Endocrine-Disrupting Chemicals: the UNEP and WHO Assessment

Effects of human exposure to hormone-disrupting chemicals examined in landmark UN report

State-of-the-Science-of-Endocrine disrupting chemicals
Effects of human exposure to hormone-disrupting chemicals examined in landmark UN report.

An assessment of the state of the science of endocrine disruptors prepared by a group of experts for the United Nations Environment Programme (UNEP) and WHO

This document provides the global status of scientific knowledge on exposure to and effects of endocrine disrupting chemicals (EDCs).

The work is based on the fact that endocrine systems are very similar across vertebrate species and that endocrine effects manifest themselves independently of species. The effects are endocrine system related and not necessarily species dependent. Effects shown in wildlife or experimental animals may also occur in humans if they are exposed to EDCs at a vulnerable time and at concentrations leading to alterations of endocrine regulation. Of special concern are effects on early development of both humans and wildlife, as these effects are often irreversible and may not become evident until later in life. The third and final chapter of this document discusses exposure of humans and wildlife to EDCs and potential EDCs.

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Histological and ultrastructural changes induced by diethylstilbestrol on renal tissues

The effects of diethylstilbestrol administration on rat kidney

lab-rats image
Diethylstilbestrol administration showed harmful effects on rats renal tissues and altered their morphology with an increased number of apoptotic cells. Lab rats via Tatiana Bulyonkova.

2013 Study Abstract

OBJECTIVE:
To assess the histological and ultrastructural changes that can be induced by diethylstilbestrol (DES) on renal tissues using histological, immunohistochemical, and ultrastructural methods.

METHODS:
Thirty adult male Wistar rats were divided into 3 groups (10 rats each): Group 1 – control; Group 2 – received DES at a dose of 60 ug/kg/day, dissolved in 0.1 ml corn oil for 20 days; and Group 3 – received the same dose of DES for 50 days by oral gavage. The renal tissues were studied histologically, immunohistochemically (using an anti-BCL2-associated X protein [BAX protein] antibody), and ultrastructurally. This study was carried out at the Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between December 2011 and December 2012.

RESULTS:
The DES administration for 50 days caused noticeable degeneration, and alteration of the morphology of the renal tissues in the form of damaged renal tubules with loss of the brush border of the proximal convoluted tubules and increased cellularity of the glomeruli. In addition, there was a significant increase in BAX protein expression based on immunoreactivity, and in renal tubules, as well as glomerular cells. These changes were less obvious after 20 days of treatment.

CONCLUSION:
Non-steroidal, synthetic estrogens showed harmful effects on the renal tissues and altered their morphology with an increased number of apoptotic cells, and these changes were duration dependent.

Sources and more information
  • The effects of diethylstilbestrol administration on rat kidney. Ultrastructural study, Saudi Med J. 2013 Nov;34(11):1114-24.. NCBI PMID: 24252888.
    Full study: scribd, doc/280424627.
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Prenatal Diethylstilbestrol Exposure and Risk of Uterine Leiomyomata

First-trimester DES exposure may be associated with an increased risk of uterine leiomyomata

image of Uterine Leiomyomata
These 2013 results suggest that first-trimester DES exposure may be associated with an increased risk of uterine leiomyomata. The association was highest for women exposed to DES in the first trimester, which corresponds to early stages of fetal mullerian development. Image by Nephron via Wikimedia Commons.

