM (4-chloro-2-methylphenoxyacetic acid, MCPA). On the average, the toxicity of phenolic compounds is greater than that of phenoxyalkanoic acids by two orders of magnitude. Quantitative structure–activity relationships (QSAR) were developed between EC 50 values and various molecular descriptors. The results suggest the existence of different mechanisms of action for the two classes of compounds. The findings obtained for phenolic herbicides are consistent with a protonophoric uncoupling mechanism, whereas for phenoxy herbicides a non-specific mode of action at membrane level can be hypothesized.
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assessment of chloroaniline toxicity by the Submitochondrial Particle assay
Environmental Toxicology and Chemistry, 2001Co-Authors: Emanuele Argese, Cinzia Bettiol, F Agnoli, Alfonso Zambon, Martina Mazzola, Annamaria Volpi GhirardiniAbstract:The effects on mitochondrial respiration of 15 chloroanilines were recorded by using the in vitro response of submi-tochondrial Particles (SMP) from beef heart mitochondria. The bioassay procedure for SMP is based on the process of reverse electron transfer, which can be negatively affected by inhibitors of electron transport, by uncouplers, and by chemicals that impair membrane integrity. The EC50 values, determined for the tested chloroanilines, indicate a general tendency of increasing toxicity with increasing chlorine substitution. In order to validate the results obtained and to evaluate the capability of the SMP assay to reproduce the toxic effects of the examined compounds on different freshwater species, the EC50 values were compared with literature data from other biological assays regarding both in vitro systems and whole organisms. A good correlation was found in particular with two widely used testing systems, the Microtox® and the ##Tetrahymena# assays. In addition, quantitative structure-activity relationships (QSARs) were established between the EC50 values and various molecular descriptors for hydrophobic, steric, and electronic interactions. The results obtained were utilized to elucidate the mechanism of toxic action of chloroanilines, which are commonly reported to act by the polar narcosis mode of action. Moreover, they confirmed that the SMP assay can be a useful tool for studying the toxicity of chemicals that act nonspecifically by impairing membrane structure and functions.
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comparison of in vitro Submitochondrial Particle and microtox assays for determining the toxicity of organotin compounds
Environmental Toxicology and Chemistry, 1998Co-Authors: Emanuele Argese, Cinzia Bettiol, Annamaria Volpi Ghirardini, M Fasolo, G Giurin, Pier Francesco GhettiAbstract:The toxicity of 14 organotin compounds was investigated by means of two short-term in vitro bioassays, the Submitochondrial Particle (SMP) test and the Microtox® test. The first bioassay makes use of SMPs and is based on the effects of toxicants on reverse electron transport, which is induced by adenosine triphosphate and succinate at the first site level of the respiratory chain. Microtox is a well known test system that uses marine luminescent bacteria and quantifies toxicity by measuring the reduction of luminescence caused by toxic chemicals. Very good agreement was observed between the median effective concentration (EC50) values determined for organotin compounds by means of the two bioassays. Toxicity depended on both the number and kind of organic substituents bound to the tin atom. It followed the order triorganotins > diorganotins ≈ tetraorganotins > monoorganotins. Within each series, butyltin and phenyltin compounds exhibited the highest toxicity. Microtox and SMP EC50 values were successfully correlated with toxicity data for aquatic organisms, demonstrating the usefulness of these bioassays as prescreening or complementary tools for monitoring aquatic toxicity. Moreover, to investigate the suitability of the two assays in providing information on the mechanism of toxic action of organotins, EC50 values were correlated with various physicochemical and structural parameters of the tested compounds. The results obtained showed that these parameters are poor descriptors of organotin toxicity; in particular, the poor correlations found between EC50 values and log Kow could be ascribed to the fact that different modes of action govern the biological activity of mono-, di-, tri-, and tetraorganotin compounds, respectively.
