EDC-Mix Risk policy brief

Key messages on the risks of exposure to mixtures of endocrine disrupting chemicals

Safe chemicals for future generations

EDC-MixRisk is an EU project designed to ultimately lead to a safer environment for our children, an environment where the next generation can grow old without their quality of life being threatened by environmental chemicals or their mixtures.

The endocrine disrupting properties of chemicals, and mixtures thereof, have become a global concern. A normally functioning healthy endocrine system is essential for our ability to reproduce and develop. Endocrine disrupting chemicals (EDCs) are linked to serious health problems such as diabetes, obesity, neurodevelopmental disorders and reproductive problems. The fact that we are exposed to complex mixtures of EDCs is of particular concern.

EDC-MixRisk is an EU Horizon 2020 research project that studied the effects of prenatal exposure to mixtures of suspected EDCs on the development and health in children. Our work emphasises potential effects of EDC mixtures during foetal development and provides new tools and approaches for mixture risk assessment.

Key findings

  • Chemicals identified in pregnant women within the general population originated from different sources and application areas which are currently regulated by different pieces of European Union legislations.
  • Epidemiological analysis showed that prenatal exposure to mixtures of EDCs was associated with various effects in children’s health and development. Some effects were sex specific.
  • The tested mixtures affected hormone-regulated and disease-relevant outcomes in a variety of experimental models at the same concentrations found in the pregnant women.
  • Applying our novel whole mixture approach indicates a higher risk for children compared to risk estimated by current methods based on a single compound assessment.

Read the full EDC-MixRisk policy brief on edcmixrisk.ki.se, 2019.
Read the press release, 26 March, 2019.

Why are ObGyns Talking Toxins ?

Let’s make environmental health part of health care

Doctors from 125 countries want policies to prevent exposure to toxic chemicals

Produced for PRHE by Susan Lamontagne, Public Interest Media Group, for the International Federation of Gynecology and Obstetrics (FIGO) XXI World Congress on September 30, 2015.

Why are Doctors Talking Toxins ?

And how to reduce exposure to toxic chemicals worldwide ?

It’s time to shift the burden of proof, from scientists, back to the chemical industry

Video published on 5 June 2019, by UCSF Program on Reproductive Health and the Environment.

The effects of an EDCs cocktail of BPA + DES + NP

Analysis of individual and combined estrogenic effects of bisphenol, nonylphenol and diethylstilbestrol in immature rats with mathematical models

2019 Study Abstract

Background
Traditional toxicological studies focus on individual compounds. However, this single-compound approach neglects the fact that the mixture exposed to human may act additively or synergistically to induce greater toxicity than the single compounds exposure due to their similarities in the mode of action and targets. Mixture effects can occur even when all mixture components are present at levels that individually do not produce observable effects. So the individual chemical effect thresholds do not necessarily protect against combination effects, an understanding of the rules governing the interactive effects in mixtures is needed. The aim of the study was to test and analyze the individual and combined estrogenic effects of a mixture of three endocrine disrupting chemicals (EDCs), bisphenol A (BPA), nonylphenol (NP) and diethylstilbestrol (DES) in immature rats with mathematical models.

Method
In the present study, the data of individual estrogenic effects of BPA, NP and DES were obtained in uterotrophic bioassay respectively, the reference points for BPA, NP and DES were derived from the dose-response ralationship by using the traditional no observed adverse effect (NOAEL) or lowest observed adverse effect level (LOAEL) methods, and the benchmark dose (BMD) method. Then LOAEL values and the benchmark dose lower confidence limit (BMDL10) of single EDCs as the dose design basis for the study of the combined action pattern. Mixed prediction models, the 3 × 2 factorial design model and the concentration addition (CA) model, were employed to analyze the combined estrogenic effect of the three EDCs.

