Partial Least Squares Modelling of the Acute Toxicity of Aliphatic Compounds to Tetrahymena pyriformis

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.

[1]  M. Cronin,et al.  Pitfalls in QSAR , 2003 .

[2]  Mark T D Cronin,et al.  Structure-toxicity relationships for aliphatic chemicals evaluated with Tetrahymena pyriformis. , 2002, Chemical research in toxicology.

[3]  T W Schultz,et al.  Reproducibility of toxicity across mode of toxic action in the Tetrahymena population growth impairment assay. , 2001, Aquatic toxicology.

[4]  Ovanes Mekenyan,et al.  Quantum‐chemical Descriptors for Estimating the Acute Toxicity of Electrophiles to the Fathed minnow (Pimephales promelas): An Analysis Based on Molecular Mechanisms , 1996 .

[5]  M T D Cronin,et al.  The importance of hydrophobicity and electrophilicity descriptors in mechanistically-based QSARs for toxicological endpoints , 2002, SAR and QSAR in environmental research.

[6]  T.W. Schultz,et al.  Selection of data sets for qsars: Analyses of tetrahymena toxicity from aromatic compounds , 2003, SAR and QSAR in environmental research.

[7]  T. W. Schultz,et al.  Structure-Toxicity Relationships for Aliphatic Compounds Encompassing a Variety of Mechanisms of Toxic Action to Vibrio fischeri , 2000, SAR and QSAR in environmental research.

[8]  J Devillers,et al.  Structure-toxicity modeling of pesticides to honey bees , 2002, SAR and QSAR in environmental research.

[9]  R. Lipnick,et al.  Structural properties for determining mechanisms of toxic action , 1989 .

[10]  T. W. Schultz,et al.  TETRATOX: TETRAHYMENA PYRIFORMIS POPULATION GROWTH IMPAIRMENT ENDPOINTA SURROGATE FOR FISH LETHALITY , 1997 .

[11]  T W Schultz,et al.  Comparison of Tetrahymena and Pimephales toxicity based on mechanism of action. , 1998, SAR and QSAR in environmental research.

[12]  R. García-Domenech,et al.  General topological patterns of known drugs. , 2001, Journal of molecular graphics & modelling.

[13]  Jure Zupan,et al.  Optimisation of structure representation for QSAR studies , 1999 .

[14]  G. Veith,et al.  Relationships between descriptors for hydrophobicity and soft electrophilicity in predicting toxicity. , 1993, SAR and QSAR in environmental research.

[15]  Mark T D Cronin,et al.  Essential and desirable characteristics of ecotoxicity quantitative structure–activity relationships , 2003, Environmental toxicology and chemistry.

[16]  Alexander Golbraikh,et al.  Quantitative Structure−Activity Relationship Analysis of Functionalized Amino Acid Anticonvulsant Agents Using k Nearest Neighbor and Simulated Annealing PLS Methods , 2002 .

[17]  Joop L. M. Hermens,et al.  The acute toxicity of aldehydes to the guppy , 1988 .

[18]  A. Tropsha,et al.  Beware of q2! , 2002, Journal of molecular graphics & modelling.

[19]  John D. Walker,et al.  Quantitative structure–activity relationships (QSARs) in toxicology: a historical perspective , 2003 .

[20]  R L Lipnick,et al.  A QSAR study of the toxicity of amines to the fathead minnow. , 1991, The Science of the total environment.

[21]  John D. Walker,et al.  Global Government applications of analogues, SAR s and QSAR s to predict aquatic toxicity, chemical or physical properties, environmental fate parameters and health effects of organic chemicals , 2002, SAR and QSAR in environmental research.

[22]  Ernesto Estrada,et al.  Physicochemical Interpretation of Molecular Connectivity Indices , 2002 .

[23]  Monika Nendza,et al.  Discriminating Toxicant Classes by Mode of Action: 2. Physico‐Chemical Descriptors , 2000 .

[24]  S. Bradbury,et al.  Predicting modes of toxic action from chemical structure: an overview. , 1994, SAR and QSAR in environmental research.

[25]  Jure Zupan,et al.  Study of structure–toxicity relationship by a counterpropagation neural network , 1999 .

[26]  T W Schultz,et al.  Structure-toxicity relationships for selected halogenated aliphatic chemicals. , 1999, Environmental toxicology and pharmacology.

[27]  T W Schultz,et al.  Quantitative structure-activity analyses of nitrobenzene toxicity to Tetrahymena pyriformis. , 1998, Chemical research in toxicology.

[28]  R. Lipnick.  Outliers: their origin and use in the classification of molecular mechanisms of toxicity. , 1991, The Science of the total environment.

[29]  Mark T D Cronin,et al.  Quantitative structure-activity relationships (QSARs) for the prediction of skin permeation of exogenous chemicals. , 2002, Chemosphere.

[30]  T Wayne Schultz,et al.  Regression comparisons of Tetrahymena pyriformis and Poecilia reticulata toxicity. , 2002, Chemosphere.

[31]  Mark T. D. Cronin,et al.  Multivariate Discrimination between Modes of Toxic Action of Phenols , 2002 .

[32]  Paola Gramatica,et al.  The Importance of Being Earnest: Validation is the Absolute Essential for Successful Application and Interpretation of QSPR Models , 2003 .