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Submitochondrial Particle response to linear alkylbenzene sulfonates nonylphenol polyethoxylates and their biodegradation derivatives
Environmental Toxicology and Chemistry, 1994Co-Authors: Emanuele Argese, Cinzia Bettiol, Antonio Marcomini, Guido Perin, P MianaAbstract:The effects on mitochondrial respiratory parameters of linear alkylbenzene sulfonates (LAS), nonylphenol polyeth-oxylates (NPEO), and some of their biotransformation products, namely sulfophenyl carboxylates (SPCs), nonylphenol (NP), and nonylphenoxy acetic acid (NP1EC), were recorded by using the in vitro response of Submitochondrial Particles (SMP) from beef heart. The toxicity of these compounds was estimated by determining their effects on the energy-coupled reverse electron transfer (RET), which is induced by ATP and succinate at the first site level of the respiratory chain and reduces exogenous NAD+ to NADH. The toxicity of the substances, expressed as the toxicant concentration decreasing the reduction rate of NAD+ to an extent of 50% (EC50), ranged from 0.61 mg/L for a commercial LAS mixture to 18,000 mg/L for individual SPCs; from 1.3 mg/L for NPEO, with an average of 10 ethoxy units, to 8.2 and 1.8 mg/L for NP1EC and NP, respectively. These results were related to the molecular structure of each compound class and compared with the toxicity values obtained by a variety of biological systems currently used for toxicity testing. The acute toxicity data have demonstrated that (a) the SMP bioassay is suitable for reproducing the toxicological response of whole organisms, such as fishes and invertebrates, to the tested chemicals; and (b) the hydrophobic moiety of these compounds plays a significant role in eliciting their toxic effects. From a toxicological standpoint, attention must be paid to the occurrence in natural waters of residual LAS, whereas in the case of NPEO both unaltered surfactant and all biotransformation products need to be identified and quantified.
John M Harkin - One of the best experts on this subject based on the ideXlab platform.
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comparisons of human cell based and Submitochondrial Particle bioassay responses to the meic compounds in reference to human toxicity data
Toxicology, 2002Co-Authors: Karl E. Gustavson, Harry W Read, John M HarkinAbstract:Abstract Toxicity results from Submitochondrial Particle (SMP) bioassays were compared to results from multiple human-cell-based assays to evaluate the SMP tests’ ability to indicate cellular toxicity. Correlation analyses between cell-based and SMP responses were conducted on a series of diverse chemicals of human toxicologic interest chosen in the Multicentre Evaluation of In vitro Cytotoxicity (MEIC) study and suggest a high degree of ordering. The r2 correlation coefficient obtained when comparing the log-transformed SMP results to the average cellular response for all compounds was 0.75 (n=42). When specific mitochondrial inhibitors (to which SMP arc extremely sensitive) and toxic metals (which SMP modeled poorly) were removed, the correlation improved to 0.91 (n=34). When the SMP assay of each individual cell-based assay was compared to the average toxic response of all the cell-based assays for these 34 compounds, the SMP r2 was greater than the median r2 of the cell-based assays, indicating its ability to predict cell-based toxic responses with a high degree of accuracy. Comparisons of the SMP data to the human toxicity data are similar to the cell line assays, where removal of the specific mitochondrial toxicants and metals greatly improves the relationship.
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comparison of toxicities and mechanism of action of n alkanols in the Submitochondrial Particle and the vibrio fischeri bioluminescence microtox bioassay
Environmental Toxicology and Chemistry, 1998Co-Authors: Karl E. Gustavson, Anders Svenson, John M HarkinAbstract:Many studies on the toxicity of n-alkanols have been conducted and quantitative structure-activity relationships (QSARs) established comparing bioassay toxicity data to carbon number. The results typically indicate increasing toxicity with increasing n-alkanol chain length, but often higher homologues are not assessed, where toxicity no longer increases with carbon number—a phenomenon commonly called the cutoff effect. The mode of toxic action of these compounds has been designated narcosis I; however, the specific mechanism is unknown and widely debated. This study compares results for two commonly used bioassays, the Submitochondrial Particle (SMP) and the Microtox® bioassay, for the homologous series of n-alkanols ranging from methanol (C1-OH) to stearyl alcohol (C18-OH). Analysis of dose-response curve slopes indicates that the SMP assay exhibits a general mechanism of toxicity, whereas the Microtox assay exhibits this general mechanism to short-chain alkanols, but subsequently switches to specific interaction with the higher alkanols. This specific interaction is likely competitive inhibition of the bacterial luciferase. Comparison of the toxicities in these assays with octanol/water partition coeffients (Kow), the results of whole-organism tests, and a bacterial luciferase assay further substantiate this claim and indicate that the SMP is a better model of toxicity in whole organisms.
Pier Francesco Ghetti - One of the best experts on this subject based on the ideXlab platform.