2013 Study Abstract

Previous studies evaluating the association of prenatal exposure to diethylstilbestrol (DES), a potent endocrine disruptor, with incidence of uterine leiomyomata (UL) have had conflicting results. We evaluated the association between prenatal DES exposure and incident UL in women in the Nurses’ Health Study II from 1989 to 2009. Women were aged 25–42 years at enrollment and had a prenatal exposure window corresponding to DES use. The analytical sample was larger than previous studies and included 102,164 premenopausal women with intact uteri, no prior history of UL or cancer, and prenatal DES exposure. Multivariable-adjusted Cox proportional hazard models were used to estimate the relationship between DES exposure and UL risk. During 1,273,342 person-years of follow-up, there were 11,831 incident cases of UL. Women with prenatal exposure to DES had a higher incidence of UL compared with unexposed women, with an adjusted hazard ratio of 1.12 (95% confidence interval: 0.98, 1.27). Risk was strongest for women exposed to DES in the first trimester, when exposure corresponds to early stages of fetal Müllerian development (adjusted hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). These results suggest that first-trimester DES exposure may be associated with an increased risk of UL, but they must be interpreted with concern for detection and recall biases.

2013 Study Conclusions

We found a small positive association between DES exposure and risk of UL. Among women reporting trimester of DES initiation, the association was strongest when DES was initiated in the first trimester. These results should be interpreted with caution because of the possibility of recall bias in both participants and their mothers, as well as detection bias due to increased gynecological surveillance in exposed women. Because DES-exposed women are aging out of leiomyomata research, the possibility for future study of this association is limited. However, studies of DES exposure and outcomes of concern may provide a framework for other similarly acting estrogenic endocrine disruptors, such as Bisphenol A and dioxin.

Sources and Full Study
  • Prenatal Diethylstilbestrol Exposure and Risk of Uterine Leiomyomata in the Nurses’ Health Study II, Oxford Journals, American Journal of Epidemiology, doi: 10.1093/aje/kwt250, 179 (2): 186-191, October 18, 2013.
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Les infiltrés: au coeur des laboratoires pharmaceutiques

2013: Sophie Bonnet enquête sur les laboratoires pharmaceutiques

Les laboratoires pharmaceutiques sont habituellement fermés aux médias. L’équipe de journalistes du magazine de France 2 est parvenue à pénétrer cette industrie, souvent décrite comme l’un des plus puissants lobbys au monde. Documentaire de Sophie Bonnet diffusé le 22 février 2013 sur France 2.

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Ben Goldacre discusses Clinical Data Transparency at the Clinical Data Live!

Quanticate hosted a free symposium, which took place at the Royal College of Surgeons, September 2013

Dr Ben Goldacre, author of ‘Bad Pharma‘ presented a keynote speech at the Clinical Data Live! symposium. In this video hear Ben Goldacre present ‘ALLTrials: Transparency is moving forwards, industry can benefit from doing the right thing‘. This symposium was hosted by Quanticate who support Pharma and Biotech companies with statistical consultancy services.

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What does the black triangle mean?

The black triangle is used in all EU Member States to identify medicines under additional monitoring

The European Union (EU) has introduced a new process to label medicines that are being monitored particularly closely by regulatory authorities. These medicines are described as being under ‘additional monitoring‘.

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Does Cancer start in the Womb? Predisposition to Breast Cancer due to in utero Exposure to DES, EDCs

Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood

BPA-and-DES molecular images
Fetal and neonatal exposures to EDCs cause persistent alterations in the mammary glands of rodents, including pre- and neoplastic lesions, long after the exposure ended.

Abstract

We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to Diethylstilbestrol (DES)  resulted in clear cell carcinoma of the vagina and breast cancer.

In this review the effects of the endocrine disruptor bisphenol A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer..

Excerpts

“… Breast cancer risk at 40 years of age and older is 2.5 fold higher in DES-exposed women than in unexposed women of the same age. In rats, prenatal exposure to DES also resulted in increased mammary cancer incidence during adulthood when these animals were challenged with the chemical carcinogen dimethylbenzanthracene (DMBA) at puberty. DES was administered to rats at pharmacological doses to mimic its medical use… ”

“… The causal link between fetal exposure to estrogens and the development of breast cancer that was first suggested by epidemiologists has now been confirmed by the increased risk to develop breast cancer during adulthood of women exposed to DES during their fetal life. Fetal and neonatal exposures to EDCs cause persistent alterations in the mammary glands of rodents, including pre- and neoplastic lesions, long after the exposure ended. In the case of BPA, mammary neoplasias may have their origin in the altered mammary morphogenesis that occurs during fetal and neonatal exposure. The data obtained from laboratory animals support the extrapolation that exposure to BPA and other xenoestrogens during organogenesis in humans contributes to the increase in the incidence of breast cancer observed over recent decades….”

