Report of the First ONTOX Stakeholder Network Meeting: Digging Under the Surface of ONTOX Together With the Stakeholders.

The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13-14 March 2023, in Brussels, Belgium. The discussion centred around identifying specific challenges, barriers and drivers in relation to the implementation of non-animal new approach methodologies (NAMs) and probabilistic risk assessment (PRA), in order to help address the issues and rank them according to their associated level of difficulty. ONTOX aims to advance the assessment of chemical risk to humans, without the use of animal testing, by developing non-animal NAMs and PRA in line with 21st century toxicity testing principles.

Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating.

Update of the Cancer Potency Database (CPDB) to enable derivations of Thresholds of Toxicological Concern (TTC) for cancer potency.

The purpose of this study was to update the existing Cancer Potency Database (CPDB) in order to support the development of a dataset of compounds, with associated points of departure (PoDs), to enable a review and update of currently applied values for the Threshold of Toxicological Concern (TTC) for cancer endpoints. This update of the current CPDB, last reviewed in 2012, includes the addition of new data (44 compounds and 158 studies leading to additional 359 dose-response curves). Strict inclusion criteria were established and applied to select compounds and studies with relevant cancer potency data.

High Throughput Read-Across for Screening a Large Inventory of Related Structures by Balancing Artificial Intelligence/Machine Learning and Human Knowledge.

Read-across is an in silico method applied in chemical risk assessment for data-poor chemicals. The read-across outcomes for repeated-dose toxicity end points include the no-observed-adverse-effect level (NOAEL) and estimated uncertainty for a particular category of effects. We have previously developed a new paradigm for estimating NOAELs based on chemoinformatics analysis and experimental study qualities from selected analogues, not relying on quantitative structure-activity relationships (QSARs) or rule-based SAR systems, which are not well-suited to end points for which the underpinning data are weakly grounded in specific chemical-biological interactions.

A New CSRML Structure-Based Fingerprint Method for Profiling and Categorizing Per- and Polyfluoroalkyl Substances (PFAS).

The term PFAS encompasses diverse per- and polyfluorinated alkyl (and increasingly aromatic) chemicals spanning industrial processes, commercial uses, environmental occurrence, and potential concerns. With increased chemical curation, currently exceeding 14,000 structures in the PFASSTRUCTV5 inventory on EPA's CompTox Chemicals Dashboard, has come increased motivation to profile, categorize, and analyze the PFAS structure space using modern cheminformatics approaches. Making use of the publicly available ToxPrint chemotypes and ChemoTyper application, we have developed a new PFAS-specific fingerprint set consisting of 129 TxP_PFAS chemotypes coded in CSRML, a chemical-based XML-query language.