Results
From the dose-response relationship of estrogenic effects of BPA, NP and DES in the model of the prepuberty rats, the BMDL10(NOAEL) of the estrogenic effects of BPA, NP and DES were 90(120) mg/kg body weight, 6 mg/kg body weight and 0.10(0.25) μg/kg body weight, and the LOAEL of the the estrogenic effects of three EDCs were 240 mg/kg body weight, 15 mg/kg body weight and 0.50 μg/kg body weight, respectively. At BMDL10 doses based on the CA concept and the factorial analysis, the mode of combined effects of the three EDCs were dose addition. Mixtures in LOAEL doses, NP and DES combined effects on rat uterine/body weight ratio indicates antagonistic based on the CA concept but additive based on the factorial analysis. Combined effects of other mixtures are all additive by using the two models.

Conclusion
Our results showed that CA model provide more accurate results than the factorial analysis, the mode of combined effects of the three EDCs were dose addition, except mixtures in LOAEL doses, NP and DES combined effects indicates antagonistic effects based on the CA model but additive based on the factorial analysis. In particular, BPA and NP produced combination effects that are larger than the effect of each mixture component applied separately at BMDL doses, which show that additivity is important in the assessment of chemicals with estrogenic effects. The use of BMDL as point of departure in risk assessment may lead to underestimation of risk, and a more balanced approach should be considered in risk assessment.

References

  • Full study (free access) : Analysis of individual and combined estrogenic effects of bisphenol, nonylphenol and diethylstilbestrol in immature rats with mathematical models, Environmental health and preventive medicine, NCBI PubMed PMC6515622, 2019 May 13.
  • Image credit Helena Yankovska.
DES DiEthylStilbestrol Resources

Endocrine disruptors have an impact on reproduction for several generations

Endocrine disruptors transgenerationally alters pubertal timing through epigenetic reprogramming of the hypothalamus

2019 Study Abstract

Endocrine disruptors are a rising concern for public health due to their ubiquitous presence affecting reproductive development throughout generations.

We aim at studying the transgenerational effect of an EDC mixture on female sexual development and reproduction.

Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butylparaben and the analgesic Acetaminophen. Doses were in the human exposure range (μg/kg).

Sexual development and reproductive parameters (vaginal opening, GnRH secretion, estrous cyclicity and folliculogenesis) were studied from F1 to F3 generations. Maternal behavior was measured from F0 to F2 generations. At PND21, mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis (RNAseq, RT-PCR) as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes.

The results show multiple multi- and transgenerational effects after ancestral EDC exposure. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles, decreased GnRH interpulse interval and altered folliculogenesis, no such changes were detected in F1 animals. These alterations were accompanied with transcriptional and histone posttranslational modifications of key hypothalamic genes involved in puberty and reproduction. We observed a downregulation of estrogen signaling (Esr1), genes involved in the GnRH network (Kisspeptin, Grin2d, Tac3R), maternal behavior (Th, Oxt, Avp, Drd1, Drd2) and stress responsiveness (Nr3c1). Upregulated gens involved glucocorticoid activity (Crh) and metabolism (Pomc, Cart). Concomitantly with transcriptional levels, while downregulated genes present higher levels of repressive histone marks (H3K9me3, H3K27me3) and decreased levels of activational histone marks (H3K4me3, H3K9ac), upregulated genes present the opposite pattern. Such histone marks related to changes in the polycomb/thritorax group of protein balance, involved in the control of female puberty. F1 and F2 females displayed decreased licking while spending more time resting alone. F1 RNAseq showed a reduction in Th, Drd1 and Drd2 mRNA expression. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis.

In conclusion, exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development and reproduction throughout epigenetic reprogramming of the hypothalamus. While not yet clear, such effects could be mediated by alterations of maternal behavior caused by exposure to the first generation.

ReferenceImage.

DES and the GENES

Nearly half of (Italian) playgrounds tested contaminated by pesticide(s)

Pesticide contamination and associated risk factors at public playgrounds near intensively managed apple and wine orchards

2019 Study Abstract

Background
Pesticide levels are generally monitored within agricultural areas, but are commonly not assessed at public places. To assess possible contamination of non-target areas, 71 public playgrounds located next to intensively managed apple and wine orchards were selected in four valleys of South Tyrol (northern Italy). Further, the impact of environmental site characteristics on the number and concentration of pesticides was assessed. Grass samples from the selected playgrounds were collected and screened for 315 pesticide residues using standard gas chromatography and mass spectrometry.

