Reduced specificity for the local lymph node assay for lipophilic chemicals: Implications for the validation of new approach methods for skin sensitization.

Meaningful and accurate reference data are crucial for the validation of New Approach Methodologies (NAMs) in toxicology. For skin sensitization, multiple reference datasets are available including human patch test data, guinea pig data and data from the mouse local lymph node assay (LLNA). When assessed against the LLNA, a reduced sensitivity has been reported for in vitro and in chemico assays for lipophilic chemicals with a LogP ≥3.

Standardisation and international adoption of defined approaches for skin sensitisation.

In the absence of stand-alone one-to-one replacements for existing animal tests, efforts were made to integrate data from , and methods to ensure sufficient mechanistic coverage of the skin sensitisation Adverse Outcome Pathway (AOP) and generate predictions suitable for hazard identification and potency sub-categorisation. A number of defined approaches (DAs), using fixed data interpretation procedures (DIP) to integrate data from multiple non-animal information sources, were proposed and documented using a standard reporting template developed by the Organisation for Economic Co-operation and Development (OECD). Subsequent international activities focused on the extensive characterisation of three of these DAs with respect to the reference data, applicability domains, limitations, predictive performances and characterisations of the level of confidence associated with the predictions.

Towards a qAOP framework for predictive toxicology - Linking data to decisions.

The adverse outcome pathway (AOP) is a conceptual construct that facilitates organisation and interpretation of mechanistic data representing multiple biological levels and deriving from a range of methodological approaches including , and assays. AOPs are playing an increasingly important role in the chemical safety assessment paradigm and quantification of AOPs is an important step towards a more reliable prediction of chemically induced adverse effects. Modelling methodologies require the identification, extraction and use of reliable data and information to support the inclusion of quantitative considerations in AOP development.

SpheraCosmolife: a new tool for the risk assessment of cosmetic products.

A new, freely available software for cosmetic products has been designed that considers the regulatory framework for cosmetics. The software allows an overall toxicological evaluation of cosmetic ingredients without the need for additional testing and, depending on the product type, it applies defined exposure scenarios to derive risk for consumers. It takes regulatory thresholds into account and uses either experimental values, if available, or predictions.

EURL ECVAM Genotoxicity and Carcinogenicity Database of Substances Eliciting Negative Results in the Ames Test: Construction of the Database.

The bacterial reverse mutation test (Ames test) is the most commonly used genotoxicity test; it is a primary component of the chemical safety assessment data required by regulatory agencies worldwide. Within the current accepted in vitro genotoxicity test battery, it is considered capable of revealing DNA reactivity, and identifying substances that can produce gene mutations via different mechanisms. The previously published consolidated EURL ECVAM Genotoxicity and Carcinogenicity Database, which includes substances that elicited a positive response in the Ames test, constitutes a collection of data that serves as a reference for a number of regulatory activities in the area of genotoxicity testing.

Role of Physiologically Based Kinetic modelling in addressing environmental chemical mixtures - A review.

The role of Physiologically Based Kinetic (PBK) modelling in assessing mixture toxicology has been growing for the last three decades. It has been widely used to investigate and address interactions in mixtures. This review describes the current state-of-the-art of PBK models for chemical mixtures and to evaluate the applications of PBK modelling for mixtures with emphasis on their role in chemical risk assessment.

Computational models for the assessment of manufactured nanomaterials: Development of model reporting standards and mapping of the model landscape.

Different types of computational models have been developed for predicting the biokinetics, environmental fate, exposure levels and toxicological effects of chemicals and manufactured nanomaterials (MNs). However, these models are not described in a consistent manner in the scientific literature, which is one of the barriers to their broader use and acceptance, especially for regulatory purposes. Quantitative structure-activity relationships (QSARs) are models based on the assumption that the activity of a substance is related to its chemical structure.

Physiologically based mathematical models of nanomaterials for regulatory toxicology: A review.

The development of physiologically based (PB) models to support safety assessments in the field of nanotechnology has grown steadily during the last decade. This review reports on the availability of PB models for toxicokinetic (TK) and toxicodynamic (TD) processes, including and dosimetry models applied to manufactured nanomaterials (MNs). In addition to reporting on the state-of-the-art in the scientific literature concerning the availability of physiologically based kinetic (PBK) models, we evaluate their relevance for regulatory applications, mainly considering the EU REACH regulation.

Grouping of nanomaterials to read-across hazard endpoints: from data collection to assessment of the grouping hypothesis by application of chemoinformatic techniques.

Background: An increasing number of manufactured nanomaterials (NMs) are being used in industrial products and need to be registered under the REACH legislation. The hazard characterisation of all these forms is not only technically challenging but resource and time demanding. The use of non-testing strategies like read-across is deemed essential to assure the assessment of all NMs in due time and at lower cost.

Grouping of nanomaterials to read-across hazard endpoints: a review.

The use of non-testing strategies like read-across in the hazard assessment of chemicals and nanomaterials (NMs) is deemed essential to perform the safety assessment of all NMs in due time and at lower costs. The identification of physicochemical (PC) properties affecting the hazard potential of NMs is crucial, as it could enable to predict impacts from similar NMs and outcomes of similar assays, reducing the need for experimental (and in particular animal) testing. This manuscript presents a review of approaches and available case studies on the grouping of NMs to read-across hazard endpoints.

Silver Nanoparticles and Metallic Silver Interfere with the Griess Reaction: Reduction of Azo Dye Formation via a Competing Sandmeyer-Like Reaction.

