In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes?

Jacobs, Miriam N.

doi:10.14573/altex.2013.3.331

Cited by 41 publications

(36 citation statements)

References 101 publications

(100 reference statements)

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“…Incorporation of phase I and II enzymes into test cell lines through genetic engineering is also currently technically challenging due to decreased cell viability when too many P450s are expressed in the same cells (Coecke et al, 2006). In a follow-up paper, Jacobs et al (2013) described the general lack of progress in developing and standardizing methods to incorporate metabolic and toxicokinetic aspects into in vitro assays. The lack of metabolic competency in in vitro assays remains one of the most highly cited limitations in predictive toxicity methodology.…”

Section: Discussionmentioning

confidence: 99%

A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From anIn VitroEstrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to theIn VivoUterotrophic Assay Using Oral Exposure

et al. 2016

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In vitro estrogen receptor assays are valuable tools for identifying environmental samples and chemicals that display estrogenic activity. However, in vitro potency cannot necessarily be extrapolated to estimates of in vivo potency because in vitro assays are currently unable to fully account for absorption, distribution, metabolism, and excretion. To explore this issue, we calculated relative potency factors (RPF), using 17a-ethinyl estradiol (EE2) as the reference compound, for several chemicals and mixtures in the T47D-KBluc estrogen receptor transactivation assay. In vitro RPFs were used to predict rat oral uterotrophic assay responses for these chemicals and mixtures. EE2, 17b-estradiol (E2), benzyl-butyl phthalate (BBP), bisphenol-A (BPA), bisphenol-AF (BPAF), bisphenol-C (BPC), bisphenol-S (BPS), and methoxychlor (MET) were tested individually, while BPS þ MET, BPAF þ MET, and BPAF þ BPC þ BPS þ EE2 þ MET were tested as equipotent mixtures. In vivo ED 50 values for BPA, BPAF, and BPC were accurately predicted using in vitro data; however, E2 was less potent than predicted, BBP was a false positive, and BPS and MET were 76.6 and 368.3-fold more active in vivo than predicted from the in vitro potency, respectively. Further, mixture ED 50 values were more accurately predicted by the dose addition model using individual chemical in vivo uterotrophic data (0.7-1.5-fold difference from observed) than in vitro data (1.4-86.8-fold). Overall, these data illustrate the potential for both underestimating and overestimating in vivo potency from predictions made with in vitro data for compounds that undergo substantial disposition following oral administration. Accounting for aspects of toxicokinetics, notably metabolism, in in vitro models will be necessary for accurate in vitro-to-in vivo extrapolations.

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Section: Discussionmentioning

confidence: 99%

A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From anIn VitroEstrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to theIn VivoUterotrophic Assay Using Oral Exposure

et al. 2016

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“…It is necessary to consider the absorption, distribution and the metabolism of the substance in the human organism, the metabolism and interaction among organs (Yoon et al, 2012;Jacobs et al, 2013). This fundamental aspect is often underestimated.…”

Section: Comparison Of the European And American Approachesmentioning

confidence: 99%

Integrated testing strategies (ITS) for safety assessment

Rovida

2015

ALTEX

147

128

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SummaryIntegrated testing strategies (ITS), as opposed to a single definitive test or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and "Good ITS Practices".Keywords: in vitro methods, testing strategy, Tox21c, skin sensitization, computational toxicology this is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited. *A report of t 4 -the transatlantic think tank for toxicology, a collaboration of the toxicologically oriented chairs in Baltimore, Konstanz and Utrecht sponsored by the Doerenkamp-Zbinden Foundation; participants do not represent their institutions and do not necessarily endorse all recommendations made.

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“…Several EDCs are known to undergo fast metabolic transformation and some pathways are induced by metabolites rather than by the parent compounds. However, in vitro assays that incorporate metabolizing systems still need to be validated (Jacobs et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The accuracy of metabolite simulators differs depending on the software and target chemical but can range from 50% to even 93% (Shin et al, 2011;T'Jollyn et al, 2011). Jacobs et al (2013) suggested that in silico systems that predict metabolites can provide input for quantitative structure-activity relationship (QSAR) models to assess the effects of untested metabolites.…”

Section: Introductionmentioning

confidence: 99%

Identifying potential endocrine disruptors among industrial chemicals and their metabolites – development and evaluation of in silico tools

et al. 2015

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The aim of this study was to improve the identification of endocrine disrupting chemicals (EDCs) by developing and evaluating in silico tools that predict interactions at the estrogen (E) and androgen (A) receptors, and binding to transthyretin (T). In particular, the study focuses on evaluating the use of the EAT models in combination with a metabolism simulator to study the significance of bioactivation for endocrine disruption. Balanced accuracies of the EAT models ranged from 77-87%, 62-77%, and 65-89% for E-, A-, and T-binding respectively. The developed models were applied on a set of more than 6000 commonly used industrial chemicals of which 9% were predicted E- and/or A-binders and 1% were predicted T-binders. The numbers of E- and T-binders increased 2- and 3-fold, respectively, after metabolic transformation, while the number of A-binders marginally changed. In-depth validation confirmed that several of the predicted bioactivated E- or T-binders demonstrated in vivo estrogenic activity or influenced blood levels of thyroxine in vivo. The metabolite simulator was evaluated using in vivo data from the literature which showed a 50% accuracy for studied chemicals. The study stresses, in summary, the importance of including metabolic activation in prioritization activities of potentially emerging contaminants.

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In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes?

Abstract: SummaryLegislation and prospective legislative proposals internationally (may)

Cited by 41 publications

References 101 publications

A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From anIn VitroEstrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to theIn VivoUterotrophic Assay Using Oral Exposure

A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From anIn VitroEstrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to theIn VivoUterotrophic Assay Using Oral Exposure

Integrated testing strategies (ITS) for safety assessment

Identifying potential endocrine disruptors among industrial chemicals and their metabolites – development and evaluation of in silico tools

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