How to limit the effects of endocrine disruptors on the brains of children
- Last April, the European Commission published a roadmap for banning thousands of dangerous substances in consumer products by 2030 – including endocrine disruptors.
- Contrary to most toxicological measures, their dose does not predict the toxicity of exposure – a tiny amount can lead to long-term damage to health and there is there is a “cocktail” effect of different molecules.
- Using the EDC-MixRisk project which studies children's health in relation to mothers’ exposure to endocrine disruptors, researchers identified a realistic “cocktail” that was potentially damaging to brain development.
- Eleven molecules were identified as being at risk for a delay in cognitive development including phthalates, perfluorinated compounds and phenols.
- The study suggests that if they had used these doses to control chemicals in everyday products, they could have prevented 57% of women from being exposed to dangerous doses.
As the European Commission prepares a blacklist of toxic substances to be banned from consumer products circulating in the EU, the question that has haunted toxicologists for the past 20 years becomes inescapable: how do we assess endocrine disruptors? Present in plastics, cosmetics, paints and even fruit and vegetables because of pesticides, this family of chemical molecules is not defined by its chemical structure nor the nature of its applications. Rather, it is defined but by the type of undesirable effects it induces in living organisms – effects involving disruption of hormones.
The family of endocrine disruptors includes various types of molecules: phthalates, perfluorinated compounds, parabens, etc. And their cumulative action within a biological system is difficult to predict. Yet, this is what we expect from regulations, in the form of thresholds below which consumers, professionals using these products or users of the spaces where they are present are protected from their harmful effects. A seemingly simple problem.
Changing the regulatory paradigm
But “the dose makes the poison” is the paradigm of toxicology, not endocrinology. Indeed, exposure to infinitesimal doses of cyanide, for example, is not very risky. It is even found naturally in hydrangea leaves, apple seeds and cherry pits; yet this does not mean that apple trees should be banned.
However, if cyanide were an endocrine disruptor, we would have to think differently. Because of their mode of action, the dose does not predict the toxicity of exposure to endocrine disruptors. An infinitesimal amount administered at a key moment during a crucial process such as brain development in children can lead to long-term damage to health.
An infinitesimal amount administered at a key moment during brain development can lead to long-term damage to health.
Similarly, the sum of small doses accumulated on the same target can produce consequences later in life. This is the “cocktail” effect. Hence, assessing action of endocrine disruptors is a challenge for regulatory science. And research by several European laboratories, in collaboration with the Icahn School of Medicine at Mount Sinai, within the H2020 EDC-MixRisk project (2015–2019), is seeking a solution to this problem. They presented a very ambitious approach last February1.
Jean Baptiste Fini, a biologist specialising in endocrine disruptors and one of the authors of the article, explains, “our idea was to study the effects of mixtures instead of testing them molecule by molecule. This approach better represents the exposure of individuals in real life because the risk of developing a disease depends on a multitude of exposures to molecules, the doses of which are often low and below current regulatory thresholds.”
The aim is to increase the number of tests to better account for the risks. Their work takes advantage of the Swedish Selma cohort, which follows more than 2000 mother-child pairs since the 10th week of pregnancy2. The EDC-MixRisk project has set out to study children’s health in relation to mothers’ exposure to endocrine disruptors.
Endocrine disruptors affect the brain
“We studied the health of the subjects from several angles. The first study we published concerned the cognitive aspect,” explains Jean-Baptiste Fini. The scientists researched which chemical molecules were associated with language delay in children whose mothers were exposed to these products. Eleven molecules were identified as being at risk for this cognitive-delay criterion. The panel of chemicals chosen will not surprise any toxicologist: phthalates, perfluorinated compounds, phenols… these molecules are known to specialists, and some are already subject to regulatory restrictions.
“Once we had established the mix of chemicals, it was sent to all the laboratories participating in this study,” says the French specialist. The cocktail was subjected to a battery of tests, on human cells in culture and on recognised animal models such as zebrafish and xenopus. The strength of this study is that it links epidemiological data with controlled laboratory tests.
On human brain cells in culture, the researchers from the University of Milan demonstrated that the cocktail causes cellular reprogramming. As such, gene activation was modified, in particular genes involved in learning disorders.
In animal research, scientists from the Museum National d’Histoire Naturelle in France and the University of Gothenburg in Sweden observed thyroid effects on amphibian and zebrafish larvae. The molecular mechanisms involved do not, however, involve exactly the same genes as those in human cells. “This highlights the fact that, even if physiological traits, in particular disruption of the nervous system, are conserved among vertebrates, the genes involved may be different between aquatic models and mammals,” explains Jean-Baptiste Fini.
Risk calculation
Together, these data contribute to a body of scientific evidence demonstrating the risk of exposure to these endocrine disruptors during the prenatal phase – even at doses accepted by current regulations.
But the great power of this study lies in the risk analysis of the cocktail of molecules. “This is a very innovative and complex approach developed by Chris Gennings, a statistician from Mount Sinai,” he explains. Using the experimental data, she was able to calculate the risk of the mixture and predict a threshold above which the children would have been protected from cognitive impairment.
“If we had used these doses to control chemicals in everyday products, we would have prevented 57% of women from being exposed to dangerous doses,” summarises the French specialist.
This research comes at a time of regulatory change in Europe. Last April, the European Commission published a roadmap for banning thousands of dangerous substances in consumer products by 20303. The inclusion of products on this future blacklist is a crucial issue for regulatory science, and the consideration of endocrine disruptors will be central to it. The approach devised by the European consortium could contribute to this.
“We hope that our work will help regulatory science to address the problem in order to better protect the public,” says Jean-Baptiste Fini.
