There has been increasing interest in endocrine-disrupting chemicals (EDCs) among scientists and public authorities over the last 30 years, notably because of their wide use and the increasing evidence of detrimental effects on humans and the environment. However, test systems for the detection of potential EDCs as well as testing strategies still require optimization. Thus, the aim of the present project was the development of an integrated test protocol that merges the existing OECD test guidelines (TGs) 229 (fish short-term reproduction assay) and 234 (fish sexual development test) and implements thyroid-related endpoints for fish. The integrated fish endocrine disruptor test (iFEDT) represents a comprehensive approach for fish testing, which covers reproduction, early development, and sexual differentiation, and will thus allow the identification of multiple endocrine-disruptive effects in fish. Using zebrafish (Danio rerio) as a model organism, two exposure tests were performed with well-studied EDCs: 6-propyl-2-thiouracil (PTU), an inhibitor of thyroid hormone synthesis, and 17α-ethinylestradiol (EE2), an estrogen receptor agonist. In part A of this article, the effects of PTU and EE2 on established endpoints of the two existing TGs are reported, whereas part B focuses on the novel thyroid-related endpoints. Results of part A document that, as expected, both PTU and EE2 had strong effects on various endocrine-related endpoints in zebrafish and their offspring. Merging of TGs 229 and 234 proved feasible, and all established biomarkers and endpoints were responsive as expected, including reproductive and morphometric changes (PTU and EE2), vitellogenin levels, sex ratio, gonad maturation, and histopathology (only for EE2) of different life stages. A validation of the iFEDT with other well-known EDCs will allow verification of the sensitivity and usability and confirm its capacity to improve the existing testing strategy for EDCs in fish. Integr Environ Assess Manag 2024;20:817-829. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Peroxisome proliferator-activated receptors (PPARs), with the α, β/δ and γ isoforms, are nuclear receptors that control the expression of genes involved in glucose and lipids\' metabolism and into inflammatory processes and play a central role in metabolic syndrome. PPARs are a particular class of nuclear receptors because of their larger and more flexible ligand-binding domain with a particular Y shape. As nuclear receptors, PPARs are sensitive to exposure to xenobiotic compounds, called endocrine disruptions, even at low concentrations that could alter their homeostasis. Among these, food contact materials (FCMs), like phthalates, are synthetic compounds able to migrate from packaging to food and represent a significant source of exposure because of the increased use of plastic in the packaging in the last years. Through multiple docking and consensus scoring, we can analyse the ligand-binding domain\'s chemical and physical features, understand the mechanism of activation and predict the interaction with possible endocrine disruptions with an evaluation of their effects.

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The regulatory assessment of endocrine disrupting chemicals (EDCs) is complex due to the lack of a standardized definition of EDCs and validated testing criteria. In spite of these challenges, there is growing scientific interest in EDCs which has resulted in the rapid expansion of published literature on endocrine disruption upon chemical exposure. Here, we explore how academic research leading to curated knowledgebases can inform current chemical regulations on EDCs. To this end, we present an updated knowledgebase, DEDuCT 2.0, containing 792 potential EDCs with supporting evidence from 2218 research articles. Thereafter, we study the distribution of potential EDCs across several chemical lists that reflect guidelines for use or regulations. Further, to understand the scale of possible exposure to the potential EDCs present in chemical lists, we compare them with high production volume chemicals. Notably, we find many potential EDCs are in use across various product categories such as \'Food additives and Food contact materials\' and \'Cosmetics and household products\'. Several of these EDCs are also produced or manufactured in high volume across the world. Lastly, we illustrate using an example how diverse information in curated knowledgebases such as DEDuCT 2.0 can be helpful in the risk assessment of EDCs. In sum, we highlight the need to bridge the gap between academic and regulatory aspects of chemical safety, as a step towards the better management of environment and health hazards such as EDCs.

Breast cancer risk from pesticides may be missed if effects on mammary gland are not assessed in toxicology studies required for registration. Using US EPA\'s registration documents, we identified pesticides that cause mammary tumors or alter development, and evaluated how those findings were considered in risk assessment. Of 28 pesticides that produced mammary tumors, EPA\'s risk assessment acknowledges those tumors for nine and dismisses the remaining cases. For five pesticides that alter mammary gland development, the implications for lactation and cancer risk are not assessed. Many of the mammary-active pesticides activate pathways related to endocrine disruption: altering steroid synthesis in H295R cells, activating nuclear receptors, or affecting xenobiotic metabolizing enzymes. Clearer guidelines based on breast cancer biology would strengthen assessment of mammary gland effects, including sensitive histology and hormone measures. Potential cancer risks from several common pesticides should be re-evaluated, including: malathion, triclopyr, atrazine, propylene oxide, and 3-iodo-2-propynyl butylcarbamate (IPBC).

