Neurotoxicologie et neuroplasticité – Construire la neurotoxicologie du 21ème siècle à la lumière des neuroplasticités développementale et adulte/ A multidisciplinary Seminar for the 21st century neurotoxicology, in light of the developmental and adult neuroplasticities
Seminar organized by Alain Trembleau and Anna Bencsik from September 27 – October 2, 2021
Anna BENCSIK (Anses, Lyon, France), Patrick CHASKIEL (Université de Toulouse, France), Ellen FRITSCHE (IUF – Leibniz Research Institute for Environmental Medicine in Duesseldorf, Germany), Jean HARRY (NIH/NIEHS, Research Triangle Park, USA), Loïc MANGIN (Pour La Science, Paris, France), Sakina MHAOUTY-KODJA (CNRS/INSERM/Sorbonne Université, Paris, France), Martin PAPARELLA (Medical University of Innsbruck, Austria), Stefano RENZETTI* (Università degli Studi di Brescia, Italy), Alain TREMBLEAU (Sorbonne Université, Paris, France), Remco WESTERINK (Universiteit Utrecht, Netherlands). *Junior researcher/jeune chercheur
Ce séminaire avait pour objectif de mener une réflexion approfondie sur la construction d’une neurotoxicologie du 21ème siècle, à la lumière des connaissances les plus actuelles et des dernières avancées méthodologiques issues de la recherche fondamentale sur le système nerveux, et d’élaborer des stratégies de communication efficace de cette problématique et de ses enjeux envers les différents acteurs de la société. Cette réflexion collective a réuni des spécialistes internationaux de disciplines variées telles que la neurotoxicologie et la neurobiologie du développement, avec une expertise des expérimentations in vitro ou in vivo, la toxicologie règlementaire au niveau européen, la biostatistique appliquée à l’épidémiologie environnementale, la sociologie de la communication des risques technologiques, et le journalisme scientifique.
The aim of this seminar was to have an in-depth reflection on the construction of a neurotoxicology for the 21st century, in the light of the up-to-date knowledge and the latest methodological advances resulting from fundamental research on the nervous system, and to develop strategies for effective communication of this issue and its stakes to the various stakeholders in society. It brought together international experts from different disciplines: neurotoxicologists and developmental neurobiologists with strong expertise in in vitro or in vivo experimental approaches, a specialist in European toxicology risk assessment and regulation, a young biostatistician specialising in environmental epidemiology, a sociologist expert in technological risk communication, and a scientific journalist. The multidisciplinary approach of this seminar made it possible to create close scientific relationships between the participants, and to open further collaborative perspectives as well as editorial projects for the future.
Humans are exposed to a growing number of putative neurotoxic substances, and their effects on the highly adaptable brain remain largely unknown. The reasons why the putative neurotoxicological effects of most these substances are currently not clear are multiple. First, investigating such effects in human is extremely challenging. Second, among the biological models available for neurotoxicity studies, the results obtained on these animal models or human-derived cellular models, in many cases, cannot be simply translated to humans. Third, should there be evidence for defects in a brain containing detectable putative toxic agents, a causal link between these two parameters remains to be proven, meaning that the mechanisms or modes of action by which the neurotoxic agent may trigger the pathology should be identified. Last and not least, even if for a given substance, significant toxic effects on neural networks are demonstrated, determining if they are predictive of a truly deleterious effect is difficult. The challenge comes from the known spectacular structural and functional adaptative processes occurring in the central nervous system, not only during its development, but throughout life and upon aging. Therefore, identifying the precise and subtle short-term and long-term effects of agents modifying the brain ideally requires exhaustive analyses performed on appropriate animal models endowed with translational validity or on standardized and validated biologically relevant cell based models, i.a. from human derived cells, using state-of-the-art techniques.
Today more than ever, there is thus a need to reinvigorate the human neurotoxicology research, building upon the recent and spectacular advances in the field of neuroscience and to renew the neurotoxicity testing and regulatory strategies. This important issue motivated the organization of a seminar at the Fondation des Treilles, which ideally enables to explore in depth its different aspects. Bridging different types of expertise (neurotoxicology, neuroplasticity, risk assessment, biostatistics applied to environmental epidemiology, industrial risk communication, and scientific communication to the public), our multidisciplinary Seminar aimed at delivering a new strategic view for future neurotoxicological research and risk assessment, and to propose improved communication strategies.
To reach this objective, all the participants of the Seminar extensively discussed:
- the contemporary approaches used in the field of neurotoxicology, which emerged from recent advances in fundamental research in neuroscience;
- the current knowledge about the acute and long-term effects of neurotoxic substances on the developing, adult, and aging nervous system, in light of its remarkable neuroplastic properties;
- the strategies to be implemented in terms of i) neurotoxicological risk evaluation, ii) design of standardized tests and tools, iii) development of accurate expertise for this challenging emerging field;
- the issue of communicating, by the different actors (scientists producing the data, experts, media…), such complex, highly sensitive, and ongoing results to the different publics of the society.
Along these discussions, various specific and often complex issues were addressed, e.g.: Can we identify priorities for neurotoxicants assessment? Can the rapidly developing in vitro models, i.a. designed from human-derived cells (including organoids) replace in vivo investigation on animal models? Which innovative tools/approaches should be implemented into the current strategies of risk assessment? How to integrate the needs of the mechanistic toxicology, based on the AOP (Adverse Outcome Pathways) concept, in assay design and in the selection of most relevant endpoints to support better prediction of neurotoxic outcomes linked to some substance? How to identify realistic expectations, stimulate innovative perspectives and establish an efficient communication on neurotoxicology with the different stakeholders of the society (non-governmental organizations, general public, regulators, politicians, worker unions…)?
The Seminar ended up with a focus on three integrated questions, which emerged during the week as key challenges, and which were addressed by sub-groups of participants who presented their analyses to the full panel:
– The challenge of real-life exposure doses: strategies to be implemented.
– From a chemical substance to the assessment of its adult neurotoxicity (including upon aging) – towards an ideal paradigm.
– Communication with non-governmental organizations: possible message(s) to deliver.
The participants finally designed the outputs of this Seminar as follows:
– A meeting report for the general public, published in the scientific magazine “Pour la Science”, having a large diffusion in France and a potential for diffusions in other countries of the PLS Group if the editors select this paper for publication in their country.
– A scientific paper exploring a new strategic view for future neurotoxicological research and risk assessment. A possible target journal has been identified: Environmental Health Perspectives, in which our views may be published in the section Commentaries.
The unifying subject addressed in this unique setting – undoubtedly an added value to this seminar – gave rise to thoughtful debates of the highest quality. Beyond the essential question of how to drive the evolution of neurotoxicology, particularly in the light of the neuroplasticity capacities of the brain, the participants were able to open up to the fundamental questions of communicating the challenges of this discipline. The objectives were therefore achieved, even exceeded, insofar as, in a very positive way, the multidisciplinary approach of this fruitful seminar made it possible to create close scientific relationships between the participants, and to open further collaborative perspectives as well as editorial projects for the future.
The participants of this seminar “Neurotoxicology and Neuroplasticity” thus express their deep gratitude to La Fondation des Treilles for its support.