Results
Nearly half of the playgrounds (45%) were contaminated by at least one pesticide and a quarter (24%) by more than one. Eleven of the 12 different detected pesticides are classified as endocrine-active substances including the insecticide phosmet and the fungicide fluazinam showing the highest concentrations (0.069 and 0.26 mg kg−1, respectively). Additionally, one disinfectant and one preservation agent was found. Playgrounds in Venosta valley were most often contaminated (76% of all investigated playgrounds), highest concentrations were found in the Low Adige (2.02 mg kg−1). Pesticide concentrations were positively associated with areal proportion of apple orchards in the surroundings, the amount of rainfall and wind speed. In contrast, increasing global irradiance, opposite wind direction, increasing distance to agricultural sites and high wind speeds when pesticide application was not allowed were associated with decreasing pesticide contamination.

Conclusion
This study is among the first investigating pesticide contamination of public playgrounds together with environmental factors in areas with pesticide-intensive agriculture at the beginning of the growing season. It is likely that playgrounds will be affected by more pesticides and higher concentrations over the course of the crop season. The result, that the majority of the detected pesticides are classified as endocrine active is worrisome as children are especially vulnerable. Hence, we recommend that pesticide risk assessments should better include protection measures for non-target areas.
Image Antonio Thomás Koenigkam Oliveira.

PFCs chemicals impact young men fertility, Endocrine Society reports

Endocrine Disruption of Androgenic Activity by Perfluoroalkyl Substances: Clinical and Experimental Evidence, 2019

Perfluoroalkyl compounds (PFCs) are a class of organic molecules that are used in many everyday products such as oil and water repellents, coatings for cookware, carpets, and textiles.

The crucial emerging role of PFCs as pollutants of water, soil, and air and their persistent level in males warrant for more investigation on the mechanisms of PFC toxicity in humans.

There is a new reason to be concerned about toxic chemicals used in nonstick pans, waterproof products, and firefighting foam: PFCs impair male reproductive health, according to a recent study, the intercept reports.

Abstract

Background
Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern.

Objective
To investigate the relationship between PFC exposure and male reproductive health.

Design
This study was performed within a screening protocol to evaluate male reproductive health in high schools.

Patients
This is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 nonexposed controls.

Main Outcome Measures
Anthropometrics, seminal parameters, and sex hormones were measured in young males from exposed areas compared with age-matched controls. We also performed biochemical studies in established experimental models.

Results
We found that increased levels of PFCs in plasma and seminal fluid positively correlate with circulating testosterone (T) and with a reduction of semen quality, testicular volume, penile length, and anogenital distance. Experimental evidence points toward an antagonistic action of perfluorooctanoic acid on the binding of T to androgen receptor (AR) in a gene reporter assay, a competition assay on an AR-coated surface plasmon resonance chip, and an AR nuclear translocation assay.

Discussion
This study documents that PFCs have a substantial impact on human health as they interfere with hormonal pathways, potentially leading to male infertility.

EU Parliament calling for the EU Commission to stop dithering and start acting on endocrine disruption

Endocrine disruptors drop the curtain on this European Parliament

On Thursday (18 April), the European Parliament adopted a non-binding resolution asking the European Commission to ensure a higher level of protection against endocrine disruptors (EDCs) by making a legislative proposal on the matter no later than June 2020.

It passed with 447 votes in favour, 14 against and 41 abstentions, and was actually the last text to be dealt with by this Parliament.

MEPs proposed treating EDCs or potential EDCs on an equal footing with substances classified as carcinogenic, mutagenic or toxic for reproduction, the so-called CMR substances prohibited in EU cosmetics legislation.

EDCs are a class of chemicals commonly found throughout our environment in children’s products, food containers, personal care products, pesticides and furniture. These hazardous substances alter the functioning of the hormonal system, having a negative effect on the health of humans and animals.

Close to 800 chemicals are known or suspected to be capable of interfering with hormone receptors, hormone synthesis or hormone conversion, according to a report drafted in 2012 by the United Nations Environment Programme (UNEP) and the World Health Organisation (WHO).

