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In the near foreseeable future, much of toxicity testing can be replaced by computational approaches
Abstracts / Toxicology Letters 221S (2013) S2–S3
K4 Key-note lecture
K4-1 Reliability of toxicology without experimental animals? Possibilities and limitations since the ban of animal experiments with cosmetics Franz Oesch University of Mainz, Germany Ethics of animal protection demand reducing, refining and, as far as compatible with the safe use of chemical compounds, replacing toxicity tests in animals by alternative methods. The 7th amendment (1223/2009EEC) to the EU regulation of cosmetic products (76/768/EEC) has banned toxicity testing of cosmetics in animal studies and from March 2013 on also marketing of the respective products. All of this has put researchers and producers under considerable pressure to fortify attempts to develop means of satisfactorily insuring safety by toxicity testing without the use of animals. But have we now at the time point where these bans have become effective arrived at the goal to replace toxicity tests in animals by alternative tests while still maintaining safety for consumers - at least for cosmetics? The main efforts were directed to combine two crucial principles of toxicity testing: (1) to better recognize mechanisms of toxicities of groups of compounds presumed to disturb the same or closely related physiological pathways allowing for insuring that tests were included that held promise to be especially suitable for the compounds in question; and (2) to combine this with in vitro and in silico investigations encompassing a very broad range of potential disturbances. Results from such strategies to combine a great number of non-animal tests with mechanistic considerations will be critically compared with results of toxicity testing in whole animals. http://dx.doi.org/10.1016/j.toxlet.2013.06.008
K5 Bo Holmstedt Memorial Foundation (BHMF) lecture
K5-1 The developing brain: neurotoxic insults and their long term impact Sandra Ceccatelli Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Neurodevelopment is the process by which the nervous system grows from the embryonic stage to its postnatal completion as a mature, functioning system. The well-organized and reproducible formation of such a complex structure is controlled by genes and governed by a sophisticated interplay between inter- and intracellular signaling. Exposure to adverse environmental cues in early life can influence the risk of later disease, a concept defined as “early life programming”. The mechanisms underlying programming is partially understood, and epigenetic changes appear to play a critical role. Prenatal exposures to neurotoxicants are among the insults that can influence the programming. We have been investigating developmental neurotoxicity using a combined strategy ranging from cellular to behavioural analyses. My presentation will give an overview of our major in vitro and in vivo studies on prenatal
S3
neurodevelopmental insults, including synthetic glucocorticoids, methylmercury and perfluorooctane sulfonate, all inducing longlasting impairments. By using neural stem cells, we have been able to identify relevant mechanisms underlying neurotoxicity, even at very low concentrations. These results correlated with the effects observed in experimental animals exposed during the prenatal period. Cellular senescence, alterations in neurogenesis and neuronal differentiation, as well as epigenetic modifications were among the main changes observed. The analysis of behaviour, including learning, long-term memory, and affectivity-related behaviours that involve complex neural circuits, appeared to be optimal for revealing long term consequences of neurodevelopmental alterations in vivo. This sequential experimental approach can generate novel knowledge being valuable for both mechanistic studies and predictive developmental neurotoxicity testing. http://dx.doi.org/10.1016/j.toxlet.2013.06.010
K6 EUROTOX/SOT Debate
K6-1 In the near foreseeable future, much of toxicity testing can be replaced by computational approaches Rory B. Conolly 1 , George Loizou 2 US EPA, Research Triangle Park, NC, USA, 2 Health and Safety Laboratory, Buxton, United Kingdom
1
The EUROTOX/SOT debate continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of great toxicological importance. This year, our debaters will address the proposition: In the Near Foreseeable Future, Much of Toxicity Testing Can Be Replaced by Computational Approaches. During the past decade significant advances have been made in the development and application of mathematical modeling and computational simulation approaches to describing as well as predicting biological events. To a large extent, the application of computational approaches to biological systems has been driven by the exponential growth in knowledge of the underlying biological processes in living organisms. Similarly, major advances have also been made in the understanding of the molecular mechanisms by which xenobiotics modify biological processes, hence the vision and desire of applying computational approaches to toxicology. In fact, many benefits could be envisioned in applying in silico approaches to toxicity testing including a reduction in animal use, decreased costs of testing, and more rapid assessments of potential toxicity, to mention a few. In contrast, skepticism and serious concerns exist that the current understanding of the underlying biology and toxicology, especially at the organismal level, make replacement of toxicity testing by computational approaches a distant dream of the future. Regardless of framework differences and personal convictions, each scientific delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the response of the audience in order to obtain the approval or refusal of the motion. http://dx.doi.org/10.1016/j.toxlet.2013.06.012
