Collection and Evaluation of (Q)SAR Models for Mutagenicity and Carcinogenicity

This evaluation of the non-commercial (Q)SARs for mutagenicity and carcinogenicity consisted of a preliminary survey (Phase I), and then of a more detailed analysis of short listed models (Phase II). In Phase I, the models were collected from the literature, and then assessed according to the OECD principles based on the information provided by the authors-. Phase I provided the support for short listing a number of promising models, that were analyzed more in depth in Phase II. In Phase II, the information provided by the authors was completed and complemented with a series of analyses aimed at generating an overall profile of each of the short listed models. The models can be divided into two families based on their target: a) congeneric; and b) non-congeneric sets of chemicals. The QSARs for congeneric chemicals include most of the chemical classes top ranking in the EU High Production Volume list, with the notable exception of the halogenated aliphatics. They almost exclusively aim at modeling Salmonella mutagenicity and rodent carcinogenicity, which are crucial toxicological endpoints in the regulatory context. The lack of models for in vivo genotoxicity should be remarked. Overall the short listed models can be interpreted mechanistically, and agree with, and/or support the available scientific knowledge, and most of the models have good statistics. Based on external prediction tests, the QSARs for the potency of congeneric chemicals are 30 to 70 % correct, whereas the models for discriminating between active and inactive chemicals have considerably higher accuracy (63 to 100 %), thus indicating that predicting intervals is more reliable than predicting individual data points. The internal validation procedures (e.g., cross-validation, etc...) did not seem to be a reliable measure of external predictivity. Among the non-local, or global approaches for non-congeneric data sets, four models based on the use of Structural Alerts (SA) were short listed and investigated in more depth. The four sets did not differ to a large extent in their performance. In the general databases of chemicals the SAs appear to agree around 65% with rodent carcinogenicity data, and 75% with Salmonella mutagenicity data. The SAs based models do not seem to work equally efficiently in the discrimination between active and inactive chemicals within individual chemical classes. Thus, their main role is that of preliminary, or large-scale screenings. A priority for future research on the SAs is their expansion to include alerts for nongenotoxic carcinogens. A general indication of this study, valid for both congeneric and noncongeneric models, is that there is uncertainty associated with (Q)SARs; the level of uncertainty has to be considered when using (Q)SAR in a regulatory context. However, (Q)SARs are not meant to be black-box machines for predictions, but have a much larger scope including organization and rationalization of data, contribution to highlight mechanisms of action, complementation of other data from different sources (e.g., experiments). Using only non-testing methods, the larger the evidence from QSARs (several different models, if available) and other approaches (e.g. chemical categories, read across) the higher the confidence in the prediction.JRC.I.3-Toxicology and chemical substance

Exploring In Vitro/In Vivo Correlation: Lessons Learned from Analyzing Phase I Results of the US EPA's ToxCast Project

n/

Development of Structural Alerts for the In Vivo Micronucleus Assay in Rodents

In vivo mutagenicity and carcinogenicity studies are posing a high demand for test-related resources. Among these studies, the micronucleus test in rodents is the most widely used, as follow up to positive in vitro mutagenicity results. A recent survey of the (Q)SAR models for mutagenicity and carcinogenicity has indicated that no (Q)SAR models for in vivo micronucleus are available in the public domain. Therefore, the development and extensive use of estimation techniques such as (Q)SARs, read-across and grouping of chemicals, promises to have a huge animal saving potential for this endpoint. In this report, we describe the identification of structural alerts for the in vivo micronucleus assay, and provide the list of underlying chemical structures. These structural alerts provide a coarse-grain filter for the preliminary screening of potential in vivo mutagens.JRC.I.6-Systems toxicolog

The Benigni / Bossa Rulebase for Mutagenicity and Carcinogenicity - A Module of Toxtree

The Joint Resarch Centre's European Chemicals Bureau has developed a hazard estimation software called Toxtree, capable of making structure-based predictions for a number of toxicological endpoints. One of the modules developed as an extension to Toxtree is aimed at the prediction of carcinogenicity and mutagenicity. This module encodes the Benigni/Bossa rulebase for carcinogenicity and mutagenicity developed by Romualdo Benigni and Cecilia Bossa at the Istituto Superiore di Sanita¿, in Rome, Italy. The module was coded by the Toxtree programmer, Ideaconsult Ltd, Bulgaria. In the Toxtree implementation of this rulebase, the processing of a query chemical gives rise to limited number of different outcomes, namely: a) no structural alerts for carcinogenicity are recognised; b) one or more structural alerts (SAs) are recognised for genotoxic or non-genotoxic carcinogenicity; c) SAs relative to aromatic amines or aß-unsaturated aldehydes are recognised, and the chemical goes through Quantitative Structure-Activity Relationship (QSAR) analysis, which may result in a negative or positive outcome. If the query chemical belongs to the classes of aromatic amines or aß-unsaturated aldehydes, the appropriate QSAR is applied and provides a more refined assessment than the SAs, and should be given higher importance in a weight-of-evidence scheme. This report gives an introduction to currently available QSARs and SAs for carcinogenicity and mutagenicity, and provides details of the Benigni/Bossa rulebase.JRC.I.3-Consumer products safety and qualit

