Endocrine Disruptors: Should We Be Afraid?

Experts Provide Practical Advice to Share With Patients

Boris Hansel, MD; Patrick Fénichel, MD, PhD

Disclosures

June 14, 2017

Editor's note: The following is an edited discussion between endocrinologists Boris Hansel, MD, and Patrick Fénichel, MD, PhD, translated from French.

Boris Hansel, MD: There's a topic that has been raising a lot of questions and fueling debate and animosity: endocrine disruptors. It's a public health issue but also an ecological problem in that it concerns everyone.

Admittedly, many of us don't know much about endocrine disruptors, and it's difficult to separate fact from fiction. For physicians, this poses a problem in daily practice: What do we tell our patients when giving them health advice while at the same time avoiding phobias over endocrine disruptors? Is this a fad?

Patrick Fénichel, MD, PhD: No, I don't think it's a fad. It's a concept that needs to be put into proper historical context.

It started with American animal biologists, who observed decreased fertility in certain species, micropenises of Florida alligators, cryptorchidism (undescended testicles) in Florida panthers, and so on. In each case, they observed that the abnormality was caused by a local ecological disaster resulting from a chemical spill or the use of pesticides in agriculture or industrial chemicals.

Dr Hansel: These observations were made in animals in the 1950s, 1960s, and 1970s. What about humans?

Dr Fénichel: Physicians, pediatricians, and reproductive specialists made several observations in humans that came together and led to the concept of endocrine disruptors.

One of these was the unfortunate story of diethylstilbestrol (DES) involving girls who had been exposed in utero to this synthetic estrogen, which was prescribed from the 1950s to the 1970s to millions of women in the United States and Europe to reduce the risk for miscarriage. It caused cancers (such as vaginal cancer, which is very rare and serious), menstrual cycle abnormalities, and uterine abnormalities, such as the T-shaped uterus, all of which were tied back to exposure to this synthetic estrogen.

The public has the impression that endocrine disruptors are only industrial chemicals, but actually some are found in nature.

Dr Hansel: When reading the expert or scientific literature or newspapers, it's difficult to come up with an accurate definition of an endocrine disruptor. The simple definition is "a chemical that interferes with the hormonal system, either by increasing or blocking the manufacture of hormones or blocking their effects." Could we be more precise?

Dr Fénichel: The definition is exactly that. It's any substance—natural or synthetic—from a plant (such as soybeans or certain mycotoxins) or an industrial or agricultural chemical (such as a pesticide) that interferes in some way with the hormone regulation systems, thereby disturbing homeostasis. An important part of the definition is the potential consequences for the offspring.

Dr Hansel: The public has the impression that endocrine disruptors are only industrial chemicals, but actually some are found in nature.

Dr Fénichel: Most certainly. Some are found in nature. In certain circumstances, some of these have negative effects, but others can have beneficial effects.

An example of an endocrine disruptor with negative effects is genistein, which is found in soy. Resveratrol, the compound in tannin in good Bordeaux wines that is said to be an antioxidant and an anticancer agent, can in certain circumstances have beneficial effects. However, it interferes with the estrogenic system and other hormone receptors—so it's an endocrine disruptor.

Dr Hansel: So, substances of plant origin, synthetic substances, chemicals, medications, and so on can all be endocrine disruptors. Do any other medications, like DES, have potentially harmful effects?

Dr Fénichel: Certain medications used in endocrinology, with all of their negative side effects, could be considered endocrine disruptors. Take, for instance, a very well-known diuretic, spironolactone. It causes gynecomastia. It's an excellent example of a medication that's an endocrine disruptor.

Dr Hansel: You get the impression that there are endocrine disruptors everywhere—medications, foods, pesticides, etc. Can we do some ranking? In other words, what has too high a level of endocrine disruptors for our health such that we need to be especially vigilant?

Dr Fénichel: The whole issue is to find the environmental "threshold" doses.

The concept of endocrine disruptors has revolutionized toxicology. It has shown that chronic exposure to very small amounts of a given substance (which is often lipophilic and accumulates in fatty tissues) can be harmful, even in small amounts, during certain periods of life; in particular, during high-risk windows of susceptibility, such as fetal development or early childhood.

Dr Hansel: You're saying that we shouldn't simply declare that we're going to prohibit a particular level of exposure or ban a particular substance. Rather, at certain times, we should be especially vigilant over the long term and perhaps be more vigilant in certain populations, such as overweight individuals.