Silver (Ag) is the most common nanomaterial (NM) in consumer products. Much research has been focused on elucidating the potential impact of Ag-containing NMs on human health, e.g.

The virtual cell based assay: Current status and future perspectives.

In order to replace the use of animals in toxicity testing, there is a need to predict in vivo toxic doses from concentrations that cause toxicological effects in relevant in vitro systems. The Virtual Cell Based Assay (VCBA) estimates time-dependent concentration of a test chemical in the cell and cell culture for a given in vitro system. The concentrations in the different compartments of the cell and test system are derived from ordinary differential equations, physicochemical parameters of the test chemical and properties of the cell line.

Can currently available non-animal methods detect pre and pro-haptens relevant for skin sensitization?

Predictive testing to characterize substances for their skin sensitization potential has historically been based on animal tests such as the Local Lymph Node Assay (LLNA). In recent years, regulations in the cosmetics and chemicals sectors have provided strong impetus to develop non-animal alternatives. Three test methods have undergone OECD validation: the direct peptide reactivity assay (DPRA), the KeratinoSens™ and the human Cell Line Activation Test (h-CLAT).

Exploring waiving opportunities for mammalian acute systemic toxicity tests.

A survey was carried out to explore opportunities for waiving mammalian acute systemic toxicity tests. We were interested in finding out whether data from a sub-acute toxicity test could be used to predict the outcome of an acute systemic toxicity test. The survey was directed at experts in the field of toxicity testing, and was carried out in the context of the upcoming 2018 final registration deadline for chemicals under the EU REACH Regulation.

Consensus of classification trees for skin sensitisation hazard prediction.

Since March 2013, it is no longer possible to market in the European Union (EU) cosmetics containing new ingredients tested on animals. Although several in silico alternatives are available and achievements have been made in the development and regulatory adoption of skin sensitisation non-animal tests, there is not yet a generally accepted approach for skin sensitisation assessment that would fully substitute the need for animal testing. The aim of this work was to build a defined approach (i.

Electronic states of porphycene-O2 complex and photoinduced singlet O2 production.

Porphycene (PC), a structural isomer of porphine, is a promising photosensitizer for photodynamic therapy. Its excited states can be quenched by molecular oxygen, generating singlet O2. The electronic structures of PC and of the PC⋯O2 complex were investigated using complete active space perturbation theory.

Exploring the sloped-to-peaked S2/S1 seam of intersection of thymine with electronic structure and direct quantum dynamics calculations.

The role of the seam of intersection between the lowest (pi,pi*) and (n,pi*) excited states in the decay of electronically excited singlet thymine has been investigated with ab initio complete active space self-consistent field (CASSCF) calculations and direct dynamics variational multiconfiguration Gaussian (DD-vMCG) quantum dynamics on the full-dimensional CASSCF surface, with 39 degrees of freedom. The seam has a sloped-to-peaked topography, and the dynamics at the different segments of the seam have been studied by varying the initial conditions of the propagation. When the wave packet is directed to the peaked segments, part of it traverses the seam, stays on the (pi,pi*) state and heads towards decay to the ground state.

Intramolecular Basis Set Superposition Error Effects on the Planarity of DNA and RNA Nucleobases.

Molecules of utmost importance like DNA and RNA nucleobases are predicted to be nonplanar by a typical ab initio method, such as second order Møller-Plesset perturbation theory (MP2) combined with standard Pople's basis sets. Similarly to the case of other planar aromatic systems, these pitfalls can be explained in terms of intramolecular basis set superposition error (BSSE) effects, induced by local basis set deficiencies. We demonstrate that conventional BSSE correction techniques such as the Counterpoise method can account for this wrong behavior and provide proper correction whenever spurious results occur, mainly in case of thymine, uracil and guanine but also to lower extent for adenine and cytosine.

Photophysics of the pi,pi* and n,pi* states of thymine: MS-CASPT2 minimum-energy paths and CASSCF on-the-fly dynamics.

The photodynamics along the main decay paths of thymine after excitation to the lowest pi,pi* state have been studied with MS-CASPT2 calculations and semiclassical CASSCF dynamics calculations including a surface hopping algorithm. The static calculations show that there are two decay paths from the Franck-Condon structure that lead to a conical intersection with the ground state. The first path goes directly to the intersection, while the second one is indirect and involves a minimum of the pi,pi* state, a small barrier, and a crossing between the pi,pi* and n,pi* states.

Benign decay vs. photolysis in the photophysics and photochemistry of 5-bromouracil. A computational study.

The excited state potential energy surface of 5-bromouracil has been studied with ab initio CASPT2//CASSCF calculations to rationalize the competition between the benign decay and the photolysis found experimentally. The surface is characterized by an extended region of degeneracy between S(1) and S(0). The access to this region has been studied with minimum energy path calculations from the FC structure, the seam of intersection has been mapped in detail, and the decay paths from different regions of the seam have been characterized.

Intramolecular basis set superposition error effects on the planarity of benzene and other aromatic molecules: a solution to the problem.

Recently, the surprising result that ab initio calculations on benzene and other planar arenes at correlated MP2, MP3, configuration interaction with singles and doubles (CISD), and coupled cluster with singles and doubles levels of theory using standard Pople's basis sets yield nonplanar minima has been reported. The planar optimized structures turn out to be transition states presenting one or more large imaginary frequencies, whereas single-determinant-based methods lead to the expected planar minima and no imaginary frequencies. It has been suggested that such anomalous behavior can be originated by two-electron basis set incompleteness error.