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T W Schultz - One of the best experts on this subject based on the ideXlab platform.

  • validation of a fragment based profiler for thiol reactivity for the prediction of toxicity skin sensitization and Tetrahymena pyriformis
    Chemical Research in Toxicology, 2017
    Co-Authors: D J Ebbrell, Mark T D Cronin, Judith C Madden, T W Schultz, Steven J Enoch
    Abstract:

    This study outlines the use of a recently developed fragment-based thiol reactivity profiler for Michael acceptors to predict toxicity toward Tetrahymena pyriformis and skin sensitization potency as determined in the Local Lymph Node Assay (LLNA). The results showed that the calculated reactivity parameter from the profiler, −log RC50(calc), was capable of predicting toxicity for both end points with excellent statistics. However, the study highlighted the importance of a well-defined applicability domain for each end point. In terms of Tetrahymena pyriformis, this domain was defined in terms of how fast or slowly a given Michael acceptor reacts with thiol leading to two separate quantitative structure–activity models. The first, for fast reacting chemicals required only −log RC50(calc) as a descriptor, while the second required the addition of a descriptor for hydrophobicity. Modeling of the LLNA required only a single descriptor, −log RC50(calc), enabling potency to be predicted. The applicability domai...

  • building up a qsar model for toxicity toward Tetrahymena pyriformis by the monte carlo method a case of benzene derivatives
    Environmental Toxicology and Pharmacology, 2016
    Co-Authors: Alla P. Toropova, T W Schultz, Andrey A. Toropov
    Abstract:

    Data on toxicity toward Tetrahymena pyriformis is indicator of applicability of a substance in ecologic and pharmaceutical aspects. Quantitative structure-activity relationships (QSARs) between the molecular structure of benzene derivatives and toxicity toward T. pyriformis (expressed as the negative logarithms of the population growth inhibition dose, mmol/L) are established. The available data were randomly distributed three times into the visible training and calibration sets, and invisible validation sets. The statistical characteristics for the validation set are the following: r(2)=0.8179 and s=0.338 (first distribution); r(2)=0.8682 and s=0.341 (second distribution); r(2)=0.8435 and s=0.323 (third distribution). These models are built up using only information on the molecular structure: no data on physicochemical parameters, 3D features of the molecular structure and quantum mechanics descriptors are involved in the modeling process.

  • reactivity based toxicity modelling of five membered heterocyclic compounds application to Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2010
    Co-Authors: T W Schultz, C L Sparfkin, Aynur O Aptula
    Abstract:

    A diverse set of 57 heterocyclic organic chemicals, consisting of a five-membered unsaturated ring of four carbon atoms and one oxygen (furans), or sulfur (thiophenes), or nitrogen (pyrroles) were evaluated for reactivity with thiol and acute aquatic toxicity assays using glutathione (GSH) as a model nucleophile and the ciliate Tetrahymena pyriformis, respectively. Reactivity was quantified by the RC50 value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 2 hours. Under standard conditions, RC50 values are mathematically proportional to reciprocal rate constants. Toxicity was quantified by the IGC50, the concentration of the test compound that produces 50% inhibition of population growth in 40 hours. Pyrroles with polarized α,β-unsaturated substructures were found to be non-reactive with GSH and did not exhibit excess toxicity in the Tetrahymena assay. In contrast, those furans and thiophenes with polarized α,β-unsaturated substructures were reactive with GSH via ...

  • definition of the structural domain of the baseline non polar narcosis model for Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2008
    Co-Authors: Claire M Ellison, Mark T D Cronin, Judith C Madden, T W Schultz
    Abstract:

    The aim of this work was to develop a high-quality 1-octanol/water partition coefficient-dependent (log P) baseline quantitative structure-activity relationship (QSAR) for the toxicity (log ) of classic non-polar narcotics to Tetrahymena pyriformis, and subsequently use this model to define the domain of applicability for baseline narcosis. The toxicities to T. pyriformis of 514 possible non-polar narcotics were assessed. A QSAR to predict toxicity was created from a training set of 87 classic non-polar narcotics (the saturated alcohols and ketones): log = 0.78 log P–2.01 (n = 87, r 2 = 0.96). This model was then used to predict the toxicity of the remaining chemicals. The chemicals from the large dataset which were poorly predicted by the model (i.e. the prediction was > ±0.5 log units from the experimental value) were used to aid the definition of structural categories of chemicals which are not non-polar narcotics. Doing so has enabled the domain for non-polar narcosis to be defined in terms of structu...

