A four-year, European Union (EU)-funded project has concluded that the health risks associated with mixtures of man-made chemicals are underestimated. In 2015, the EU’s Horizon 2020 R&D program initiated the EDC-MixRisk project to investigate how to study the effects of these real-life relevant mixtures.
The project brought together a research consortium consisting of epidemiologists, chemists, biostatisticians, medical doctors, molecular biologists, and experimental and regulatory toxicologists from 12 European universities and Mount Sinai School of Medicine, New York.
Their starting point was that man-made chemicals can create combinations of chemical mixtures to which we all are exposed during our lifespan. However, current risk assessment and management practices focus mainly on exposure to single substances. Exposure to hazardous substances, especially endocrine disrupting chemicals (EDCs), during the fetal period is of particular concern as it can lead to irreversible changes in organ and tissue development and increased susceptibility to diseases later in life.
Together, the researchers developed a novel approach based on identifying and testing EDC mixtures associated with adverse health outcomes in humans. Using epidemiology data from a Swedish cohort study of more than 2,300 pregnant women, they created reference mixtures to mimic real-life exposures at concentrations found in the pregnant women. These mixtures were then tested in various cell and animal experimental models. The toxicological data from these tests have helped to establish new methods and strategies for mixture risk assessment to better account for complex environmental exposures.
“The novel whole-mixture approach applied in EDC-MixRisk has allowed us to assess the number of mothers in the cohort that are at risk for effects in their children, effects related to growth and metabolism, neurodevelopment and sexual development,” explains Åke Bergman of the department of environmental science and analytical chemistry and coordinator of the EDC-MixRisk project at the Karolinska Institute, Stockholm.
Other research led by Giuseppe Testa at the European Institute of Oncology, Milan, used human brain organoids to directly assess the impact of such mixtures on the closest available model of the developing human brain. The work uncovered that real-life concentrations of EDCs interfere with the same regulatory networks already involved in the genetic forms of autism spectrum disorder and intellectual disability.
“This new method enables the investigation of relevant chemical exposures on equally relevant windows of sensitivity during human brain development,” says Testa.
Meanwhile, at the Centre National de la Recherche Scientifique, Paris, endocrinology expert Barbara Demeneix and her team investigated whether the mixtures interfered with brain development and growth through modulation of thyroid hormone signalling.
“Thyroid hormone is essential for brain development and children born to mothers that have insufficient thyroid hormone also have increased risk of autism spectrum disorder and IQ loss. Thyroid hormone signalling and numerous thyroid hormone dependent genes were disrupted by the mixture in the different models tested. These findings reveal a mechanism whereby brain development is affected by exposure to the chemicals at relevant human exposure levels,” she notes.
The researchers concluded these new approaches can be used to define acceptable exposure levels based on epidemiological data, or the integration of human and experimental data. They also may provide empirical support for estimating the size of a potential additional mixture assessment factor that could then be used in a chemical risk assessment. “Our whole-mixture approaches can only be used retrospectively for chemicals for which epidemiological data are available. For ‘new chemicals’ a prospective risk assessment is required,” they note.
The EDC-MixRisk project launch coincided with the results of a 2015 study from environmental and public health organizations in Europe and the United States that estimated that exposure to EDCs likely costs the EU €157 billion ($172 billion) every year in healthcare expenses and loss of earnings.
The results of that study, published in the March 2015 issue of the Journal of Clinical Endocrinology and Metabolism, concluded that exposure to EDCs is in part responsible for a range of conditions including infertility and male reproductive dysfunctions, birth defects, obesity, diabetes, cardiovascular disease, and neurobehavioral and learning disorders.
At the time, the authors believed their €157-billion estimate to be conservative as it represented 1.23% of Europe’s gross domestic product (GDP). These costs may actually be as high as €270 billion ($294 billion), or 2% of GDP, they said. In today’s prices that’s €370 billion ($414 billion).