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study on the toxicity of phenolic and phenoxy herbicides using the Submitochondrial Particle assay
Toxicology in Vitro, 2005Co-Authors: Emanuele Argese, Cinzia Bettiol, Alfonso Zambon, P Miana, Davide Marchetto, S De Vettori, Pier Francesco GhettiAbstract:Abstract A simple and rapid in vitro toxicological assay, utilizing Submitochondrial Particles (SMP), has been used to evaluate the toxic effects of fifteen herbicides belonging to the phenol and phenoxyalkanoic acid chemical classes. The SMP assay allows the quantitative evaluation of the toxicity of compounds with different mechanisms of action: uncouplers, inhibitors of the enzyme complexes involved in reverse electron transfer and in oxidative phosphorylation and chemicals that alter the membrane structure. The two groups of herbicides showed different levels of toxicity. For phenol derivatives, EC 50 values ranged from 0.16 μM (ioxynil) to 6.7 μM (2,4-dinitrophenol), whereas for phenoxy herbicides EC 50 values ranged from 21 μM (2,4,5-trichlorophenoxyacetic acid, 2,4,5-T) to 110 μM (4-chloro-2-methylphenoxyacetic acid, MCPA). On the average, the toxicity of phenolic compounds is greater than that of phenoxyalkanoic acids by two orders of magnitude. Quantitative structure–activity relationships (QSAR) were developed between EC 50 values and various molecular descriptors. The results suggest the existence of different mechanisms of action for the two classes of compounds. The findings obtained for phenolic herbicides are consistent with a protonophoric uncoupling mechanism, whereas for phenoxy herbicides a non-specific mode of action at membrane level can be hypothesized.
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comparison of in vitro Submitochondrial Particle and microtox assays for determining the toxicity of organotin compounds
Environmental Toxicology and Chemistry, 1998Co-Authors: Emanuele Argese, Cinzia Bettiol, Annamaria Volpi Ghirardini, M Fasolo, G Giurin, Pier Francesco GhettiAbstract:The toxicity of 14 organotin compounds was investigated by means of two short-term in vitro bioassays, the Submitochondrial Particle (SMP) test and the Microtox® test. The first bioassay makes use of SMPs and is based on the effects of toxicants on reverse electron transport, which is induced by adenosine triphosphate and succinate at the first site level of the respiratory chain. Microtox is a well known test system that uses marine luminescent bacteria and quantifies toxicity by measuring the reduction of luminescence caused by toxic chemicals. Very good agreement was observed between the median effective concentration (EC50) values determined for organotin compounds by means of the two bioassays. Toxicity depended on both the number and kind of organic substituents bound to the tin atom. It followed the order triorganotins > diorganotins ≈ tetraorganotins > monoorganotins. Within each series, butyltin and phenyltin compounds exhibited the highest toxicity. Microtox and SMP EC50 values were successfully correlated with toxicity data for aquatic organisms, demonstrating the usefulness of these bioassays as prescreening or complementary tools for monitoring aquatic toxicity. Moreover, to investigate the suitability of the two assays in providing information on the mechanism of toxic action of organotins, EC50 values were correlated with various physicochemical and structural parameters of the tested compounds. The results obtained showed that these parameters are poor descriptors of organotin toxicity; in particular, the poor correlations found between EC50 values and log Kow could be ascribed to the fact that different modes of action govern the biological activity of mono-, di-, tri-, and tetraorganotin compounds, respectively.
Cinzia Bettiol - One of the best experts on this subject based on the ideXlab platform.
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study on the toxicity of phenolic and phenoxy herbicides using the Submitochondrial Particle assay
Toxicology in Vitro, 2005Co-Authors: Emanuele Argese, Cinzia Bettiol, Alfonso Zambon, P Miana, Davide Marchetto, S De Vettori, Pier Francesco GhettiAbstract:Abstract A simple and rapid in vitro toxicological assay, utilizing Submitochondrial Particles (SMP), has been used to evaluate the toxic effects of fifteen herbicides belonging to the phenol and phenoxyalkanoic acid chemical classes. The SMP assay allows the quantitative evaluation of the toxicity of compounds with different mechanisms of action: uncouplers, inhibitors of the enzyme complexes involved in reverse electron transfer and in oxidative phosphorylation and chemicals that alter the membrane structure. The two groups of herbicides showed different levels of toxicity. For phenol derivatives, EC 50 values ranged from 0.16 μM (ioxynil) to 6.7 μM (2,4-dinitrophenol), whereas for phenoxy herbicides EC 50 values ranged from 21 μM (2,4,5-trichlorophenoxyacetic acid, 2,4,5-T) to 110 μM (4-chloro-2-methylphenoxyacetic acid, MCPA). On the average, the toxicity of phenolic compounds is greater than that of phenoxyalkanoic acids by two orders of magnitude. Quantitative structure–activity relationships (QSAR) were developed between EC 50 values and various molecular descriptors. The results suggest the existence of different mechanisms of action for the two classes of compounds. The findings obtained for phenolic herbicides are consistent with a protonophoric uncoupling mechanism, whereas for phenoxy herbicides a non-specific mode of action at membrane level can be hypothesized.