  • definition of the structural domain of the baseline non polar narcosis model for Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2008
    Co-Authors: Claire M Ellison, Mark T D Cronin, Judith C Madden, T W Schultz
    Abstract:

    The aim of this work was to develop a high-quality 1-octanol/water partition coefficient-dependent (log P) baseline quantitative structure-activity relationship (QSAR) for the toxicity (log IGC(50)(-1)) of classic non-polar narcotics to Tetrahymena pyriformis, and subsequently use this model to define the domain of applicability for baseline narcosis. The toxicities to T. pyriformis of 514 possible non-polar narcotics were assessed. A QSAR to predict toxicity was created from a training set of 87 classic non-polar narcotics (the saturated alcohols and ketones): log IGC(50)(-1) = 0.78 log P-2.01 (n = 87, r(2) = 0.96). This model was then used to predict the toxicity of the remaining chemicals. The chemicals from the large dataset which were poorly predicted by the model (i.e. the prediction was > +/-0.5 log units from the experimental value) were used to aid the definition of structural categories of chemicals which are not non-polar narcotics. Doing so has enabled the domain for non-polar narcosis to be defined in terms of structural categories. Defining domains of applicability for QSAR models is important if they are to be considered for making predictions of toxicity for regulatory purposes.

Mark T D Cronin - One of the best experts on this subject based on the ideXlab platform.

  • validation of a fragment based profiler for thiol reactivity for the prediction of toxicity skin sensitization and Tetrahymena pyriformis
    Chemical Research in Toxicology, 2017
    Co-Authors: D J Ebbrell, Mark T D Cronin, Judith C Madden, T W Schultz, Steven J Enoch
    Abstract:

    This study outlines the use of a recently developed fragment-based thiol reactivity profiler for Michael acceptors to predict toxicity toward Tetrahymena pyriformis and skin sensitization potency as determined in the Local Lymph Node Assay (LLNA). The results showed that the calculated reactivity parameter from the profiler, −log RC50(calc), was capable of predicting toxicity for both end points with excellent statistics. However, the study highlighted the importance of a well-defined applicability domain for each end point. In terms of Tetrahymena pyriformis, this domain was defined in terms of how fast or slowly a given Michael acceptor reacts with thiol leading to two separate quantitative structure–activity models. The first, for fast reacting chemicals required only −log RC50(calc) as a descriptor, while the second required the addition of a descriptor for hydrophobicity. Modeling of the LLNA required only a single descriptor, −log RC50(calc), enabling potency to be predicted. The applicability domai...

  • definition of the structural domain of the baseline non polar narcosis model for Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2008
    Co-Authors: Claire M Ellison, Mark T D Cronin, Judith C Madden, T W Schultz
    Abstract:

    The aim of this work was to develop a high-quality 1-octanol/water partition coefficient-dependent (log P) baseline quantitative structure-activity relationship (QSAR) for the toxicity (log ) of classic non-polar narcotics to Tetrahymena pyriformis, and subsequently use this model to define the domain of applicability for baseline narcosis. The toxicities to T. pyriformis of 514 possible non-polar narcotics were assessed. A QSAR to predict toxicity was created from a training set of 87 classic non-polar narcotics (the saturated alcohols and ketones): log = 0.78 log P–2.01 (n = 87, r 2 = 0.96). This model was then used to predict the toxicity of the remaining chemicals. The chemicals from the large dataset which were poorly predicted by the model (i.e. the prediction was > ±0.5 log units from the experimental value) were used to aid the definition of structural categories of chemicals which are not non-polar narcotics. Doing so has enabled the domain for non-polar narcosis to be defined in terms of structu...

