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Considerations in Use of the EPA’s ToxCast Data for Environmental Toxicology (SETAC)
Citation:
Houck, K., S. Mosher, S. Frady, J. Liu, J. Phuong, D. Filer, R. Judson, M. Martin, J. Wambaugh, P. Kothiya, J. Franzosa, AND S. Padilla. Considerations in Use of the EPA’s ToxCast Data for Environmental Toxicology (SETAC). SETAC North America 35th Annual Meeting, Vancouver, BC, CANADA, November 09 - 13, 2014. https://doi.org/10.23645/epacomptox.5080033
Impact/Purpose:
Invited presentation SETAC North America 35th Annual Meeting - at the session - Cutting-edge strategies for utilizing molecular information as the basis for cross-species extrapolation
Description:
The US EPA has developed the ToxCast program to prioritize chemicals for selective toxicity testing. ToxCast relies on extensive bioactivity profiling using a panel of biochemical and cellular assays that measure chemicals effects on potential molecular initiating events and key signaling pathways. Using chemicals that have in vitro bioactivity profiles and known in vivo outcomes, models have been developed to predict in vivo adverse endpoints. These models are then applied to chemicals lacking in vivo testing to predict possible effects. To date over 2000 chemicals have been tested in over 600 assay component endpoints with models developed for a number of important health effects such as endocrine disruption, developmental toxicity, reproductive toxicity and cancer. The program has focused on human toxicity and 95% of the assays, biochemical and cellular, utilize cells and proteins of human origin. Using the ToxCast approach to support chemical prioritization for ecological health presents an opportunity to build upon the learnings from the program. Biochemical assays generally have only a single protein target; sequence similarity analyses can suggest the likelihood of chemicals affecting orthologous targets in other species. However, the actual potency comparisons are likely to be challenging since even small sequence differences could be important determinants of affinity. Cellular assays, in particular those involving complex pathways, will be difficult to analyze for all possible nodes of chemical interactions in the pathway across species. Still, the ToxCast data can differentiate chemicals into high and low bioactivity classes which may be used across species for chemical prioritization. We tested that hypothesis using the model organism Danio rerio and compared bioactivity from a zebrafish development assay with assays of human origin. Results show that while intrinsic bioactivity is important, prioritization rankings can vary greatly, at least partly due to differences in internal dose. Incorporation of more extensive bioactivity profiling of diverse ecological species may be required to broaden the ToxCast approach to better assess environmental health effects. (This abstract does not necessarily reflect EPA policy).
URLs/Downloads:
DOI: Considerations in Use of the EPA’s ToxCast Data for Environmental Toxicology (SETAC)