The Human In Vitro Developmental Toxicity Assay, devTOX quickPredict, Accurately Predicts the Developmental Toxicity Potential of Agrochemical Research Molecules
Author Block: K. Wolton, S. Hari Lal, Y. Adeleye, and R. A. Currie. Syngenta, Reading, United Kingdom.
The devTOX quickPredict platform developed by Stemina Biomarker Discovery is a human pluripotent stem cell-based assay that predicts the potential of a molecule to result in developmental toxicity based on metabolic perturbations following chemical exposure. Using eight concentration responses per compound, Syngenta have profiled over fifty research molecules through the assay to determine the perturbation in the ratio of ornithine to cystine in the stem cell media and derive points of departure (POD) for developmental toxicity prediction. The predictions were tested for a subset of 31 molecules using data from preliminary developmental toxicity studies, traditionally used to inform on developmental toxicity risk in research projects. Assay performance reached 63% accuracy with low specificity (>35%) but high sensitivity (<90%) when compared to the in vivo data. However, by comparing the in vitro POD with the achieved in vivo steady state systemic blood concentrations or Cmax from repeat dose toxicology studies, the overall accuracy of the assay was drastically improved. Assay performance increased to 87% with high specificity (>81%) and high sensitivity (>92%). As a result of this analysis Syngenta Product Safety have been employing the devTOX qP assay on research projects to directly enable decision making at much earlier stages in new active ingredient development. Future work will address whether exposure corrections using single dose kinetic data, or even modelled exposure data, is adequate for acceptable levels of predictivity.