The EU started discussing the issue as early as 1996 and recognised EDCs as a health and environmental hazard in its “Community Strategy for endocrine disruptors” adopted by the Commission in December 1999.

The EU executive revamped interest in the topic last November publishing a new strategy for endocrine disruptors and launching a comprehensive screening of the legislation applicable to EDCs through a fitness check.

According to the lawmakers, the response is so far not adequate to the health threat, as the EU framework for EDCs suggested by the Commission in November lacks both a concrete action plan to minimise exposure to EDCs and a timeline for the next steps to move forward.

Plenary debate

Representing the EU executive before the plenary, Violeta Bulc defended the EU efforts:

“We can be proud of the progress we have achieved since there, we are recognised as one of the global leaders in dealing with these substances.”

“However, this is not enough: EDCs remain today a global challenge and a source of concern for many citizens,”

she said.

She added that the Commission adopted its communication in November in order to step up the EU approach and that the cross-cutting fitness check should be finalised in the first half of 2020, followed by a 12-week-long public consultation.

Before the end of the year, the Commission will also organise the first annual meeting of stakeholders and the launch of a new web portal, as part of the comprehensive set of actions to achieve the objectives included in the communication.

Although the resolution was backed by all the political groups within the Parliament, the European People’s Party (EPP) criticised a sort of “ideological hysteria” on EDCs and, in particular, the attempt of putting on the same level suspected and proven EDCs.

“This goes too far, goes too quickly and it’s not based on scientific evidence,”

said centre-right British MEP Julie Girling.

Green and liberal lawmakers strongly criticised the definition of EDCs included in the Commission strategy, as it seems to apply only to pesticides and other plant production products.

“Now we know that 80% of exposure comes through the food, so EDCs should be banned in all of the materials in contact with food but also in cosmetics and toys,”

said Belgian liberal Frédérique Ries.

Strong political signal

EURACTIV asked Prof. Barbara Demeneix, chair of Endocrine-Disrupting Chemicals Task Force at Endocrine Society and among the authors of a scientific report on EDCs commissioned by the Parliament’s PETI committee published last March, for her thoughts.

She hailed the call to take concrete action to regulate endocrine disruptors, which are so prevalent in our daily lives.

According to the scientist, the Parliament has sent a strong political signal to both European ministers and the Commission with the adoption of this resolution by a clear cross-party consensus.

“Their call for clear and prompt EU actions is fully justified by the available science-based evidence of increasing damage to public health and it can no longer be ignored by the EU and other countries,”

Demeneix said.

Asked about the Perfluoroalkylated substances (PFAS), she said that the topic is particularly worrying, as several thousand of them exist and only a couple are banned.

“The fact that these substances interfere with thyroid hormone homeostasis and affect immune responses is clearly demonstrated, both by epidemiology and laboratory tests,”

she concluded.

Reference.

Glyphosate could be altering the wildlife and organisms at the base of the food chain

Glyphosate impairs learning in mosquito larvae (Aedes aegypti) at field-realistic doses

Glyphosate-based herbicides are not supposed to harm wildlife. But lab studies – such as this – keep finding otherwise…

What’s the world’s most widely used herbicide doing to tiny critters? asks Environmental Health News. Image Darron Birgenheier.

2019 Study Abstract

Glyphosate is the most widely used herbicide in the world. In the last years, the number of studies revealing deleterious effects of glyphosate on non-target species has been increasing. We studied the impact of glyphosate at field-realistic doses on learning in mosquito larvae (Aedes aegypti). Larvae of A. aegypti live in small water bodies and perform a stereotyped escape response when a moving object projects its shadow on the water surface. Repeated presentations of an innocuous visual stimulus induce a decrease in response due to habituation, a non-associative form of learning. In this study, different groups of larvae were reared in water containing different concentrations of glyphosate that can be found in the field (50 µg/l, 100 µg/l, 210 µg/l and 2 mg/l). Larvae reared in a glyphosate solution of 2 mg/l could complete their development. However, glyphosate impaired habituation. The higher the dose, the stronger the deleterious effects on learning abilities. This protocol opens new avenues to further studies aiming at understanding how glyphosate affects non-target organisms as insects. Habituation in mosquito larvae could serve as a parameter for testing the impact of pollutants in water bodies.

