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Toxicity testing in the 21st Century: Extrapolation from in vitro to in vivo using xenoestrogens as a model
Citation:
Hannas, B., E. Gray, AND V. Wilson. Toxicity testing in the 21st Century: Extrapolation from in vitro to in vivo using xenoestrogens as a model. Presented at USEPA EDC Forum, RTP, NC, June 12, 2013.
Impact/Purpose:
This study highlights some of the major limitations/complexities inherent to extrapolating in vitro data to in vivo responses and therefore provides useful information for considering challenges to overcome in the ongoing development of Tox21 programs.
Description:
Slides associated with the following abstract: Numerous sources contribute to widespread contamination of drinking water sources with both natural and synthetic estrogens, which is a concern for potential ecological and human health effects. In vitro screening assays are valuable tools for identifying mechanisms of toxicity but in vitro results cannot be directly extrapolated to in vivo exposures since most in vitro assays do not account for metabolism, distribution and excretion or other systemic toxicities. In this study, we highlight some of the limitations associated with using in vitro estrogen transcriptional activation assays for predicting in vivo action of xenoestrogens. In particular, we compared the ability to predict the uterine growth response (uterotrophic assay, UA) to estrogens, administered to the rat orally either individually or as mixtures, using an in vitro estrogen transcriptional activation (TA) assay (T47D-kbluc cell line). We demonstrated that a binary mixture of bisphenol-AF (BPAF) + Methoxychlor in the UA conforms to dose additive (DA) estrogenicity, whereas the degree of estrogenicity of this mixture is underestimated by the TA assay. In contrast, the TA assay responded to a binary mixture of benzylbutyl phthalate (BBP) + BPAF in a DA manner, whereas, the UA displayed no estrogenic response to this mixture. These data illustrate the limitations associated with making in vivo predictions based on in vitro assay data for compounds that are metabolically inactivated in vivo in the liver, gut or other tissues or activated by the liver in vivo. This information is critical for valid interpretation of in vitro screening assay results.