The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity

Lupu, Diana; Andersson, Patrik L.; Bornehag, Carl‐Gustaf; Demeneix, Barbara; Fritsche, Ellen; Gennings, Chris; Lichtensteiger, W.; Leist, Marcel; Leonards, P.E.G.; Ponsonby, Anne–Louise; Scholze, Martin; Testa, Giuseppe; Tresguerres, Jesús A.F.; Westerink, Remco H.S.; Zalc, Bernard; Rüegg, Joëlle

doi:10.3390/ijms21113978

Cited by 32 publications

(23 citation statements)

References 56 publications

(78 reference statements)

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“…A comprehensive gap analysis would require an extensive vision document on the future of toxicology. This is beyond the scope of this short overview, but for an overview of past and current ideas, we refer to various visionary reports and documents (Cote et al 2016 ; Hartung and Leist 2008 ; Khadka et al 2020 ; Krewski et al 2020 ; Leist et al 2014 , 2008 ; Lupu et al 2020 ; Sauer et al 2015 ; Thomas et al 2019 , 2018 ).…”

Section: Gaps and Future Requirementsmentioning

confidence: 99%

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

et al. 2020

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In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.

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Section: Gaps and Future Requirementsmentioning

confidence: 99%

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

et al. 2020

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“…Three projects within the EURION focus on improved testing strategies for thyroid hormone disrupting chemicals: ERGO [ 19 ], ATHENA [ 20 ], and SCREENED [ 21 ], while three other projects focus on integrated approaches for the testing and assessment of metabolism disrupting chemicals: OBERON [ 22 ], EDCMET [ 23 ] and GOLIATH [ 24 ]. In addition, the FREIA project develops new tests for effects of EDCs on female reproduction [ 25 ] and the ENDpoiNTs project focusses on developmental neurotoxicity [ 26 ] and methods for elucidating EDC effects.…”

Section: New Projects Within the Eurion Clustermentioning

confidence: 99%

Endocrine Disrupting Chemicals: Current Understanding, New Testing Strategies and Future Research Needs

Street

Audouze

Legler

et al. 2021

IJMS

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“…Furthermore, the keto-enol balance of one substance could be affected by presence of the other thus affecting its availability. Such underestimated mechanisms may lead to both decrease and increase of the summarized toxicity of cocktails of xenobiotics of organisms exposed (Lupu et al, 2020;Mauderly & Samet, 2009). Antecedents of these types of synergies have been seen promoting the development of some types of cancer and there are numerous studies confirming increased activity of various cancer cells exposed to these mixtures of environmental pollutants (Burke & Wei, 2009;Hansen et al, 2019;Lu et al, 2018;Ngamwong et al, 2015;Wieczerzak et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The potential interaction of environmental pollutants and circadian rhythm regulations that may cause leukemia

Lagunas‐Rangel

Kudłak

et al. 2021

Critical Reviews in Environmental Science and Technology

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Tumor suppressor genes are highly affected during the development of leukemia, including circadian clock genes. Circadian rhythms constitute an evolutionary molecular machinery involving many genes, such as BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, REV-ERBa, and RORA, for tracking time and optimizing daily life during day-night cycles and seasonal changes. For circulating blood cells many of these genes coordinate their proliferation, output, and function, and therein lies their importance for the development of leukemia. Recent findings suggest that environmental pollutants may affect circadian rhythms and thus affect cancer development and treatment. Such environmental pollutants are often found in mixtures and include benzene, tobacco smoke, pesticides and microplastics. Our understanding of the molecular basis for the interaction mechanisms within complex mixtures is also growing, confirming the plausible occurrence of synergistic (superadditive effect) and antagonistic (cancellation effect) actions of pollutant cocktails. In this work, we discuss the relationship of environmental pollutants and the alteration of circadian rhythms that potentially may cause leukemia. We highlight the need of additional dimensions and perhaps a paradigm shift for future studies in relation to continuously growing magnitude of environmental pollution using multitude of disciplines such as development of high throughput reporter cell lines, other cell screening methods, contaminant measurements in leukemia patients, advanced pharmacology and toxicological measurement of mixtures and highly efficient computer analysis including artificial intelligence, among others.

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The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity

Cited by 32 publications

References 56 publications

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

Endocrine Disrupting Chemicals: Current Understanding, New Testing Strategies and Future Research Needs

The potential interaction of environmental pollutants and circadian rhythm regulations that may cause leukemia

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