Quantitative Structure-activity-activity and Quantitative Structure-activity Investigations of Human and Rodent Toxicity

Abstract

Acute toxicity in different biological systems, including humans and rodents in vivo, human and rodent cell lines in vitro, and bacterial strains, was investigated. The data were taken from the MEIC (Multicentre Evaluation of In Vitro Cytotoxicity) programme. Principal components analysis (PCA) and cluster analysis were used to investigate relationships between the different toxicity endpoints. They revealed that human peak blood/serum LC50 concentrations were most strongly related to human liver cell toxicity, while the in vivo oral human lethal doses were most closely related to the in vivo rodent LD50 values. Quantitative structure-activity-activity relationship (QSAAR) models were developed for the in vivo human and rodent toxicity including a combination of toxicity endpoint and structural descriptors as predictor variables. Quantitative structure-activity relationships (QSARs) were derived using structural descriptors accounting for molecular hydrophobicity, size and shape, and electronic properties. These models have the potential to provide useful insights in the development of non-animal (in vitro and in silico) methods for predicting human and mammalian toxicity.