iNVERTOX: Rapid intelligent in silico prediction of sub-lethal ecotoxicological effects in invertebrates following pharmaceutical exposure

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The iNVERTOX project will be the first of its kind to discover and predict both phenotypic and molecular level effects of trace pharmaceutical residues on small, but ecologically critical invertebrate organisms living in UK and international freshwaters which are now impacted by human activity. Pharmaceuticals are widely recognised as bioactive contaminants in our environment having been measured globally at very low concentrations. They enter the environment predominantly following excretion of consumed human and animal medicines and have been shown to be resistant to wastewater treatment. This leads to their consistent and prolonged infusion into receiving water catchments. Recently, three pharmaceuticals were placed on a "watch-list" of emerging priority pollutants following extensive studies of their toxicity to biota. However, the occurrence and diversity of pharmaceuticals contamination in the environment extends much further, with significantly more compounds detected in river water, sediments, soils and recently even in environmental species at any one time. Therefore given the scale of this problem, measurement of their effects on our environment is far too slow and laborious. More innovative and rapid approaches are required to understand and mitigate any effects these may have on our environment. Realistically, this must now involve some form of advanced computational modelling to use the limited information we have to predict the effects of additional pharmaceuticals. Moreover, traditional ecotoxicity testing for micro-pollutants use lethal doses and in the case of pharmaceuticals, these are often much higher than measured environmental concentrations. This suggests that more subtle effects need to be researched instead as a more accurate assessment of risk. In some cases, such small changes have resulted in a significant ecosystem imbalance which has indirect effects on wildlife, our environment and potentially also on human health. These so called, "sub-lethal phenotypic effects" are often more difficult to determine and establishing defined links to a pharmaceutical exposure is extremely challenging. The aim of this project is to study and model four sub-lethal phenotypic effects on a model freshwater benthic invertebrate species (Gammarus pulex) including growth rate, feeding rate, ventilation and locomotion following controlled exposure to low doses of over 60 pharmaceuticals typically found in the aquatic environment. In addition to this, changes in the organism at a molecular level will form a novel, central focus and enable knowledge discovery of how biota respond to such exposures at a fundamental level. This will be achieved via metabolomics, which is the measurement of thousands of small molecules present in a biological system following exposure to environmental contaminants. Lastly, and most importantly, this information will be used to build an set of advanced computational models using new machine learning tools to rapidly allow a user to screen potential phenotypic and molecular level effects of a pharmaceutical on biota in silico and minimise or remove the need for extended use of animals in ecotoxicity testing for this purpose. This project will therefore be pioneering in its approach and draw together the best academic and industry expertise from King's College London, The Francis Crick Institute, London and a global leader in pharmaceuticals, AstraZeneca, to rapidly and responsibly understand the effects of pharmaceuticals on environmental organisms.