Anti-inflammatory drugs and contraceptive pills polluting our waters – A 20year systematic review

Monitoring, sources, receptors, and control measures for three European Union watch list substances of emerging concern in receiving waters, 2017

2017 Study Abstract

Pollution of European receiving waters with contaminants of emerging concern (CECs),

  1. such as with 17-beta-estradiol (a natural estrogenic hormone, E2),
  2. along with pharmaceutically-active compounds diclofenac (an anti-inflammatory drug, DCL)
  3. and 17-alpha-ethynylestradiol (a synthetic estrogenic hormone, EE2))

is a ubiquitous phenomenon. These three CECs were added to the EU watch list of emerging substances to be monitoring in 2013, which was updated in 2015 to comprise 10 substances/groups of substances in the field of water policy.

A systematic literature review was conducted of 3952 potentially relevant articles over period 1995 to 2015 that produced a new EU-wide database consisting of 1268 publications on DCL, E2 and EE2. European surface water concentrations of DCL are typically reported below the proposed annual average environmental quality standard (AA EQS) of 100ng/l, but that exceedances frequently occur. E2 and EE2 surface water concentrations are typically below 50ng/l and 10ng/l respectively, but these values greatly exceed the proposed AA EQS values for these compounds (0.04 and 0.035ng/l respectively). However, levels of these CECs are frequently reported to be disproportionately high in EU receiving waters, particularly in effluents at control points that require urgent attention.

Overall it was found that DCL and EE2 enter European aquatic environment mainly following human consumption and excretion of therapeutic drugs, and by incomplete removal from influent at urban wastewater treatment plants (WWTPs). E2 is a natural hormone excreted by humans which also experiences incomplete removal during WWTPs treatment. Current conventional analytical chemistry methods are sufficiently sensitive for the detection and quantification of DCL but not for E2 and EE2, thus alternative, ultra-trace, time-integrated monitoring techniques such as passive sampling are needed to inform water quality for these estrogens. DCL appears resistant to conventional wastewater treatment while E2 and EE2 have high removal efficiencies that occur through biodegradation or sorption to organic matter.

There is a pressing need to determine fate and behaviour of these CECs in European receiving waters such as using GIS-modelling of river basins as this will identify pressure points for informing priority decision making and alleviation strategies for upgrade of WWTPs and for hospital effluents with advanced treatment technologies. More monitoring data for these CECs in receiving waters is urgently needed for EU legislation and effective risk management

Environmental impact of estrogens on human, animal and plant life: A critical review

Water Pollution Caused by Birth Control Poses Dilemma – Environment International, 2017

2017 Study Abstract

Background
Since the inception of global industrialization, steroidal estrogens have become an emerging and serious concern. Worldwide, steroid estrogens including estrone, estradiol and estriol, pose serious threats to soil, plants, water resources and humans. Indeed, estrogens have gained notable attention in recent years, due to their rapidly increasing concentrations in soil and water all over the world. Concern has been expressed regarding the entry of estrogens into the human food chain which in turn relates to how plants take up and metabolism estrogens.

Objectives
In this review we explore the environmental fate of estrogens highlighting their release through effluent sources, their uptake, partitioning and physiological effects in the ecological system. We draw attention to the potential risk of intensive modern agriculture and waste disposal systems on estrogen release and their effects on human health. We also highlight their uptake and metabolism in plants.

Methods
We use MEDLINE and other search data bases for estrogens in the environment from 2005 to the present, with the majority of our sources spanning the past five years. Published acceptable daily intake of estrogens (μg/L) and predicted no effect concentrations (μg/L) are listed from published sources and used as thresholds to discuss reported levels of estrogens in the aquatic and terrestrial environments. Global levels of estrogens from river sources and from Waste Water Treatment Facilities have been mapped, together with transport pathways of estrogens in plants.

Results
Estrogens at polluting levels have been detected at sites close to waste water treatment facilities and in groundwater at various sites globally. Estrogens at pollutant levels have been linked with breast cancer in women and prostate cancer in men. Estrogens also perturb fish physiology and can affect reproductive development in both domestic and wild animals. Treatment of plants with steroid estrogen hormones or their precursors can affect root and shoot development, flowering and germination. However, estrogens can ameliorate the effects of other environmental stresses on the plant.

Conclusions
There is published evidence to establish a causal relationship between estrogens in the environment and breast cancer. However, there are serious gaps in our knowledge about estrogen levels in the environment and a call is required for a world wide effort to provide more data on many more samples sites. Of the data available, the synthetic estrogen, ethinyl estradiol, is more persistent in the environment than natural estrogens and may be a greater cause for environmental concern. Finally, we believe that there is an urgent requirement for inter-disciplinary studies of estrogens in order to better understand their ecological and environmental impact.