  • definition of the structural domain of the baseline non polar narcosis model for Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2008
    Co-Authors: Claire M Ellison, Mark T D Cronin, Judith C Madden, T W Schultz
    Abstract:

    The aim of this work was to develop a high-quality 1-octanol/water partition coefficient-dependent (log P) baseline quantitative structure-activity relationship (QSAR) for the toxicity (log IGC(50)(-1)) of classic non-polar narcotics to Tetrahymena pyriformis, and subsequently use this model to define the domain of applicability for baseline narcosis. The toxicities to T. pyriformis of 514 possible non-polar narcotics were assessed. A QSAR to predict toxicity was created from a training set of 87 classic non-polar narcotics (the saturated alcohols and ketones): log IGC(50)(-1) = 0.78 log P-2.01 (n = 87, r(2) = 0.96). This model was then used to predict the toxicity of the remaining chemicals. The chemicals from the large dataset which were poorly predicted by the model (i.e. the prediction was > +/-0.5 log units from the experimental value) were used to aid the definition of structural categories of chemicals which are not non-polar narcotics. Doing so has enabled the domain for non-polar narcosis to be defined in terms of structural categories. Defining domains of applicability for QSAR models is important if they are to be considered for making predictions of toxicity for regulatory purposes.

  • comparative quantitative structure activity activity relationships for toxicity to Tetrahymena pyriformis and pimephales promelas
    Atla-alternatives To Laboratory Animals, 2007
    Co-Authors: Iiris Kahn, Emilio Benfenati, Wayne T Schultz, Tatiana I Netzeva, Uko Maran, Mark T D Cronin
    Abstract:

    An approach for predicting acute aquatic toxicity, in the form of a quantitative structure-activity-activity relationship (QSAAR), is described. This study assessed relative toxic effects to a fish, Pimephales promelas, and a ciliate, Tetrahymena pyriformis, and attempted to form relationships between them. A good agreement between toxic potencies (R 2 = 0.754) was found for a chemically diverse dataset of 364 compounds, when using toxicity to the ciliate as a surrogate to that for fish. This relationship was extended by adding three theoretical structural descriptors of the molecules. The inclusion of these descriptors improved the relationship further (R 2 = 0.824). The structural features that were found to improve the extrapolation between the toxicity to the two different species were related to the electron distribution of the carbon skeleton of the toxicant, its hydrogen-bonding ability, and its relative nitrogen content. Such a QSAAR approach provides a potential tool for predicting the toxicities of chemicals for environmental risk assessment and thus for reducing animal tests.

  • chemistry toxicity relationships for the effects of di and trihydroxybenzenes to Tetrahymena pyriformis
    Chemical Research in Toxicology, 2005
    Co-Authors: Aynur O Aptula, Mark T D Cronin, David W Roberts, T W Schultz
    Abstract:

    This paper presents a mechanistic analysis of aquatic toxicity data, quantified as pIGC50 assessed in the 40 h Tetrahymena pyriformis population growth impairment assay, for 40 polyhydroxybenzene derivatives. The toxicity trends of these phenolic compounds have been shown to be consistent with mechanistic organic chemistry principles. Thus, it is shown that the compounds can be grouped into two chemical mechanism of action domains, according to whether they can be oxidized to electrophilic quinones or quinone methides. Compounds in which the hydroxy groups are oriented meta, but not ortho or para, to one another cannot be oxidized to electrophilic quinones or quinone methides and act as polar narcotics. Their toxicities are found to be well-correlated with hydrophobicity (modeled by log D):  pIGC50 = 0.83 (±0.04) log D − 1.27 (±0.09):  n = 10, r2 (adj) = 0.981, q2 = 0.974, s = 0.15, and F = 460. Compounds with hydroxy groups oriented ortho or para to one another are more toxic than predicted by this equat...

Wayne T Schultz - One of the best experts on this subject based on the ideXlab platform.