K4 Key-note lecture
K4-1 Reliability of toxicology without experimental animals? Possibilities and limitations since the ban of animal experiments with cosmetics Franz Oesch University of Mainz, Germany Ethics of animal protection demand reducing, refining and, as far as compatible with the safe use of chemical compounds, replacing toxicity tests in animals by alternative methods. The 7th amendment (1223/2009EEC) to the EU regulation of cosmetic products (76/768/EEC) has banned toxicity testing of cosmetics in animal studies and from March 2013 on also marketing of the respective products. All of this has put researchers and producers under considerable pressure to fortify attempts to develop means of satisfactorily insuring safety by toxicity testing without the use of animals. But have we now at the time point where these bans have become effective arrived at the goal to replace toxicity tests in animals by alternative tests while still maintaining safety for consumers - at least for cosmetics? The main efforts were directed to combine two crucial principles of toxicity testing: (1) to better recognize mechanisms of toxicities of groups of compounds presumed to disturb the same or closely related physiological pathways allowing for insuring that tests were included that held promise to be especially suitable for the compounds in question; and (2) to combine this with in vitro and in silico investigations encompassing a very broad range of potential disturbances. Results from such strategies to combine a great number of non-animal tests with mechanistic considerations will be critically compared with results of toxicity testing in whole animals. http://dx.doi.org/10.1016/j.toxlet.2013.06.008
K5 Bo Holmstedt Memorial Foundation (BHMF) lecture
K5-1 The developing brain: neurotoxic insults and their long term impact Sandra Ceccatelli Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Neurodevelopment is the process by which the nervous system grows from the embryonic stage to its postnatal completion as a mature, functioning system. The well-organized and reproducible formation of such a complex structure is controlled by genes and governed by a sophisticated interplay between inter- and intracellular signaling. Exposure to adverse environmental cues in early life can influence the risk of later disease, a concept defined as “early life programming”. The mechanisms underlying programming is partially understood, and epigenetic changes appear to play a critical role. Prenatal exposures to neurotoxicants are among the insults that can influence the programming. We have been investigating developmental neurotoxicity using a combined strategy ranging from cellular to behavioural analyses. My presentation will give an overview of our major in vitro and in vivo studies on prenatal
S3
neurodevelopmental insults, including synthetic glucocorticoids, methylmercury and perfluorooctane sulfonate, all inducing longlasting impairments. By using neural stem cells, we have been able to identify relevant mechanisms underlying neurotoxicity, even at very low concentrations. These results correlated with the effects observed in experimental animals exposed during the prenatal period. Cellular senescence, alterations in neurogenesis and neuronal differentiation, as well as epigenetic modifications were among the main changes observed. The analysis of behaviour, including learning, long-term memory, and affectivity-related behaviours that involve complex neural circuits, appeared to be optimal for revealing long term consequences of neurodevelopmental alterations in vivo. This sequential experimental approach can generate novel knowledge being valuable for both mechanistic studies and predictive developmental neurotoxicity testing. http://dx.doi.org/10.1016/j.toxlet.2013.06.010
K6 EUROTOX/SOT Debate
K6-1 In the near foreseeable future, much of toxicity testing can be replaced by computational approaches Rory B. Conolly 1 , George Loizou 2 US EPA, Research Triangle Park, NC, USA, 2 Health and Safety Laboratory, Buxton, United Kingdom
1
The EUROTOX/SOT debate continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of great toxicological importance. This year, our debaters will address the proposition: In the Near Foreseeable Future, Much of Toxicity Testing Can Be Replaced by Computational Approaches. During the past decade significant advances have been made in the development and application of mathematical modeling and computational simulation approaches to describing as well as predicting biological events. To a large extent, the application of computational approaches to biological systems has been driven by the exponential growth in knowledge of the underlying biological processes in living organisms. Similarly, major advances have also been made in the understanding of the molecular mechanisms by which xenobiotics modify biological processes, hence the vision and desire of applying computational approaches to toxicology. In fact, many benefits could be envisioned in applying in silico approaches to toxicity testing including a reduction in animal use, decreased costs of testing, and more rapid assessments of potential toxicity, to mention a few. In contrast, skepticism and serious concerns exist that the current understanding of the underlying biology and toxicology, especially at the organismal level, make replacement of toxicity testing by computational approaches a distant dream of the future. Regardless of framework differences and personal convictions, each scientific delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the response of the audience in order to obtain the approval or refusal of the motion. http://dx.doi.org/10.1016/j.toxlet.2013.06.012