Endocrine Disruptors : from Scientific Evidence to Human Health Protection

The European Parliament publishes new report on endocrine disrupting chemicals, 2019

The European Society of Endocrinology welcomes the new European Parliament report on Endocrine Disrupting Chemicals (EDCs) written by Prof Barbara Demeneix of the Muséum National d’Histoire Naturelle in Paris, France and member of the ESE EDC Working Group and Dr Rémy Slama, INSERM (National Institute of Health and Medical Research), Grenoble, France.

Abstracts

Presentation

This study, commissioned by the PETI Committee of the European Parliament, presents the scientific knowledge regarding the health effects of endocrine disruptors, a class of hazards recognized in EU regulation since 1999. This report reviews the scientific evidence regarding the concept of endocrine disruption, the extent of exposure, associated health effects and costs. The existing relevant EU regulations are discussed and recommendations made to better protect human health.

1.1.2 The drug diethylstilboestrol (DES)

DES was developed as a synthetic oestrogen. It was prescribed from the 1940s onwards. Prescriptions were based on the erroneous assumption that it could prevent miscarriage and other pregnancy complications, which was shown to be wrong in 1953. In 1971, the USA Food and Drug Administration (FDA) advised against its use due to vaginal cancers occurrence in girls born to mothers who had used DES, while this cancer usually develops post-menopause. DES was banned in the Netherlands in 1975 and in France and Spain in 1977. Women who took DES have a slightly higher risk of breast cancer, but the most striking effects are seen on offspring exposed during pregnancy. Epidemiology shows in utero DES exposure to be linked not only to vaginal cancer in daughters of exposed women, but also to reproductive tract disorders, infertility and higher rates of spontaneous abortion. Sons display higher rates of genital abnormalities, and increased risks of prostate cancer; in addition, an increased risk of testicular cancer has been suggested. Importantly, effects such as increased risk of malformations of the male genitalia and possibly attention deficit and hyperactivity disorders (ADHD) are also observed in the grandchildren of DES-prescribed women.

In contrast to DDT, which is persistent in the body, DES is quickly eliminated, showing that chemicals can exert effects long after they disappeared from the organism, possibly on successive generations. There are biological mechanisms whereby the organism could keep a memory of exposure. One possibility relates to adverse effects that can be traced to epigenetic modifications. Work on animal models shows that certain DES impacts could result from epigenetic effects on the germ cells (the sperm and egg cells) forming in the in utero DES exposed foetuses).

Both DDT and DES provide examples of compounds able to interact with the endocrine system in humans or wildlife species (DES was designed to mimic a natural hormone, oestrogen; DDT and its metabolites were found to alter hormone production, mimic oestrogen and block androgen actions) and to cause adverse effects. They resonate with a concept developed in 1.7 and 1.9: the Developmental origin of Health and Disease (DOHaD), underlining foetal life as a determinant factor for child and adult health.

The scientific report, commissioned by the Parliament’s Committee on Petitions, provides an excellent overview of the severe threat EDCs pose for EU society and highlights the many shortcomings of current EU policies and legislation. Amongst the many proposed regulatory measures, it urges the European Union to rapidly develop a set of trans-sectorial and harmonised regulations to minimise human and environmental exposure to EDCs. As discussed in the report, based on an extensive literature review, EDCs or suspected EDCs are currently present in all media (water, diet, food contact materials, cosmetics…) and most EU citizens have dozens of (suspected) EDCs in their bodies.

In addition to improved regulatory measures, the report stresses the importance of speeding up test development to effectively identify EDCs and calls for additional research to address the many knowledge gaps in this relatively new scientific area.

These calls for additional regulation and research at the EU level are in line with a recent ESE Statement in response to the disappointing European Commission Communication on EDCs from 7 November 2018, which in ESE’s view lacks ambition to effectively tackle the many challenges in this area.

DES DiEthylStilbestrol Resources