Correction to: Toxicogenomics directory of chemically exposed human hepatocytes

Correction to: Arch Toxicol (2014) 88:2261–2287 https://doi.org/10.1007/s00204-014-1400-x.

NAM-supported read-across: From case studies to regulatory guidance in safety assessment

The use of new approach methodologies (NAMs) in support of read-across (RAx) approaches for regulatory purposes is a main goal of the EU-ToxRisk project. To bring this forward, EU-ToxRisk partners convened a workshop in close collaboration with regulatory representatives from key organizations including European regulatory agencies, such as the...

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

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...

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A mode-of-action ontology model for safety evaluation of chemicals: Outcome of a series of workshops on repeated dose toxicity

Repeated dose toxicity evaluation aims at assessing the occurrence of adverse effects following chronic or repeated exposure to chemicals. Non-animal approaches have gained importance in the last decades because of ethical considerations as well as due to scientific reasons calling for more human-based strategies. A critical aspect of this...

Paradigm shift in safety assessment using new approach methods: The EU-ToxRisk strategy

The EU-ToxRisk research project is an interdisciplinary research project that aims to advance the paradigm shift in toxicology towards new approach methodology (NAM)–based approaches for risk assessment. In this European research project, experts in the fields of in vitro and in silico techniques and risk assessment from academia, industry and...

Towards grouping concepts based on new approach methodologies in chemical hazard assessment: the read-across approach of the EU-ToxRisk project: editorial

Read-across is one of the most frequently used alternative tools for hazard assessment, in particular for complex endpoints such as repeated dose or developmental and reproductive toxicity. Read-across extrapolates the outcome of a specific toxicological in vivo endpoint from tested (source) compounds to “similar” (target) compound(s). If...

A systematic analysis of Nrf2 pathway activation dynamics during repeated xenobiotic exposure

Oxidative stress leads to the activation of the Nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. While most studies have focused on the activation of the Nrf2 pathway after single chemical treatment, little is known about the dynamic regulation of the Nrf2 pathway in the context of repeated exposure scenarios. Here we employed single...

Adverse outcome pathways: Opportunities, limitations and open questions

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event...

Changing the field of carcinogenicity testing of human pharmaceuticals by emphasizing mode of action

Lifetime testing for carcinogenicity of pharmaceuticals in rodents has been a controversial issue since the start of the International Conference on Harmonisation in 1990. Since 2010 the debate reached a new level following the proposal that a negative outcome of carcinogenicity studies can be predicted based upon the findings of 6 months...

Toxicogenomics directory of chemically exposed human hepatocytes

A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge...

Macrophage p53 controls macrophage death in atherosclerotic lesions of apolipoprotein E deficient mice

The cellular composition of atherosclerotic lesions is determined by many factors including cell infiltration, proliferation and cell death. Tumor suppressor gene p53 has been shown to regulate both cell proliferation and cell death in many cell types. In the present study, we investigated the role of macrophage p53 in the pathogenesis of early...

Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice

The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE...

Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice

Cell proliferation and cell death (either necrosis or apoptosis) are key processes in the progression of atherosclerosis. The tumor suppressor gene p53 is an essential gene in cell proliferation and cell death and is upregulated in human atherosclerotic plaques, both in smooth muscle cells and in macrophages. In the present study, we...