Estrogenic activity of water, sediment, and fish bile of the Pearl River, Southern China

Evaluation of estrogenic activity in the Pearl River by using effect-directed analysis

Abstract

This study investigated estrogenic activity of water, sediment, and fish bile of the Pearl River in southern China by effect-directed analysis based on in vitro yeast screen assay and chemical analysis.

Results showed higher estradiol equivalents (EEQ) for surface water in dry season than in wet season. Simple risk assessment suggested that high estrogenic risk would be expected in Shima River and Danshui River receiving discharge of effluents from cities in the region. Fractionation and effect-directed analysis showed that estrogenic activity mainly occurred in relatively polar fractions of surface water.

Evaluation of estrogenic activity in the Pearl River by using effect-directed analysis, Environmental science and pollution research international, NCBI PubMed PMID: 27522204, 2016 Nov.

Pearl River by toyohara.

Seven target estrogenic compounds

  1. bisphenol A,
  2. 4-nonylphenol,
  3. 4-tert-octylphenol,
  4. 17α-ethynyl estradiol,
  5. estrone,
  6. diethylstilbestrol,
  7. and 17β-estradiol

only accounted for part of the measured estrogenic activity, with the rest contributions from other potential estrogenic chemicals such as phenols.

Findings from this study suggest that fish in the river could be affected by those estrogenic chemicals. Proper measures should be taken to reduce the estrogenic activity in wastewaters before they are discharged into the riverine system in order to protect aquatic organisms.

Circulating Sex Hormones and Risk of Uterine Fibroids

Hormone plays previously unrecognized role in common fertility problem

image of estradiol
Elevated testosterone and estrogen levels may raise risk of uterine fibroids. test by outcast104.

Women who have high levels of both testosterone and estrogen in midlife may face a greater risk of developing benign tumors on the uterus called uterine fibroids than women with low levels of the hormones.

2015 Study Abstract

Context:
Estrogen has been implicated in the development of uterine fibroids. However, the contribution of androgen in women is unknown.

Objective:
Our objective was to assess the longitudinal relations of circulating androgens and estradiol (E2) and their joint effects to the risk of developing fibroids.

Design:
This is a 13-year longitudinal study in the Study of Women’s Health Across the Nation.

Setting:
This study was conducted in seven sites across the United States (1997–2013).

Participants:
At baseline, 3240 pre- or early peri-menopausal women with an intact uterus, ages 45–52 years were included; 43.6% completed the follow-up. There were 512 incident and 478 recurrent fibroid cases.

Exposures:
We measured near-annual time-varying serum levels of bioavailable E2 and bioavailable T, dichotomized at the median (high vs low).

Main Outcomes and Measures:
We estimated the conditional odds ratio (OR) of fibroids in the ensuing year using discrete-time proportional odds models adjusted for race/ethnicity/site, age, body mass index, menopausal stage, reproductive factors, smoking, timing of blood draw, and FSH.

Results:
Women with high T had a statistically significant increased risk of incident fibroids (OR, 1.33; 95% confidence interval [CI], 1.01–1.76; P = .04), but not recurrent fibroids. This risk was further elevated in those with high T and E2 (OR, 1.52; 95% CI, 1.07–2.17; P = .02). High E2 and T was associated with lower risk of recurrent fibroids (OR, 0.50; 95% CI, 0.26–0.96; P = .04).

Conclusions:
High T with high E2 was associated with an elevated risk of incident fibroids in midlife women who never reported fibroids before baseline. Conversely, the risk of recurrent fibroids was mitigated in women with high E2 and high T.

Sources and more information
  • Elevated Testosterone Levels May Raise Risk of Uterine Fibroids, Endocrine Society, December 15, 2015.
  • Circulating Sex Hormones and Risk of Uterine Fibroids: Study of Women’s Health Across the Nation (SWAN), Endocrine Society, doi.org/10.1210/jc.2015-2935, December 15, 2015.

The effects of both natural and synthetic hormones at extremely low doses

Fredrick Vom Saal is a Professor of Biological Sciences, University of Missouri

lab-tests
A leading researcher in the field of developmental biology, Vom Saal has studied the effects of both natural and synthetic hormones at extremely low doses. His studies have shown that extremely low doses of hormones can permanently alter development of the reproductive system in mice. He has also studied how manmade chemicals, including plastics, can mimic hormones at extremely low doses.

You’ve said that the doses at which hormones affect the body are extremely low. Give me an example to make me understand that.

F Vom Saal:  “The issue of the amount of hormone that actually causes effects is very difficult for scientists to talk to people about because we’re dealing with numbers that are outside of the frame of reference that anybody is going to be thinking about. We see changes, profound changes, in the course of development of essentially the whole body of experimental animals, and we’re working with mice and rats, and we see these changes at fifty femtograms of the hormone per milliliter of blood. That’s 0.05 trillionths of a gram of this hormone in a milliliter of blood.”