Sexual and Reproductive Effects

Dr Hansel: Let's look at some concrete examples. We hear a lot about the effect of endocrine disruptors on the reproductive system. Is it a real problem? Does it pose a public health problem in terms of fertility?

Dr Fénichel: It's not only the effects on fertility. We should look at the reproductive system in a broad sense. We can extend this to sexual identity. Researchers have even raised the possibility of a link with the increase in the number of transsexual and homosexual persons.

We have to look at the reproductive system in its entirety. The main endocrine disruptors and many compounds are estrogenomimetic. They resemble female hormones. This probably has to do with evolution.

Substances very similar to estrogens are even found in plants, like soy and genistein. In other words, a lot of natural and synthetic compounds are similar to estrogens and possibly exert estrogenomimetic activity. As a result, there are going to be some repercussions for the reproductive system.

A great deal of attention was at first given to boys. For four conditions, the question of exposure to endocrine disruptors has been raised:

  • Cryptorchidism, which affects 2% of male infants at birth;

  • Hypospadias, in which the urinary meatus is on the underside of the penis at birth;

  • Testicular cancer; and

  • Decreased male fertility.

These four conditions have been increasing in incidence since the 1930s. These conditions have been reproduced in animals by exposing mothers to certain estrogenic endocrine disruptors. Boys born to mothers treated with DES had a higher prevalence of cryptorchidism, hypospadias, and testicular cancer.

In medicine, an experiment or study never proves anything 100%. Rather, it's a bundle of arguments.

In the story of DES, we have experimental and epidemiologic arguments. There's a link between exposure to some of these estrogenomimetic endocrine disruptors and abnormalities of the male reproductive system and male reproductive function.

Impact on Obesity and Diabetes

Dr Hansel: The second main area is the obesity epidemic. Some have made a link between endocrine disruptors and obesity; specifically, its metabolic consequences—metabolic syndrome and diabetes. Can we yet establish, and with what degree of certainty, a link between endocrine disruptors and the metabolic diseases associated with overweight?

Dr Fénichel: With respect to metabolic disorders—obesity (especially metabolically active obesity), metabolic syndrome, and type 2 diabetes—there are three types of arguments.

Accidental exposure. After the factory explosion in Seveso, Italy, in 1975, the local population was exposed to very high levels of dioxin. In the years that followed, the rate of diabetes was much higher than in the general population.

Another example of accidental exposure involves veterans who returned from Vietnam and who had been in the planes that dropped bombs with the defoliant Agent Orange. This substance also contained dioxin. Unfortunately, we don't have all the Vietnamese data, but it's known that many of the American veterans developed diabetes, especially if they were in the planes that spread the substance. These events can be described as "acute."

Epidemiologic studies in general populations. The Nurses' Health Study was a very fine study in which American nurses were followed for 15 years. The nurses provided blood and urine samples, which were tested for phthalates (found in plastics) and bisphenol A (found in plastics, resins, polyvinylchloride, and just about everywhere).

The levels in these nurses were higher in those who developed diabetes during the 15-year follow-up.[1] This was a fine correlative, prospective study, but it didn't offer any proof.

Fundamental studies. Some terrific studies[2,3] have been carried out in Europe, in particular, by a Spanish team in Alicante with my friend Angel Nadal. They showed that in utero exposure to bisphenol A in mice promoted the development of insulin resistance, glucoregulation disorders, and obesity—not only in the mothers but in the male offspring as well, possibly because of sex hormones or the estrogenic action of bisphenol A.

As adults, the male offspring developed insulin resistance, glucoregulation disorders, and abnormalities of the pancreatic beta islets. In the end, they had impaired insulin secretion, with resulting insulin resistance, and pancreatic secretion disorders, which led to "experimental" type 2 diabetes.

Do we really have to be afraid in our daily lives when we drink from a plastic bottle?

Dr Hansel: So, we're talking about both insulin resistance and impaired pancreatic secretion. If we take these epidemiologic examples and experimental studies that point to a probable causal link and extrapolate this to what we experience on a day-to-day basis, isn't there (and this counterargument is often given) a considerable difference in the level of exposure to these endocrine disruptors?

You mentioned a couple of epidemiologic accidents and some experimental studies where, I imagine, very high doses of endocrine disruptors were administered. Do we really have to be afraid in our daily lives when we drink from a plastic bottle or eat food from a container that was heated up and may have released endocrine disruptors? Is such exposure the type that was seen in these experimental epidemiologic studies?

Dr Fénichel: There are two classes of endocrine disruptors. One type is highly lipophilic substances, and they persist in the water table and in fatty tissues, where they accumulate. Others are much less persistent.

