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Effects of endocrine-disrupting chemicals potentially serious, but difficult to prove

With updated scientific and policy statements expected this year, the use of endocrine-disrupting chemicals is at the center of impassioned discussions among citizens, scientists and policymakers worldwide. Mounting evidence for the health consequences of these ubiquitous compounds is inciting public concern, but proof of their harm to humans has been difficult to demonstrate.

Experts argue that chemical testing methods are antiquated, and a clear definition for the toxic substances remains a debate — just one of many unfolding as consumers live with uncertainty and clinicians practice in unknowns.

“No one is exposed to one single chemical. All of us are experiencing mixtures,” Jean-Pierre Bourguignon, MD, PhD, co-chair of the Endocrine Society Global and European EDC Policy Task Forces and head of pediatric endocrinology at University Hospital Center, Liège, Belgium, told Endocrine Today. “When it comes to finding out how one chemical in this complex mixture has been possibly responsible for this or that disorder, the task is difficult.”

Testing and regulation

A statement of principles from the Endocrine Society published in Endocrinology in 2012 defined an endocrine-disrupting chemical (EDC) as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action.”

After a resolution by the European Union Parliament in March 2013 that identified concerns regarding the use of EDCs, the EU Commission initiated a public consultation to explore what definition criteria should be used.

Jean-Pierre Bourguignon, MD, PhD, co-chair of the Endocrine Society’s European EDC Policy Task Force, said clinicians can look to epidemiology to observe relationships between endocrine-disrupting chemicals and numerous conditions, including testicular, breast and prostate cancers, along with obesity, diabetes and metabolic syndrome.

Photo by Jean-Louis Wertz.

 

“The international community is looking at this carefully,” Andrea C. Gore, PhD, a neuroendocrinologist at the University of Texas, Austin, told Endocrine Today. “It is time to take some significant steps as far as regulatory policy. The EU is ahead of the U.S. in making genuine efforts.”

Chemical production has increased exponentially in recent years. Using data from the toxic chemical registry, Gore and colleagues detailed the sharp increase in chemicals — from approximately 120,000 in 1988 to 250,000 in 2008 — in a paper published in Endocrine Reviews.

Not all are endocrine disruptors, but many have not been tested.

R. Thomas Zoeller, PhD, co-chair of the Endocrine Society Global and European EDC Policy Task Forces, and member of the U.N. Environment Programme (UNEP) Advisory Group on EDCs, of the University of Massachusetts, said mechanisms of action of these agents are not being adequately identified by the Environmental Protection Agency and the FDA.

The agencies’ testing methods are weak, Zoeller told Endocrine Today.

“The way the system is set up, you need to see absence of evidence for adverse effect rather than safety,” Zoeller said.

“The methods they’re using today are no different than the methods they’ve been using since the 1970s,” he said. “The assays are largely based on organ weight. That’s not a specific or sensitive endpoint.”

Zoeller said “the single biggest problem” is assessing toxicity in a way that does not work for EDCs.

“The concept of viewing chemicals that interact with the endocrine system from a baseline of understanding how the endocrine system works is actually controversial,” Zoeller said.

Endocrinology perspective needed

In the classical toxicology approach to endocrine disruption, researchers attempt to determine thresholds below which no effect would occur.

R. Thomas Zoeller

“Endocrine science has demonstrated during the past decade that the relationship between EDCs and effect was not a simple linear relation that would allow for the line-of-thought that ‘dose equals poison,’” Bourguignon said.

A series of papers published in Toxicology argued that EDC risk assessment is under the purview of toxicologists and spurred a “vocal response” from endocrinologists, Zoeller said.

Tapping expertise from both arenas would be the ideal way to responsibly develop and test chemicals, Gore said.

“If knowledgeable chemists work with people who are knowledgeable about hormone action, that could result in an important kind of partnership where the chemicals, as they get developed, are being tested in a way that is likely to reveal an endocrine-acting activity.”

The Strategic Approach to International Chemicals Management (SAICM), a chemical safety policy framework organized by UNEP with contributions from WHO, is working on the global front to achieve, by 2020, sound management of chemicals to minimize adverse effects on health and the environment.

Stakeholders from industry and policymakers from nations and nongovernmental organizations convened in December in Geneva for a second meeting of the SAICM Open-ended Working Group, where they discussed initiatives to identify potential EDCs and safer alternatives.