  • experimental reactivity parameters for toxicity modeling application to the acute aquatic toxicity of sn2 electrophiles to Tetrahymena pyriformis
    Chemical Research in Toxicology, 2010
    Co-Authors: David W Roberts, Wayne T Schultz, Erika M Wolf, Aynur O Aptula
    Abstract:

    A diverse set of 60 haloaliphatic compounds were evaluated for reactivity with cysteine thiol groups in the previously described RC50 assay using glutathione (GSH) as a model nucleophile. Reactivity was quantified by the RC50 value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 120 min. Under standard conditions, RC50 values are mathematically proportional to reciprocal rate constants. Quantitative structure−activity relationship (QSAR) analysis correlating acute aquatic toxicity (IGC50) to Tetrahymena pyriformis with RC50 values was carried out. It was found that subdivision of the compounds into subdomains according to their reaction mechanism characteristics enabled toxicity−reactivity relationships to be identified. The largest subdomain consisting of 22 compounds in which a primary halogen is α to a carbonyl or other electronegative unsaturated group and which can be confidently assigned as SN2 electrophiles fits the equation pIGC50 (mM) = 0.94 (±0.07) pRC50...

  • comparative quantitative structure activity activity relationships for toxicity to Tetrahymena pyriformis and pimephales promelas
    Atla-alternatives To Laboratory Animals, 2007
    Co-Authors: Iiris Kahn, Emilio Benfenati, Wayne T Schultz, Tatiana I Netzeva, Uko Maran, Mark T D Cronin
    Abstract:

    An approach for predicting acute aquatic toxicity, in the form of a quantitative structure-activity-activity relationship (QSAAR), is described. This study assessed relative toxic effects to a fish, Pimephales promelas, and a ciliate, Tetrahymena pyriformis, and attempted to form relationships between them. A good agreement between toxic potencies (R 2 = 0.754) was found for a chemically diverse dataset of 364 compounds, when using toxicity to the ciliate as a surrogate to that for fish. This relationship was extended by adding three theoretical structural descriptors of the molecules. The inclusion of these descriptors improved the relationship further (R 2 = 0.824). The structural features that were found to improve the extrapolation between the toxicity to the two different species were related to the electron distribution of the carbon skeleton of the toxicant, its hydrogen-bonding ability, and its relative nitrogen content. Such a QSAAR approach provides a potential tool for predicting the toxicities of chemicals for environmental risk assessment and thus for reducing animal tests.

  • structure toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic carbonyl containing alpha beta unsaturated chemicals
    Chemical Research in Toxicology, 2005
    Co-Authors: Wayne T Schultz, Tatiana I Netzeva, David W Roberts, Mark T D Cronin
    Abstract:

    Toxicity data for 82 aliphatic chemicals with an α,β-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic pote...

  • structure toxicity relationships for aliphatic chemicals evaluated with Tetrahymena pyriformis
    Chemical Research in Toxicology, 2002
    Co-Authors: Wayne T Schultz, Mark T D Cronin, Tatiana I Netzeva, Aynur O Aptula
    Abstract:

    Quantitative structure−activity relationships were developed for the toxicity data of 500 aliphatic chemicals tested in the two-day Tetrahymena pyriformis population growth impairment assay. These ...

  • regression comparisons of Tetrahymena pyriformis and poecilia reticulata toxicity
    Chemosphere, 2002
    Co-Authors: J R Seward, Elizabeth L Hamblen, Wayne T Schultz
    Abstract:

    Abstract The toxicity data of chemicals common to both the Poecilia reticulata mortality assay and the Tetrahymena pyriformis growth impairment assay were evaluated. Two chemicals were not toxic at saturation in the T. pyriformis assay. In addition, due to abiotic transformation, a third chemical was removed from further consideration. Each chemical was a priori assigned a mode of toxic action: neutral non-covalent, polar non-covalent, or electrophilic covalent toxicity. To further investigate comparisons between endpoints, polar and electrophilic chemicals were separated into class-based groups. The polar non-covalent chemicals were separated into phenols and anilines, while the electrophilic chemicals were separated into those reacting via Schiff-base formation (i.e., aldehydes) and those reacting via bimolecular substitution to a nucleophile (i.e., selected nitroaromatics). A comparison of toxic potency as a collective set was statistically described by the relationship; log ( LC 50 −1 )=1.05log(( IGC 50 − 1))+0.56,n=124;r 2 =0.85;s=0.42; F =682; Pr > F =0.0001 . The relationship between endpoints was inversely proportional to reactivity associated with the mode of action. While the comparative toxicity for neutral narcotics exhibited an excellent fit ( r 2 =0.94), the fits for polar narcotics and electrophiles were poorer, r 2 =0.69 and 0.62, respectively. Investigations into class-based groupings indicated fit of toxic potency data for aldehydes ( r 2 =0.85) and phenols ( r 2 =0.81) were quite good. However, fits for anilines ( r 2 =0.43) and nitroaromatics ( r 2 =0.68) revealed that toxicity was not as well related between endpoints for these chemicals.

Min Jun Kim - One of the best experts on this subject based on the ideXlab platform.

  • galvanotactic behavior of Tetrahymena pyriformis under electric fields
    Journal of Micromechanics and Microengineering, 2013
    Co-Authors: Dal Hyung Kim, Paul Kim, Kyoungwoo Lee, Jinseok Kim, Min Jun Kim
    Abstract:

    Tetrahymena pyriformis, a eukaryotic ciliate, swims toward a cathode in straight or cross-shaped microchannels under an applied electric field, a behavioral response called cathodal galvanotaxis. In straight channel experiments, a one-dimensional electric field was applied, and the galvanotactic swimming behavior of Tetrahymena pyriformis was observed and described in detail while the polarity of this field is switched. In most individual cases, the cell would immediately switch its direction toward the cathode; however, exceptional cases have been observed where cells exhibit a turning delay or do not turn after a polarity switch. In cross-channel experiments, feedback control using vision-based tracking was used to steer a cell in the microchannel intersection using a two-dimensional electric field generated by four electrodes placed at four ends of the cross channel. The motivation for this work is to study the swimming behavior of Tetrahymena pyriformis as a microrobot under the control of electric fields.

  • feedback control of many magnetized Tetrahymena pyriformis cells by exploiting phase inhomogeneity
    Intelligent Robots and Systems, 2013
    Co-Authors: Aaron T Becker, Paul Kim, Min Jun Kim, Agung A Julius
    Abstract:

    Biological robots can be produced in large numbers, but are often controlled by uniform inputs. This makes position control of multiple robots inherently challenging. This paper uses magnetically-steered ciliate eukaryon {Tetrahymena pyriformis) as a case study. These cells swim at a constant speed, and can be turned by changing the orientation of an external magnetic field. We show that it is possible to steer multiple T. pyriformis to independent goals if their turning - modeled as a first-order system - has unique time constants. We provide system identification tools to parameterize multiple cells in parallel. We construct feedback control-Lyapunov methods that exploit differing phase-lags under a rotating magnetic field to steer multiple cells to independent target positions. We prove that these techniques scale to any number of cells with unique first-order responses to the global magnetic field. We provide simulations steering hundreds of cells and validate our procedure in hardware experiments with multiple cells.

  • mixing enhancement by biologically inspired convection in a micro chamber using alternating current galvanotactic control of the Tetrahymena pyriformis
    Applied Physics Letters, 2013
    Co-Authors: Jihoon Kim, Doyoung Byun, Dal Hyung Kim, Yonghee Jang, Min Jun Kim
    Abstract:

    Recently, there has been increasing interest in the swimming behavior of microorganisms and biologically inspired micro-robots. In this study, we investigated biologically induced convection flow with living microorganism using galvanotaxis. We fabricated and evaluated our micro-mixer with motile cells. For the cell based active micro-mixers, two miscible fluids were used to measure the mixing index. Under alternating current (AC) electric fields with varying frequency, a group of motile Tetrahymena pyriformis cells generated reciprocal motion with circulating flows around their pathline, enhancing the mixing ratio.

