Analysis of the Cramer classification scheme for oral systemic toxicity - implications for its implementation in Toxtree

In the application of the Threshold of Toxicological Concern (TTC) concept to non-cancer endpoints, the decision tree proposed by Cramer, Ford and Hall in 1978, commonly referred to as the Cramer scheme, is probably the most widely used approach for classifying and ranking chemicals according to their expected level of oral systemic toxicity. The decision tree categorises chemicals, mainly on the basis of chemical structure and reactivity, into three classes indicating a high (Class III), medium (Class II) or low (Class I) level of concern. Each Cramer class is associated with a specified human exposure level, below which chemicals are considered to present a negligible risk to human health. In the absence of experimental hazard data, these exposure threshold (TTC) values have formed the basis of priority setting in the risk assessment process. To facilitate the application of the TTC approach, the original Cramer scheme, and an extended version, have been implemented in Toxtree, a freely available software tool for predicting toxicological effects and mechanisms of action. Building on previous work by Patlewicz and coworkers, this report provides some suggestions for improving the Cramer scheme based on a review of the scientific literature, a survey of Toxtree users, and an analysis of lists of body and food components incorporated in Toxtree.JRC.DG.I.6-Systems toxicolog

Comparative Analysis of Antimalarial Principles in Artemisia Annua L. Herbal Drugs from East Africa

Malaria mortality continues to increase across the world and represents the most important parasitic disease of man. Artemisia annua L. (Asteraceae) has been used to treat fevers in China for over two millennia and recently the clinical efficacy of teas and decoctions derived from this species have been demonstrated, using high artemisinin-yielding plants. Therefore, it is important to verify the artemisinin levels in local cultivations in areas where malaria is endemic and to assess how different geographical and climatic conditions may affect the efficacy of traditional treatments. In this study, samples of the aerial parts of A. annua (ANAMED 3 hybrid) cultivated in three different locations in Burundi were compared for their content of active principles. Artemisinin levels in the plant materials ranged from 0.20% to 0.35%, while total flavonoid contents ranged from 0.32% to 0.80%

A Framework for assessing in silico Toxicity Predictions: Case Studies with selected Pesticides

In the regulatory assessment of chemicals, the use of in silico prediction methods such as (quantitative) structure-activity relationship models ([Q]SARs), is increasingly required or encouraged, in order to increase the efficiency and effectiveness of the risk assessment process, and to minimise the reliance on animal testing. The main question for the assessor concerns the usefulness of the prediction approach, which can be broken down into the practical applicability of the method and the adequacy of the predictions. A framework for assessing and documenting (Q)SAR models and their predictions has been established at the European and international levels. Exactly how the framework is applied in practice will depend on the provisions of the specific legislation and the context in which the non-testing data are being used. This report describes the current framework for documenting (Q)SAR models and their predictions, and discuses how it might be built upon to provide more detailed guidance on the use of (Q)SAR predictions in regulatory decision making. The proposed framework is illustrated by using selected pesticide active compounds as examples.JRC.DG.I.6-Systems toxicolog

The Applicability of Software Tools for Genotoxicity and Carcinogenicity Prediction: Case Studies relevant to the Assessment of Pesticides

This report presents research results obtained in the framework of a project on the Applicability of Quantitative Structure-Activity Relationship (QSAR) analysis in the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances. During this project, which was funded by the European Food Safety Authority (EFSA), the Joint Research Centre (JRC) performed several investigations to evaluate the comparative performance of selected software tools for genotoxicity and carcinogenicity prediction, and to develop a number of case studies to illustrate the opportunities and difficulties arising in the computational assessment of pesticides. This exercise also included an investigation of the chemical space of several pesticides datasets. The results indicate that different software tools have different advantages and disadvantages, depending on the specific requirements of the user / risk assessor. It is concluded that further work is needed to develop acceptance criteria for specific regulatory applications (e.g. evaluation of pesticide metabolites) and to develop batteries of models fulfilling such criteria.JRC.DG.I.6-Systems toxicolog

