Validating CombiDART in the agrochemical sector

Regulations require that compounds released into the environment must first be tested for developmental and reproductive toxicity (DART) using OECD414 and 416 tests (assessing prenatal development toxicity and two generation reproductive toxicity respectively). Establishing the DART effects of new compounds in mammals is currently achieved by one or two generational tests in rats and/or rabbits and these tests use many thousands of animals per year. Use of single model organisms for identifying abnormalities caused by compounds is well established, however, these models can lead to false negative/ positive results or organism-specific effects.

CombiDART is a low-cost combinatorial approach that uses two non-vertebrate model systems (the nematode C. elegans and the social amoeba Dictyostelium discoideum) to rapidly assess compounds for DART. A library of fluorescent biomarkers has been developed in both organisms to facilitate phenotypic characterisation and molecular analysis of DART effects, thus pinpointing adverse outcome pathways (AOPs) and molecular initiating events (MIEs). Results are evaluated from the two organisms, so pathways absent in one organism can often be detected in the other. Thus, the combinatorial approach will reduce false negative results as well as identify organism-specific effects, reducing the risk of false positives.

Through CRACK IT Solutions, industrial partners were sought to further validate CombiDART. The researchers at the University of Oxford partnered with Syngenta, and with support of funding from the scheme, aim to demonstrate that the CombiDART model can provide DART alerts for new compounds early in the product development pipeline. Syngenta will provide compounds with known teratogenic potential in rats, rabbits and zebrafish to run in the CombiDART assay; evaluating the efficacy of the CombiDART model in an industrial setting.

If successful, CombiDART will provide a primary screen to identify chemicals with high potential for mammalian DART, facilitating compound removal before vertebrate testing. Each compound removed before OECD tests will reduce the number of animals used in DART assessments by approximately 4500. The percentage of compounds that will show DART in the CombiDART screen cannot currently be predicted but there is potential to reduce the number of animals by many thousands.

Full details about this CRACK IT Solution can be found on the CRACK IT website.