Lessons learned, challenges, and opportunities: The U.S. Endocrine Disruptor Screening Program

Juberg, Daland R.; Borghoff, Susan J.; Becker, Richard A.; Casey, Warren; Hartung, Thomas; Holsapple, Michael P.; Marty, M. Sue; Mihaich, Ellen; Kraak, Glen Van Der; Wade, Michael G.; Willett, Catherine; Andersen, Melvin E.; Borgert, Christopher J.; Coady, Katherine K.; Dourson, Michael; Fowle, John R.; Gray, L. Earl; Lamb, James C.; Ortego, Lisa S.; Schug, Thaddeus T.; Toóle, Colleen; Zorrilla, Leah M.; Kroner, Oliver; Patterson, Jacqueline; Rinckel, Lori A.; Jones, Brett R.

doi:10.14573/altex.1309171

Cited by 23 publications

(9 citation statements)

References 16 publications

(15 reference statements)

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“…Endocrine disruption was chosen as the pilot for the human toxome because of the urgency to complement current risk assessment approaches ( Juberg et al, 2014 ) and the fact that many endocrine system molecular pathways are known. This allows comparison of the PoT (deduced in an untargeted way) with established toxicity pathways.…”

Section: Endocrine Disruption As a Pilotmentioning

confidence: 99%

The Human Toxome Project

Bouhifd

Andersen

Baghdikian

et al. 2015

ALTEX

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SummaryThe Human Toxome Project, funded as an NIH Transformative Research grant 2011-2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectrometry-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies.

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Section: Endocrine Disruption As a Pilotmentioning

confidence: 99%

The Human Toxome Project

Bouhifd

Andersen

Baghdikian

et al. 2015

ALTEX

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“…A whole industry sector has needed revise its research and development strategy concerning new products and hazards (e.g., nanoparticles), and there is still an ongoing debate on whether sufficient alternative methods are already available for this 1 (Adler et al, 2011;BUAV, 2011;Hartung et al, 2011;Taylor et al, 2011). It is also not yet clear, how the politically motivated ban on using a certain technology (animal testing) is balanced by public investments into alternative technologies that are now urgently required; and v) ongoing discussions on the regulation of endocrine disruptors, such as the question whether risk assessment and its further legal/ regulatory use should continue to be based on the established scientific, and in particular toxicological, principles of a careful evaluation of exposure and hazard (Dietrich et al, 2013;Juberg et al, 2014) or rather on other types of concepts (a purported mode-of-action) not otherwise used in toxicology. Moreover, several large national changes have taken place, such as the adoption of animal rights into the constitution in Germany ( §20a of the German Grundgesetz (Constitution)) and the civil code in France (Neumann, 2015).…”

Section: Introductionmentioning

confidence: 99%

Animal use for science in Europe

Daneshian

Busquet

Hartung³

et al. 2015

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“…Several in-vitro assays have been proposed for inclusion in an ED screening and testing programme (Juberg et al, 2014) by the United States Environmental Protection Agency (USEPA). These assays serve as first-tier screens to identify the potential EDC activity and suggested MOA of man-made chemicals detected in the environment (Hecker et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The potential anti-androgenic effect of agricultural pesticides used in the Western Cape: In vitro investigation of mixture effects

Archer¹,

Wyk²

2015

WSA

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Although it is known that environmental chemicals can affect the oestrogenic system, far less attention has been paid to chemicals interacting with the androgen receptor (AR). Pesticides, particularly fungicides, have been shown to competitively bind or affect expression of the AR in an inhibiting manner. Few studies have addressed anti-androgenic effects of agrochemical use in South Africa. The aim of this study was to screen for the ability of commonly-used pesticides (mostly fungicides) in Western Cape agricultural areas to alter the binding of an androgen (DHT) to the human AR (hAR) using a recombinant yeast androgen screen (YAS), and also to test the additivity mixture interaction hypothesis when commonly-used pesticides with similar modes of action (MOAs) are exposed in mixture. Fungicides vinclozolin, folpet, procymidone, dimethomorph, fenarimol, mancozeb, and the insecticide chlorpyrifos, all independently antagonised the binding of the androgen dihydrotestosterone (DHT) to the AR in a dose-dependent manner. The fungicide mancozeb was found to be the most potent anti-androgen in the assay. Binary, equimolar mixtures of the pesticides also antagonised the binding of DHT to the AR, but at lower IC 50 concentration potencies relative to their individual counterparts. The mixtures of the majority of the selected pesticides did not conform to the expected additive mixture interaction. Only the mixture between dimethomorph and mancozeb showed an additive mixture response at IC 50 concentrations, and, therefore, revealed a more severe AR antagonistic effect compared to their individual counterparts. This study confirmed that pesticides regularly used in agriculture inhibit the binding of androgens to the AR, but when in mixture do not always conform to the predictive addition mixture response model. Also, high relative potencies of individual chemicals in the assay were suppressed when combined with less potent chemicals, showing that the potent chemicals may not be granted access to bind with the AR when exposed in mixture.

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Lessons learned, challenges, and opportunities: The U.S. Endocrine Disruptor Screening Program

Cited by 23 publications

References 16 publications

The Human Toxome Project

The Human Toxome Project

Animal use for science in Europe

The potential anti-androgenic effect of agricultural pesticides used in the Western Cape: In vitro investigation of mixture effects

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