Sources and full study
  • Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors, J Mammary Gland Biol Neoplasia. PMID: 23702822, 2013 Jun;18(2):199-208. doi: 10.1007/s10911-013-9293-5. Epub 2013 May 24.
  • Full study 18(2), 199–208. doi:10.1007/s10911-013-9293-5 PMC3933259, 2013 Jun.
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Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects

DES usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption

DES legacy of heritable health effects ianalysis image
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

Abstract

Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to 1970s in hopes of preventing miscarriage in pregnant women. Decades later, DES is known to enhance breast cancer risk in exposed women, and cause a variety of birth related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound which demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren.

Summary

The legacy of the adverse effects that stem from DES administration to pregnant women in the 1950s to 1970s has not completely formed. The male and female offspring of those women have reported significant fertility, cancer, and birth-related outcomes, but the cancer outcomes are not completely understood, with few exceptions (CCA and breast cancer in women over 40 yr old). Information on DES mothers and daughters, in addition to substantial animal data, earned DES a place in the First Annual Report on Carcinogens, a critical review of carcinogenic compounds produced by the National Toxicology Program, in 1980 and was noted by the International Agency for Research on Cancer in their Monographs (IARC 1974). As the male and female offspring of those women age, the overall effect of DES on reproductive cancers will be better understood. Even more important to understand is the potential effect of this endocrine disruptor and carcinogen on the 3rd generation offspring who were not directly exposed, but may be affected in a heritable way through estrogen reprogramming and DNA modification. Further research is needed to indicate the mechanisms of action on the target tissues, so that future pharmaceuticals/environmental estrogen mimics will avoid these pathways, leading to healthier future generations.

Sources and full study
  • Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects, NCBI PMID: 23897597, Birth Defects Res C Embryo Today.;99(2):134-46. doi: 10.1002/bdrc.21035, 2013 Jun.
  • Full text: PMCID: PMC3817964, NIHMSID: NIHMS520381, doi: 10.1002/bdrc.21035, Nov 5, 2013.
      • INTRODUCTION
      • DES EXPOSURE MAGNITUDE
      • HEALTH EFFECTS
      • Effects in DES Mothers
      • Effects in DES Daughters
      • Effects in DES Sons
      • EFFECTS OF DES IN A 3rd GENERATION
      • GENE CHANGES AND PROPOSED MECHANISMS OF ACTION
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Champions of Medicine’s next Revolution

Alan Cassels at TEDx Victoria 2013

A drug policy researcher for the University of Victoria, Alan Cassels is a known for having a knack for finding and describing the chasm between what the market says and what science does in modern healthcare. Over the past two decades Cassels has spent much of his research energy studying clinical research and the marketing tactics of the pharmaceutical industry, turning some of that research into journalism and books, including international best-sellers Selling Sickness: How the World’s Biggest Pharmaceutical Companies are Turning us All into Patients and The ABC’s of Disease Mongering: An Epidemic in 26 Letters.

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Conséquences pour les petits-enfants DES – Etude Distilbène trois générations 2013-2014

Deux PDF (4 – 10 pages) à télécharger

3ème Génération: “petits-enfants DES

image de Resultats-Etude-DES-3
Regardez le résumé conséquences pour les petits-enfants DES de l’étude Réseau DES France Distilbène trois générations 2013-2014 sur Flickr. Téléchargez le PDF 4 pages résultats étude 2013 et le PDF 10 pages résultats en détail 2014.

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Le Distilbène DES, en savoir plus