Conformational fluctuations and electronic properties in myoglobin

Abstract: In this article we use the recently developed perturbed matrix method (PMM) to investigate the effect of conformational fluctuations on the electronic properties of heme in Myoglobin. This widely studied biomolecule has been chosen as a benchmark for evaluating the accuracy of PMM in a large and complex system. Using a long, 80-ns, molecular dynamics simulation and unperturbed Configuration Interaction (CISD) calculations in PMM, we reproduced the main spectroscopic features of deoxy-Myoglobin. Moreover, in line with our previous results on a photosensitive protein, this study reveals a clear dynamical coupling between electronic properties and conformational fluctuations, suggesting that this correlation could be a general feature of proteins

Fragmentos de bosque nativo como nodo para la restauración, conservación dinámica de la biodiversidad y educación para el desarrollo sostenible de la región centro

El proyecto se asienta en la Estrategia Mundial para la Conservación de las Especies Vegetales (GSPC), asumido por el gobierno como un programa más dentro del Convenio de Diversidad Biológica (CDB); la cual incluye 5 objetivos y 16 metas para lograr la conservación vegetal hacia el 2020. En este contexto se propone trabajar en los objetivos II, IV y V referentes al % de conservación in-situ de flora nativa y al % de material disponible para restauración y recuperación. En la faz educativa re refiere a las acciones para promover la educación y la concienciación sobre la diversidad de las especies vegetales, su papel en los medios de vida sostenible y su importancia para el mantenimiento de la vida en la Tierra; así como el último objetivo apunta a incrementar la cantidad de personas dedicadas al estudio y conservación de la flora regional. En este contexto se realizará investigación, restauración, valorización y cuidado de fragmentos de bosque nativo, ubicados en el Campus universitarios, entendidos como nodos de conservación dinámica de la biodiversidad tanto como al intercambio y utilización de nuevos conocimientos, basados en la educación ambiental. Con respecto a los fragmentos se realizarán acciones tendientes a unificarlos para estabilizar el sistema. Se relevará la presencia de avifauna a fin de determinar la importancia de la preservación de estos relictos en el mantenimiento de la biodiversidad y se estudiará la expansión del bosque en el área de clausura. Por otra parte se relevará el efecto del fuego en una forestación de algarrobos de 7 años vecino a los fragmentos. Por último, el diálogo sobre la ciencia y la tecnología se plantea hoy como una necesidad ligada a los procesos de democratización, la ciencia no tiene sentido si no llega a los ciudadanos por lo que se realizarán visitas educativas destinadas a alumnos de nivel primario y medio. Por otra parte, el proyecto se basa en el trabajo de los educadores extraescolares, cuyo papel resulta esencial para vitalizar a unas sociedades necesitadas de permanente reflexión acerca de los objetivos que persiguen, la sustentabilidad de las estrategias que utilizan para conseguirlos, y la equidad en su reparto y utilización.Fil: Perazzolo, Diana Alicia. Universidad Católica de Córdoba. Facultad de Arquitectura; ArgentinaFil: Eynard, María Cecilia. Universidad Católica de Córdoba. Facultad de Arquitectura; ArgentinaFil: Bossa, Selma Raquel. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias; Argentin

Chemical Similarity and Threshold of Toxicological Concern (TTC) Approaches: Report of an ECB Workshop held in Ispra, November 2005

There are many national, regional and international programmes – either regulatory or voluntary – to assess the hazards or risks of chemical substances to humans and the environment. The first step in making a hazard assessment of a chemical is to ensure that there is adequate information on each of the endpoints. If adequate information is not available then additional data is needed to complete the dataset for this substance. For reasons of resources and animal welfare, it is important to limit the number of tests that have to be conducted, where this is scientifically justifiable. One approach is to consider closely related chemicals as a group, or chemical category, rather than as individual chemicals. In a category approach, data for chemicals and endpoints that have been already tested are used to estimate the hazard for untested chemicals and endpoints. Categories of chemicals are selected on the basis of similarities in biological activity which is associated with a common underlying mechanism of action. A homologous series of chemicals exhibiting a coherent trend in biological activity can be rationalised on the basis of a constant change in structure. This type of grouping is relatively straightforward. The challenge lies in identifying the relevant chemical structural and physicochemical characteristics that enable more sophisticated groupings to be made on the basis of similarity in biological activity and hence purported mechanism of action. Linking two chemicals together and rationalising their similarity with reference to one or more endpoints has been very much carried out on an ad hoc basis. Even with larger groups, the process and approach is ad hoc and based on expert judgement. There still appears to be very little guidance about the tools and approaches for grouping chemicals systematically. In November 2005, the ECB Workshop on Chemical Similarity and Thresholds of Toxicological Concern (TTC) Approaches was convened to identify the available approaches that currently exist to encode similarity and how these can be used to facilitate the grouping of chemicals. This report aims to capture the main themes that were discussed. In particular, it outlines a number of different approaches that can facilitate the formation of chemical groupings in terms of the context under consideration and the likely information that would be required. Grouping methods were divided into one of four classes – knowledge-based, analogue-based, unsupervised, and supervised. A flowchart was constructed to attempt to capture a possible work flow to highlight where and how these approaches might be best applied.JRC.I.3-Toxicology and chemical substance

Evaluation of the applicability of existing (Q)SAR models for predicting the genotoxicity of pesticides and similarity analysis related with genotoxicity of pesticides for facilitating of grouping and read across

n/

Conformational fluctuations in proteins. A molecular dynamics based study

Mario Compiani, Sfefano Pascarella, Enrico Staderin