For example, pesticides are very persistent. If you're exposed to a very small amount of pesticides, they will accumulate in your fatty tissues and be released gradually.

A compound like bisphenol A, which is found in plastics, is not persistent at all, but you're exposed to it every day. It's oxidized in the liver in 2-3 hours, conjugated, and eliminated in the urine. Therefore, if you're exposed to it in the morning, you will no longer be exposed to it in the afternoon.

However, in reality, we're exposed to it continuously, so there is always some circulating in our blood. It's as if you are exposed to large amounts of bisphenol A all the time, even if the amount was small at the beginning.

Neurologic Impact

Dr Hansel: A third topic that we often hear about is the conditions that might be associated with endocrine disruptors. It concerns everything in the behavioral and neurologic sphere. I'm talking about Parkinson disease, autism, hyperactivity syndrome, and so on.

What do we know about the causal link?

Dr Fénichel: The thyroid is especially important for fetal brain development. Women with profound hypothyroidism, especially in early pregnancy, have children with mental disorders. Hypothyroidism is therefore very serious.

Many of these endocrine disruptors are thyroid disruptors. In other words, they block the action of thyroid hormones on their target cells, including brain cells.

PCBs probably play a role in the high incidence of attention-deficit hyperactivity disorder, certain forms of autism, and neurodegenerative diseases.

Let's look at polychlorinated biphenyls (PCBs), which we've heard a lot about. PCBs are found, for example, in fish from Brittany in France at extremely high levels because, being highly lipophilic, they accumulate in the fatty tissues.

PCBs, which were used as electrical insulators for years and are now banned, are still present in the water table and in the fatty tissues of animals and humans. They are thyroid hormone antagonists. They block the action of thyroid hormones on their target cells and can block fetal brain development.

PCBs probably play a role in the high incidence of attention-deficit hyperactivity disorder, certain forms of autism, and neurodegenerative diseases.

In a study[4] that we conducted in Nice, we measured PCB levels in cord blood and followed 50 children every 6 months for 3 years (using the same psychologist) to study their language acquisition. We found that the higher the cord blood PCB levels, the more frequent the language acquisition disorders.

Practical Recommendations

Dr Hansel: And now we come to some practical recommendations for our colleagues, so that they can give the right advice in their daily practice. Without making this an obsession or a phobia, which would end up causing distress on a daily basis, what recommendations should we give our patients to avoid harmful exposure to endocrine disruptors?

Dr Fénichel: Very simply, we should say the following:

  • Smoking is very harmful to pregnant women. What is less known is that it's harmful because of the endocrine disruptors in tobacco tar. Benzopyrene, aromatic polycyclic hydrocarbons, and cadmium (a metal found in tobacco tar) are endocrine disruptors. Therefore, pregnant women should absolutely stop smoking, and their partners should stop smoking too because of second-hand exposure.

  • Avoid heating up food in plastic containers in a microwave because they contain bisphenol, which the heat releases into the food, and avoid covering the food with plastic wrap to make it heat up faster.

  • During pregnancy, it's better to eat organic fruits and vegetables. Even if you don't know exactly where they're from, you will be exposed to fewer pesticides by eating organic products during this brief period of time.

  • Don't paint your future baby's room during pregnancy because paints contain solvents that are endocrine disruptors.

  • Of course, don't use pesticides or insecticides in your garden.

  • Avoid canned foods and canned soft drinks. Many cans have a plastic coating to prevent the food or beverage from coming into contact with the metal. This plastic coating contains bisphenol A.

  • Women who plan to become pregnant are told to take folic acid or vitamin B9. Despite this recommendation, only 5% of French women who were planning to become pregnant were taking folic acid. Why is folic acid so important? It blocks gene methylation, a mechanism of endocrine disruption. It's an epigenetic mechanism. So, women of childbearing age should take folic acid.

  • Women should also take iodine. The greater a person's iodine deficiency and subclinical hypothyroidism, the higher the susceptibility to endocrine disruptors.

Dr Hansel: Outside of pregnancy, should these recommendations be followed as much as possible on a daily basis? And if you had to choose two of them, which ones would they be?

Dr Fénichel: In addition to pregnancy, the focus should be on young children during their development and cancer patients on chemotherapy. Certain endocrine disruptors, such as bisphenol, can interfere with these drugs. This isn't widely known, but it's important.

Dr Hansel: We can largely assume that greater caution should be exercised during cancer treatment and in those at high risk of developing certain hormone-dependent cancers.

Thank you very much for your comments and practical advice.

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