Modelling of human acute toxicity from physicochemical properties and non-vertebrate acute toxicity of the 38 organic chemicals of the MEIC priority list by PLS regression and neural network

Abstract

Linear and non-linear modelling of human acute toxicity (as human lethal concentrations; HLCs) of the 38 organic chemicals from the 50 priority compounds of the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme was investigated. The models obtained were derived either from a set of 23 physicochemical properties of the compounds or from their acute toxicities to five aquatic non-vertebrates together with the physicochemical properties. For the linear type, modelling was performed using a partial least square projection to latent structures (PLS) regression method; for the non-linear models, both PLS regression and neural network were utilized. A neural network using a combination of backpropagation and cascade-correlation algorithms was applied in this study. The results generally reveal a slightly better predictive performance of the models obtained from PLS regression than those obtained from neural networks. However, the model composed of physicochemical properties (PC-model) from the trained neural network using a back propagation algorithm with pruning technique proved superior to that trained with a combination of back propagation and cascade-correlation algorithms after leave-one-out cross-validation. The predictive power of the PC-models, whether linear or non-linear, was comparable with that of the corresponding models consisting of both structural descriptors and the ecotoxicological tests (ECOPC-models), except for the battery (ECOPC-model) from the neural network. The composition of the ‘best’ PLS and neural network models points to the importance of the combination of physicochemical properties reflecting lipophilicity, size, volume, intermolecular binding forces and electronic properties of the molecule. All the aquatic non-vertebrate tests are shown to be essential in explaining human acute toxicity. However, the degree of contribution differed, with the crustacean ( Artemia salina) and the bacterial (Microtox) bioassays being more important to the linear and non-linear PLS models, whereas the crustacean ( Artemia salina and Streptocephalus proboscideus) tests, and the rotifer ( Brachionus calyciflorus) assay were important to the neural network models. The organochlorine (lindane) and bipyridinium (paraquat) pesticides were common outliers in all the models. Moreover, the latter two compounds and the organophosphate (malathion) pesticide were also common outliers in all ECOPC-models. Other types of pesticides, however, fit the models. The predicted HLCs of a number of non-pesticides, including some chlorinated compounds, also deviated from the observed HLCs by more than one order of magnitude.