The Use of Computational Methods in the Toxicological Assessment of Chemicals in Food: Current Status and Future Prospects

A wide range of chemicals are intentionally added to, or unintentially found in, food products, often in very small amounts. Depending on the situation, the experimental data needed to complete a dietary risk assessment, which is the scientific basis for protecting human health, may not be available or obtainable, for reasons of cost, time and animal welfare. For example, toxicity data are often lacking for the metabolites and degradation products of pesticide active ingredients. There is therefore an interest in the development and application of efficient and effective non-animal methods for assessing chemical toxicity, including Quantitative Structure-Activity Relationship (QSAR) models and related computational methods. This report gives an overview of how computational methods are currently used in the field of food safety by national regulatory bodies, international advisory organisations and the food industry. On the basis of an international survey, a comprehensive literature review and a detailed QSAR analysis, a range of recommendations are made with the long-term aim of promoting the judicious use of suitable QSAR methods. The current status of QSAR methods is reviewed not only for toxicological endpoints relevant to dietary risk assessment, but also for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their reaction products. By referring to the concept of the Threshold of Toxicological Concern (TTC), the risk assessment context in which QSAR methods can be expected to be used is also discussed. This Joint Research Centre (JRC) Reference Report provides a summary and update of the findings obtained in a study carried out by the JRC under the terms of a contract awarded by the European Food Safety Authority (EFSA).JRC.DG.I.6-Systems toxicolog

A study of the ligand-receptor interactions of ecdysteroids

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

L'importanza della tutela giurisdizionale. L'istituzione del Garante nazionale dei diritti delle persone private della libertà personale.

Il lavoro tratta dell'importanza della tutela giurisdizionale nel sistema delle garanzie dei diritti dei detenuti. Vengono analizzate le figure preposte all'esecuzione di tale garanzia, analizzate nel contesto storico-geografico. Vengono analizzati, a larghissime linee, i punti critici della tutela giurisdizionale. Viene, infine, analizzata con cura la figura del Garante Nazionale dei diritti delle persone private della libertà personale istituito con Legge 21 febbraio 2014, n. 10

Weak estrogenic transcriptional activities of Bisphenol A and Bisphenol S

In 2011, the European Commission has restricted the use of Bisphenol A in plastic infant feeding bottles. In a response to this restriction, Bisphenol S is now often used as a component of plastic substitutes for the production of babybottles. One of the major concerns leading to the restriction of Bisphenol A was its weak estrogenic activity. By using two highly standardised transactivation assays, we could demonstrate that the estrogenic activity of Bisphenol A and Bisphenol S is of a comparable potency. Furthermore, some insights about the structure-activity relationships of these two chemicals and their metabolites could be gained from in silico predictions of their relative estrogen receptor-binding affinities and their liver phase-I biotransformation.JRC.I.5-Systems Toxicolog

QSAR and Metabolic Assessment Tools in the Assessment of Genotoxicity

In this chapter, a range of computational tools for applying (Q)SAR and grouping/read-across methods are described, and their integrated use in the computational assessment of genotoxicity is illustrated through the application of selected tools to two case-study compounds - 2-amino-9H-pyrido[2,3-b]indole (AaC) and 2-aminoacetophenone (2-AAP). The first case study compound (AaC) is an environment pollutant and a food contaminant that can be formed during the cooking of protein-rich food. The second case study compound (2-AAP) is a naturally occurring compound in certain foods and also proposed for use as a flavouring agent. The overall aim is to describe and illustrate a possible way of combining different information sources and software tools for genotoxicity and metabolism prediction by means of a simple stepwise approach. The chapter is aimed at researchers and assessors who have a basic knowledge of computational toxicology and some familiarity with the practical use of computational tools. The emphasis is on how to evaluate the data generated by multiple tools, rather than the practical use of any specific tool.JRC.I.5-Systems Toxicolog