And what sort of effect does it have?

F Vom Saal:  “We see changes in the functioning of the prostate. We see dramatic change in the sprouting of glands within the fetal prostate. We see changes in testicular sperm production. We see changes in the structure of the endocrine control region in the brain, which is accompanied by changes in sex behavior, aggression, the way these animals behave towards infants, their whole social interaction, the way they age, the time that they enter puberty, the age at which they cease reproduction. It changes their entire life history, and these changes are capable of occurring at very low levels of hormones.
I remember when we first did this and I was a post doctoral fellow, and my advisor and I looked at the hormone levels and said, “My God, these levels are so staggeringly small and the consequences are so immense it’s amazing.” Even to biologists, it’s amazing.

But what you have is the entire field of toxicology thinking of a millionth of a gram of a hormone or a chemical as being this staggeringly tiny amount, and to most people if I said there’s only a millionth of a gram of it here you’d say, “How can it do anything?” A millionth of a gram of estradiol in blood is toxic. The natural hormone is actually operating at something like a hundred million times lower than that. So when you have a physiologist thinking of a millionth of a gram, you have that physiologist thinking this is a toxic high dose. When you are raised in the field of toxicology you are looking at that from the other perspective of “My gosh, that’s such a tiny dose, it couldn’t do anything.”

So now what we have are two different fields coming into this issue and looking at a dose as either staggeringly high or staggeringly low, and it’s not surprising that there is a clash occurring with regard to dose effects.”

Continue reading the interview conducted in February 1998 by Doug Hamilton, producer of FRONTLINE’s “Fooling With Nature.”, February 1998.

Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women

Reproductive hormone levels in DES-exposed premenopausal women

menopause-lane
In this 2015 study, prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age.

2015 Study Abstract

Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones.

We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36-45 years from Massachusetts (1995-1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (β), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders.

DES-exposed women had lower mean concentrations of estradiol (pg/ml) (β=-15.6%, 95% confidence interval (CI): -26.5%, -3.2%) and inhibin B (pg/ml) (β=-20.3%, CI: -35.1%, -2.3%), and higher mean concentrations of FSH (IU/I) (β=12.2%, CI: -1.5%, 27.9%) and LH (IU/I) (β=10.4%, CI: -7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml – indicators of low ovarian reserve – were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88-18.1), respectively.

Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age.

Sources
  • Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women, Wise LA, Troisi R, Hatch EE, Titus LJ, Rothman KJ, Harlow BL, J Dev Orig Health Dis. 2015 Jun;6(3):208-16. doi: 10.1017/S2040174415000082. NCBI PMID: 25698132, Epub 2015 Feb 20. full study.
More DES DiEthylStilbestrol Resources

Estrogen responsible for more severe allergic reactions in Women

Established link between estrogen and eNOS in severe anaphylactic reactions in the female mice

NIH Study May Help Explain Gender Disparity Observed in People…

Estrogen worsens allergic reactions in mice
Airways of male (right) and female (left) mice respond differently to anaphylactic triggers. The female response is more severe, showing more accumulation of fluids and cells around the respiratory tract (arrows). Image credit @NIAIDNews.

Estradiol, a type of estrogen, enhances the levels and activity in mice of an enzyme that drives life-threatening allergic reactions, according to researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The study results may help explain why women frequently experience more severe allergic reactions compared to men. Furthermore, the results reaffirm the importance of accounting for gender in the design of animal experiments.

Anaphylaxis is an allergic reaction triggered by food, medication or insect stings and bites. Immune cells, particularly mast cells, release enzymes that cause tissues to swell and blood vessels to widen. As a result, skin may flush or develop a rash, and in extreme cases, breathing difficulties, shock or heart attack may occur. Clinical studies have shown that women tend to experience anaphylaxis more frequently than men, but why this difference exists is unclear.

In the current study, NIAID researchers found that female mice experience more severe and longer lasting anaphylactic reactions than males. Instead of targeting immune cells, estrogen influences blood vessels, enhancing the levels and activity of endothelial nitric oxide synthase (eNOS), an enzyme that causes some of the symptoms of anaphylaxis. When the researchers blocked eNOS activity, the gender disparity disappeared. In addition, giving estrogen-blocking treatments to female mice reduced the severity of their allergic responses to a level similar to those seen in males.

While the study has identified a clear role for estrogen and eNOS in driving severe anaphylactic reactions in female mice, more work is needed to see if the effects are similar in people and may be applied toward future preventive therapies.

Sources and more information

  • Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, article/S0091-6749(14)01597-8, December 29, 2014.
  • Estrogen Worsens Allergic Reactions in Mice, National Institute of Allergy and Infectious Diseases (NIAID), NIH News, Dec. 29, 2014
  • Is estrogen to blame for more severe allergic reactions in women?, medicalnewstoday, 30 December 2014.