Evaluation of pesticide toxicity : a hierarchical QSAR approach to model the acute aquatic toxicity and avian oral toxicity of pesticides
The thesis aimed to extract information relevant to the hazard and risk
assessment of pesticides. In particular, quantitative structure-activity
relationship (QSAR) approaches have been used to build up a mathematical
model able to predict the aquatic acute toxicity, Leso, and the avian oral toxicity,
LDso, for pesticides. Ecotoxicological values were collected from several
databases, and screened according to quality criteria.
A hierarchical QSAR approach was applied for the prediction of acute aquatic
toxicity. Chemical structures were encoded into molecular descriptors by an
automated, seamless procedure available within the OpenMolGRID system.
Different linear and non-linear regression techniques were used to obtain
reliable and thoroughly validated QSARs. The final model was developed by a
counter-propagation neural network coupled with genetic algorithms for variable
selection. The proposed QSAR is consistent with McFarland's principle for
biological activity and makes use of seven molecular descriptors. The model
was assessed thoroughly in test (R2 = 0.8) and validation sets (R2 = 0.72), the
y-scrambling test and a sensitivity/stability test.
The second endpoint considered in this thesis was avian oral toxicity. As
previously, the chemical description of chemicals was generated automatically
by the OpenMolGRID system. The best classification model was chosen on the
basis of the performances on a validation set of 19 data points, and was
obtained from a support vector machine using 94 data points and nine variables
selected by genetic algorithms (Error Ratetraining = 0.021, Error Ratevaiidalion =
0.158). The model allowed for a mechanistic estimation of the toxicological
action. In fact, several descriptors selected for the final classification model
encode for the interaction of the pesticides with other molecules. The presence
of hetero-atoms, e.g. sulphur atoms, is correlated with the toxicity, and the pool
of descriptor selected is generally dependent from the 3D conformation of the
structures. These suggest that, in the case of avian oral toxicity, pesticides
probably exert their toxic action through the interaction with some
macromolecule and/or protein of the biological system.