March 16, 2017 by Owen Green & Louise Youngs
Supporting wca’s extensive expertise in endocrine disruption, Dr Louise Youngs attended the Platform Presentations on ‘Endocrine Toxicology’, which primarily focused on in vitro models to assess endocrine relevant mechanism of action. Obesity is a risk factor for diabetes, ischemic heart disease and cancer. Manushree Bharadwaj (NIEHS, US) outlined the use of 3T3-L1 preadipocyte cells to evaluate obesogenic potential. Whilst the assay showed potential to detect positive and negative regulators of adipogenesis and lipogenesis in vitro, the relevance of findings to the in vivo scenario were not considered. In another mechanistic study, Elyse Caron-Beudoin (INRS, Canada) detailed the use of H295R and Hs578t cells to elucidate VEGF-signalling pathways in breast carcinogenesis. The potential clinical relevance of α-palindromic binding protein (NRF1) community genes in breast neoplasms were discussed by Jaio Ramos (Florida University, US), whom reported on the METABRIC and TCGA cohorts.
Due to differences in the endometrium, standard animal models are not considered to be physiologically relevant models of endometriosis, which has only been assessed in non-human primates and chimeric rodents. Majorie van Duursen (Utrecht University, Netherlands) detailed an in vitro model of human endometrial tissue from premenopausal women. The 3D co-culture was stimulated by IL8, which induced cell proliferation, attachment and neutrophil chemotaxis. Whilst the assay is still in development, the model may enable toxicological assessment of local effects on the endometrium and implantation. Providing insight into the future of high-throughput screening, Audrey Bone (US EPA, US) detailed the identification of androgen receptor antagonists using Tox21 qHTS data and cell-free microarrays for real-time evaluation of coregulators (MARCoNI, Pamgene). The MARCoNI assay identified patterns of coregulator recruitment, providing further insight on the potential adverse outcome pathway. To close the session, Vickie Wilson (US EPA, US) discussed the use of in vitro estrogen, androgen, and glucocorticoid bioactivity to screen stream waters in the US.
Dr Owen Green attended the information session on ‘Thresholds of Toxicological Concern’ which incorporated presentations on the concept and how it is used together with associated tools such as Physiologically Based Pharmacokinetic (PBPK) modelling to support the derivation of TTCs and also the application of the Cramer Decision Tree to categorise substances currently into one of three structural classes. Limitations of the process were exposed in the absence of metabolic data and by using structural endpoints without considering activity of the substance. Szabina Stice (US FDA, USA) gave a presentation on her work to update the Cramer Decision Tree approach to an Extended Decision Tree which incorporates more questions and more categories but is still based exclusively on structural characteristics.
In the afternoon sessions, the team attended a workshop on ‘Low-dose non-monotonic responses’ chaired by Suzanne Fitzpatrick (US FDA, US), which aimed to question whether current risk assessment methods are adequate to assess low-dose non-monotonic dose-response relationships. In a presentation prepared by Edward Calabrese (University of Massachusetts, US), the potential benefits and risks to different organs were discussed, and Alan Boobis (Imperial College London, UK) further developed these concepts, suggesting that methods need to be fit-for-purpose and consider the adequacy of biology.