  • motion control of magnetized Tetrahymena pyriformis cells by a magnetic field with model predictive control
    The International Journal of Robotics Research, 2013
    Co-Authors: Dal Hyung Kim, Paul Kim, Min Jun Kim, Agung A Julius
    Abstract:

    This paper presents the Model Predictive Control (MPC) of magnetized Tetrahymena pyriformis ( T. pyriformis) using a magnetic field. The magnetized T. pyriformis are generated by feeding spherical iron oxide particles into the cells. Using an external magnetic field, we change the movement direction of the cell, but the speed of the cell remains constant regardless of the strength of the external magnetic field. The contributions of this paper are threefold. First, the discrete-time plant model of the magnetized cell is generated using the least-squares method. Second, using the model of each cell, they are controlled to follow a reference track by an external magnetic field with MPC. Third, by using a predictor-like scheme to execute the plant input before the measurement of the cell position, we successfully solve the image-processing delay problem in the feedback system. In our results, we show three comparisons between different control schemes and an initial tracking to prove the effectiveness of the control approach.

  • motion control of Tetrahymena pyriformis cells with artificial magnetotaxis model predictive control mpc approach
    International Conference on Robotics and Automation, 2012
    Co-Authors: Dal Hyung Kim, Paul Kim, Min Jun Kim, Agung A Julius
    Abstract:

    The use of live microbial cells as microscale robots is an attractive premise, primarily because they are easy to produce and to fuel. In this paper, we study the motion control of magnetotactic Tetrahymena pyriformis cells. Magnetotactic T. pyriformis is produced by introducing artificial magnetic dipole into the cells. Subsequently, they can be steered by using an external magnetic field. We observe that the external magnetic field can only be used to affect the swimming direction of the cells, while the swimming velocity depends largely on the cells' own propulsion. Feedback information for control is obtained from a computer vision system that tracks the cell. The contribution of this paper is twofold. First, we construct a discrete-time model for the cell dynamics that is based on first principle. Subsequently, we identify the model parameters using the Least Squares approach. Second, we formulate a model predictive approach for feedback control of magnetotactic T. pyriformis. Both the model fitness and the performance of the feedback controller are verified using experimental data.

Aynur O Aptula - One of the best experts on this subject based on the ideXlab platform.

  • reactivity based toxicity modelling of five membered heterocyclic compounds application to Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2010
    Co-Authors: T W Schultz, C L Sparfkin, Aynur O Aptula
    Abstract:

    A diverse set of 57 heterocyclic organic chemicals, consisting of a five-membered unsaturated ring of four carbon atoms and one oxygen (furans), or sulfur (thiophenes), or nitrogen (pyrroles) were evaluated for reactivity with thiol and acute aquatic toxicity assays using glutathione (GSH) as a model nucleophile and the ciliate Tetrahymena pyriformis, respectively. Reactivity was quantified by the RC50 value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 2 hours. Under standard conditions, RC50 values are mathematically proportional to reciprocal rate constants. Toxicity was quantified by the IGC50, the concentration of the test compound that produces 50% inhibition of population growth in 40 hours. Pyrroles with polarized α,β-unsaturated substructures were found to be non-reactive with GSH and did not exhibit excess toxicity in the Tetrahymena assay. In contrast, those furans and thiophenes with polarized α,β-unsaturated substructures were reactive with GSH via ...

  • experimental reactivity parameters for toxicity modeling application to the acute aquatic toxicity of sn2 electrophiles to Tetrahymena pyriformis
    Chemical Research in Toxicology, 2010
    Co-Authors: David W Roberts, Wayne T Schultz, Erika M Wolf, Aynur O Aptula
    Abstract:

    A diverse set of 60 haloaliphatic compounds were evaluated for reactivity with cysteine thiol groups in the previously described RC50 assay using glutathione (GSH) as a model nucleophile. Reactivity was quantified by the RC50 value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 120 min. Under standard conditions, RC50 values are mathematically proportional to reciprocal rate constants. Quantitative structure−activity relationship (QSAR) analysis correlating acute aquatic toxicity (IGC50) to Tetrahymena pyriformis with RC50 values was carried out. It was found that subdivision of the compounds into subdomains according to their reaction mechanism characteristics enabled toxicity−reactivity relationships to be identified. The largest subdomain consisting of 22 compounds in which a primary halogen is α to a carbonyl or other electronegative unsaturated group and which can be confidently assigned as SN2 electrophiles fits the equation pIGC50 (mM) = 0.94 (±0.07) pRC50...