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assessment of chloroaniline toxicity by the Submitochondrial Particle assay
Environmental Toxicology and Chemistry, 2001Co-Authors: Emanuele Argese, Cinzia Bettiol, F Agnoli, Alfonso Zambon, Martina Mazzola, Annamaria Volpi GhirardiniAbstract:The effects on mitochondrial respiration of 15 chloroanilines were recorded by using the in vitro response of submi-tochondrial Particles (SMP) from beef heart mitochondria. The bioassay procedure for SMP is based on the process of reverse electron transfer, which can be negatively affected by inhibitors of electron transport, by uncouplers, and by chemicals that impair membrane integrity. The EC50 values, determined for the tested chloroanilines, indicate a general tendency of increasing toxicity with increasing chlorine substitution. In order to validate the results obtained and to evaluate the capability of the SMP assay to reproduce the toxic effects of the examined compounds on different freshwater species, the EC50 values were compared with literature data from other biological assays regarding both in vitro systems and whole organisms. A good correlation was found in particular with two widely used testing systems, the Microtox® and the ##Tetrahymena# assays. In addition, quantitative structure-activity relationships (QSARs) were established between the EC50 values and various molecular descriptors for hydrophobic, steric, and electronic interactions. The results obtained were utilized to elucidate the mechanism of toxic action of chloroanilines, which are commonly reported to act by the polar narcosis mode of action. Moreover, they confirmed that the SMP assay can be a useful tool for studying the toxicity of chemicals that act nonspecifically by impairing membrane structure and functions.
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comparison of in vitro Submitochondrial Particle and microtox assays for determining the toxicity of organotin compounds
Environmental Toxicology and Chemistry, 1998Co-Authors: Emanuele Argese, Cinzia Bettiol, Annamaria Volpi Ghirardini, M Fasolo, G Giurin, Pier Francesco GhettiAbstract:The toxicity of 14 organotin compounds was investigated by means of two short-term in vitro bioassays, the Submitochondrial Particle (SMP) test and the Microtox® test. The first bioassay makes use of SMPs and is based on the effects of toxicants on reverse electron transport, which is induced by adenosine triphosphate and succinate at the first site level of the respiratory chain. Microtox is a well known test system that uses marine luminescent bacteria and quantifies toxicity by measuring the reduction of luminescence caused by toxic chemicals. Very good agreement was observed between the median effective concentration (EC50) values determined for organotin compounds by means of the two bioassays. Toxicity depended on both the number and kind of organic substituents bound to the tin atom. It followed the order triorganotins > diorganotins ≈ tetraorganotins > monoorganotins. Within each series, butyltin and phenyltin compounds exhibited the highest toxicity. Microtox and SMP EC50 values were successfully correlated with toxicity data for aquatic organisms, demonstrating the usefulness of these bioassays as prescreening or complementary tools for monitoring aquatic toxicity. Moreover, to investigate the suitability of the two assays in providing information on the mechanism of toxic action of organotins, EC50 values were correlated with various physicochemical and structural parameters of the tested compounds. The results obtained showed that these parameters are poor descriptors of organotin toxicity; in particular, the poor correlations found between EC50 values and log Kow could be ascribed to the fact that different modes of action govern the biological activity of mono-, di-, tri-, and tetraorganotin compounds, respectively.
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Submitochondrial Particle response to linear alkylbenzene sulfonates nonylphenol polyethoxylates and their biodegradation derivatives
Environmental Toxicology and Chemistry, 1994Co-Authors: Emanuele Argese, Cinzia Bettiol, Antonio Marcomini, Guido Perin, P MianaAbstract:The effects on mitochondrial respiratory parameters of linear alkylbenzene sulfonates (LAS), nonylphenol polyeth-oxylates (NPEO), and some of their biotransformation products, namely sulfophenyl carboxylates (SPCs), nonylphenol (NP), and nonylphenoxy acetic acid (NP1EC), were recorded by using the in vitro response of Submitochondrial Particles (SMP) from beef heart. The toxicity of these compounds was estimated by determining their effects on the energy-coupled reverse electron transfer (RET), which is induced by ATP and succinate at the first site level of the respiratory chain and reduces exogenous NAD+ to NADH. The toxicity of the substances, expressed as the toxicant concentration decreasing the reduction rate of NAD+ to an extent of 50% (EC50), ranged from 0.61 mg/L for a commercial LAS mixture to 18,000 mg/L for individual SPCs; from 1.3 mg/L for NPEO, with an average of 10 ethoxy units, to 8.2 and 1.8 mg/L for NP1EC and NP, respectively. These results were related to the molecular structure of each compound class and compared with the toxicity values obtained by a variety of biological systems currently used for toxicity testing. The acute toxicity data have demonstrated that (a) the SMP bioassay is suitable for reproducing the toxicological response of whole organisms, such as fishes and invertebrates, to the tested chemicals; and (b) the hydrophobic moiety of these compounds plays a significant role in eliciting their toxic effects. From a toxicological standpoint, attention must be paid to the occurrence in natural waters of residual LAS, whereas in the case of NPEO both unaltered surfactant and all biotransformation products need to be identified and quantified.
