 Zva što je tudi tudi tudi izglasnosim, ki tudi da je zpronavate postupnjenje provedaj spazitvropših klasoj slučanost, kad je to zelo v blažnih in drobenih ročinje. To tudi je to slučanost, kaj je vzobjetno začunjala zdavnjenja. Vzobятся, da je stavniti vzobjetno v vratu, v potrednji način, za to, da je sločnje potranost, vzobjetno in sur sens variable, z vsej materijali, ki jih se včasno posleda, uživljajo je to vsej vsej. Vsej vsej regulatorijne sistem vsej način je spremelji, ki so načino vsej način, ki se izgleda način, način je ta vsej način površen, in vsej vsej regulatorijne sistem and which checks for toxicity on a one by one basis. So basically each of these substances is tested in isolation and for most of them, at least in our part of the world, indeed the individual compounds are below the threshold. But for many years, we and many others had hypothesized that it would actually be the Malaysian, the mixtures of these compounds that could still have a detrimental effect Even if individually each substance was below the threshold. And so we set out together with several colleagues from other European countries, Sweden, France and several others. We actually set out to undertake a longitudinal study that would combine epidemiology, so the real life of people exposed to such substances followed through many years and experimental molecular biology in order to understand whether there was such a risk and how we could actually deal with it. And the result is that the risk is there because over 2,000 pregnant women were tested for the actual levels of these substances at about the 10th week of gestation. And then the children originating from these pregnancies were followed through several years and our Swedish colleagues measured the number of words that these children spoke at 30 months of age. The number of words at 30 months of age is a very important indicator of cognitive proficiency and is also an indicator when it is decreased, so when children speak fewer words of problems that will unfold later in life, such as, for example, intellectual disability and also autism spectrum disorder. And it was possible to associate mixtures of these endocrine disruptors to a detrimental outcome in terms of language at 30 months. And so this mixture was then synthesized in vitro in the lab and we exposed this mixture to brain organoids, so to structures, to cultures in vitro that are very complex and that recapitulate over time some of the important features of how the human brain develops in vivo, including its temporal dynamics. And we could find that it was actually the mixture of the substances that had a very significant alteration on the neural cells as they did develop and this alteration included pathways that are regulated by hormones and in fact these are endocrine disruptors, so they interfere with the way in which hormones work and most importantly they actually targeted genes that we already knew on the basis of human genetic evidence to be causally implicated in autism and intellectual disability. The implication for this assessment is very profound because this study demonstrates in a rigorous way for the first time that mixtures need to be taken into account. This of course means that alongside the established systems of testing for toxicity we actually need to take mixtures into account and to update the assays, the systems through which these compounds are tested so that their toxicity is actually taking into account what happens in the real world and this study has demonstrated that the exposures of the real world that is pervasive is actually the one that needs to be confronted. One of the most significant aspects of the study is that once it was determined what were the experimental thresholds of concern, namely on the basis of the experiments that were done in VITRA, what were the thresholds of exposure to these mixtures that were of concern, we then went back to the original data from the pregnant women in Sweden and found that up to 54% of them had been exposed during their pregnancy to such levels of concern. Luckily, this did not mean that 54% of the children ended up having a retardation of language acquisition, but it is because of course there is an individual predisposition, but this really should ring a bell because it means that the way in which we produce these substances and the way in which we test them and the way in which we live is actually exposing a very significant part of the population to an interference that has very detrimental impact later on on such fundamental features of the human condition such as language and cognitive development. This research started at the European Institute of Oncology in my lab as part of this very large European project, EDC Mix Risk, funded by the European Commission, precisely as a project that had to test whether the mixtures was a relevant unit that we should take into account in order to actually protect our health. And on the basis of this result, we will now of course proceed to one technopol on a number of fronts. First of all, to actually have an even greater mechanistic understanding of how different classes of such compounds and mixtures can interfere with the neural pathways. Meanwhile, the children have been profiled for their cognitive attainment through seven years of age, so we can have an even greater granularity in the combination between the mixtures and these various neurodevelopmental outcomes. We are also very interested in how the same mixtures actually impact also the formation of the germ cells and how this impact can actually then influence also the formation of the brain in the following generation. And we are of course very interested together with our colleagues as part of another major European project called Endpoints in actually developing assays of neurodevelopmental toxicity. In other words, taking fully on board the implication of this study and making sure that we provide the community with standardized assay that can hopefully allow us all to have a healthier life and a healthier environment.