Transgenic fish are powerful models that can provide mechanistic information regarding the endocrine activity of test chemicals. In this study, our objective was to use a newly developed transgenic zebrafish line expressing eGFP under the control of the cyp19a1a promoter in the OECD Fish Short Term Reproduction Assay (TG 229) to provide additional mechanistic information on tested substances. For this purpose, we exposed adult transgenic zebrafish to a reference substance of the TG 229, i.e. prochloraz (PCZ; 1.7, 17.2 and 172.6 μg/L). In addition to \"classical\" endpoints used in the TG 229 (reproductive outputs, vitellogenin), the fluorescence intensity of the ovaries was monitored at 4 different times of exposure using in vivo imaging. Our data revealed that 172.6 μg/L PCZ significantly decreased the number of eggs laid per female per day and the concentrations of vitellogenin in females, reflecting the decreasing E2 synthesis due to the inhibition of the ovarian aromatase activities. At 7 and 14 days, GFP intensities in ovaries were similar over the treatment groups but significantly increased after 21 days at 17.2 and 172.6 μg/L. A similar profile was observed for the endogenous cyp19a1a expression measured by qPCR thereby confirming the reliability of the GFP measurement for assessing aromatase gene expression. The overexpression of the cyp19a1a gene likely reflects a compensatory response to the inhibitory action of PCZ on aromatase enzymatic activities. Overall, this study illustrates the feasibility of using the cyp19a1a-eGFP transgenic line for assessing the effect of PCZ in an OECD test guideline while providing complementary information on the time- and concentration-dependent effects of the compound, without disturbing reproduction of fish. The acquisition of this additional mechanistic information on a key target gene through in vivo fluorescence imaging of the ovaries was realized without increasing the number of individuals.

By the new Medical Device Regulation (MDR, EU 2017/745) the use of certain phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties, above 0.1% by weight (w/w) is only allowed after a proper justification. The SCHEER provide Guidelines on the benefit-risk assessment (BRA) of the presence of such phthalates in certain medical devices. The Guidelines describe the methodology on how to perform a BRA for the justification of the presence of CMR/ED phthalates in medical devices and/or or parts or materials used therein at percentages above 0.1% w/w. They also describe the evaluation of possible alternatives for these phthalates used in medical devices, including alternative materials, designs or medical treatments. Relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies, can use the guidelines. The approach of these guidelines may also be used for a BRA of other CMR/ED substances present in medical devices. SCHEER noticed that a number of BRA methodologies are theoretically available. However, there is a considerable lack of data needed for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices.

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.

Recently several OECD test guidelines were updated to include thyroid hormone measurements for assessing endocrine disruptor potency, which led to an imperative need to align interpretation of these results by the different stakeholders. We therefore evaluated 124 repro screening studies, which showed in 38% of the studies a statistical significant finding for T4 in at least one treatment group, probably due to disturbances of normal homeostasis causing high variation. Consequently, for a thorough evaluation it is extremely important to take the historical control range into account. In conclusion, the current testing approach is not providing specific information needed to assess endocrine disruption, as too often a statistical significant finding is noted and as down-stream adverse effects are not evaluated. Therefore, major modifications are urgently needed. Instead of extending the in vivo experiments, it should be investigated if in vitro assessments will provide more relevant information on human endocrine disruptor potential.

The nuclear androgen receptor (AR) is one of the most relevant biological targets of Endocrine Disrupting Chemicals (EDCs), which produce adverse effects by interfering with hormonal regulation and endocrine system functioning. This paper describes novel in silico models to identify organic AR modulators in the context of the Collaborative Modeling Project of Androgen Receptor Activity (CoMPARA), coordinated by the National Center of Computational Toxicology (U.S. Environmental Protection Agency). The collaborative project involved 35 international research groups to prioritize the experimental tests of approximatively 40k compounds, based on the predictions provided by each participant. In this paper, we describe our machine learning approach to predict the binding to AR, which is based on a consensus of a multivariate Bernoulli Naive Bayes, a Random Forest, and N-Nearest Neighbor classification models. The approach was developed in compliance with the Organization of Economic Cooperation and Development (OECD) principles, trained on 1687 ToxCast molecules classified according to 11 in vitro assays, and further validated on a set of 3,882 external compounds. The models provided robust and reliable predictions and were used to gather novel data-driven insights on the structural features related to AR binding, agonism, and antagonism.