  • chemistry toxicity relationships for the effects of di and trihydroxybenzenes to Tetrahymena pyriformis
    Chemical Research in Toxicology, 2005
    Co-Authors: Aynur O Aptula, Mark T D Cronin, David W Roberts, T W Schultz
    Abstract:

    This paper presents a mechanistic analysis of aquatic toxicity data, quantified as pIGC50 assessed in the 40 h Tetrahymena pyriformis population growth impairment assay, for 40 polyhydroxybenzene derivatives. The toxicity trends of these phenolic compounds have been shown to be consistent with mechanistic organic chemistry principles. Thus, it is shown that the compounds can be grouped into two chemical mechanism of action domains, according to whether they can be oxidized to electrophilic quinones or quinone methides. Compounds in which the hydroxy groups are oriented meta, but not ortho or para, to one another cannot be oxidized to electrophilic quinones or quinone methides and act as polar narcotics. Their toxicities are found to be well-correlated with hydrophobicity (modeled by log D):  pIGC50 = 0.83 (±0.04) log D − 1.27 (±0.09):  n = 10, r2 (adj) = 0.981, q2 = 0.974, s = 0.15, and F = 460. Compounds with hydroxy groups oriented ortho or para to one another are more toxic than predicted by this equat...

  • partial least squares modelling of the acute toxicity of aliphatic compounds to Tetrahymena pyriformis
    Sar and Qsar in Environmental Research, 2003
    Co-Authors: Tatiana I Netzeva, Aynur O Aptula, T W Schultz, Mark T D Cronin
    Abstract:

    The aim of this study was to evaluate a multivariate statistical model, utilising Partial Least Squares (PLS) analysis, for the prediction of the acute toxicity of aliphatic chemicals to the ciliate Tetrahymena pyriformis. A model was developed that was capable of making a prediction regardless the mechanism of toxic action. The toxicity of 476 compounds, possessing different mechanisms of toxic action was considered. A set of 74 descriptors, including the octanol-water partition coefficient, molecular-orbital descriptors, geometrical, topological and connectivity indices, was generated. A three-component, eight-descriptor PLS model was developed. It was validated by a Y-permutation test and by simulation of external prediction for complementary subsets. A comparison with existing class or mechanism-based models, derived on the same data set, was made.

  • stepwise discrimination between four modes of toxic action of phenols in the Tetrahymena pyriformis assay
    Chemical Research in Toxicology, 2003
    Co-Authors: Gerrit Schuurmann, Aynur O Aptula, Ralph Kuhne, Ralfuwe Ebert
    Abstract:

    For a set of 220 phenols with literature data on their toxicity and associated mode of action (MOA) toward the ciliate Tetrahymena pyriformis, a stepwise classification scheme was developed that allows the identification of four MOAs from molecular hydrophobicity and AM1-based quantum chemical descriptors, employing linear discriminant analysis or binary logistic regression. Taking the AM1 lowest unoccupied molecular orbital energy as the only parameter, an initial separation of polar narcotics and proelectrophiles from oxidative uncouplers and soft electrophiles is correct to 97%, and for the subsequent discrimination between polar narcotics and proelectrophiles as well as between oxidative uncouplers and soft electrophiles, 99 and 98% correct classifications are achieved using three and two molecular descriptors, respectively. The results are discussed in terms of detailed contingency table statistics and with respect to relationships between molecular descriptors and mechanisms of toxicity. Statistical model evaluation includes simulated external validation employing complementary subset models.