Chemical in vitro bioactivity profiles are not informative about the long-term in vivo endocrine mediated toxicity

Abstract

Endocrine disrupting chemicals raise a lot of interest and concern regarding their risk for human health and the environment. They represent a broad variety of natural and synthetic chemicals with different levels of endocrine activity evaluation. In particular, for high production volume chemicals, new methods are required to enable the evaluation of the vast number of chemicals for their potential to alter the endocrine system and prioritize them for deeper characterization. The ToxCast program from the US EPA provides data from high throughput screening assays to develop computational tools aimed at rapid in vitro bioactivity screening and prioritization.Using publicly available data (ToxCast and ToxRef databases), we evaluate whether in vitro assay evaluations could predict in vivo outcomes observed in rat long-term studies for more than 400 chemicals. We focus on effects observed in three endocrine and two sex accessory organs and 42 in vitro assays related to pathways associated with endocrine related toxicity.First, using simple statistical correlation we demonstrate that there is no mutual linear correlation between the selected in vitro assays and any in vivo outcome, with balanced accuracies around 50% for each assay-outcome pair. Then, by applying machine learning to investigate potential non-linear correlations, we show that the combination of different in vitro assays is not correlated with the long-term in vivo effects and cannot help to predict them since balanced accuracies are also around 50%. Moreover, the prediction based on in vitro assays is not better than the one based on classical QSAR methods. This study highlights that the selected in vitro assays do not provide information about in vivo outcomes observed in endocrine and associated organs in long-term rat in vivo studies and stresses the need for the development of in vitro assays that reflect the compounds’ pharmacokinetic properties.