This followed the assembly of the European EDC Policy Task Force by the Endocrine Society in April 2014 in Brussels to ensure endocrine principles are incorporated into global policies.

European EDC Policy Task Force member Richard Ivell, PhD, of the University of Nottingham, United Kingdom, said the group is continually working to advise authorities as the EU decides how to regulate the compounds moving forward. But the decisions are not easy ones.

“You don’t want to be massively heavy on industry; these chemicals are useful substances, and they obviously earn money,” Ivell told Endocrine Today. “But equally, we have got to make sure the public is safe.”

In the United States, a proof-of-concept collaboration among the National Toxicology Program, National Institute of Environmental Health Sciences and the FDA — the Consortium Linking Academic and Regulatory Insight of Bisphenol A Toxicity (CLARITY-BPA) — aims to enhance the translation of scientific findings to regulation.

Endocrinologists remain the missing link in these decisions.

“When scientific studies are evaluated by expert committees, endocrinologists are rarely a part of those,” Zoeller said. “There is a weakness in the way endocrinology and basic science gets incorporated into safety consideration because the expertise required isn’t on board.”

Evidence, research and limitations

Known for its presence in plastic water bottles and food-container linings, bisphenol A (BPA) has focused the EDC debates of the past few years. The chemical has already been banned in the United States, among other countries, from use in baby bottles and children’s cups and is targeted by some for broader prohibition.

“BPA winds up being a poster child because it’s a molecule that fits into the receptors of estrogen, androgen and thyroid hormone,” Zoeller said, noting he does not know of any other molecule that reaches all three.

A U.S. ban on the pesticide DDT in 1972 raised public awareness to the dangers of EDCs, followed by a ban on polychlorinated biphenyls (PCBs), used in industrial and commercial applications as plasticizers and in pigments, in 1979.

Studies have since elucidated the harmful effects of both chemicals in humans.

Bourguignon and colleagues demonstrated precocious puberty resulting from transient DDT exposure in a study published in Human Reproduction involving 145 patients, with higher levels of a DDT derivative detected in plasma of foreign adopted girls who were exposed vs. native Belgium girls.

Buck Louis and colleagues linked a subset of persistent environmental chemicals with reduced fecundity in a cohort study of 501 couples published in Fertility and Sterility, with the strongest associations in men and women with PCB exposure.

Consuming soy milk from BPA-lined cans vs. glass bottles sent systolic blood pressure up by approximately 4.5 mm Hg and urinary BPA concentrations by more than 1,600%, in a randomized trial of 60 participants conducted by Bae and Hong and published in Hypertension.

“This study is impressive because it’s an intervention study; it’s like doing an experiment in a person,” Angel Nadal, PhD, a cell physiologist at Miguel Hernandez University of Elche in Alicante, Spain, and spokesman for the Endocrine Society, told Endocrine Today.

“These results are particularly important because they show a rapid effect,” he said. “If it is having an effect in a manner of minutes, there is no time for metabolism.”

In a cross-sectional survey of National Health and Nutrition Examination Survey data from 1999 to 2008 (n = 31,575 women) published in PLOS ONE, Grinder and colleagues documented an association between EDCs and earlier age at menopause; 15 chemicals warranted closer evaluation due to persistence and potential detrimental effects on ovarian function.

Findings in humans are limited compared with those from animal studies.

“The field has been hampered with a lack of real clinical evidence,” Gore said. “It would not be good science or ethical to give people a chemical and see what happens. Exposure studies can only be done in animals.”

Research on endocrine disruptors in rodents is highly translatable to humans, Gore said, noting the two species have 100% identical estrogen, androgen and progestin steroid hormones.

In studies on brain development published in Molecular Endocrinology and Endocrinology, Gore and colleagues showed that a short, 2-day window of low-level EDC exposure in utero changed gene expression and brain protein throughout the life cycle.

“We’ve looked at the outcomes in early life stages, during puberty and early adulthood, but we’ve also looked at the aging brain and found that there are significant changes in the brains of animals at ages comparable to humans in their 60s and 70s,” Gore said.

Andrea C. Gore

Attempting to relate chemical exposure to endocrine diseases in humans that may take decades to manifest is challenging.

“Determining exposures is not easy, and trying to get at causality is almost impossible,” Gore said.

The effect of diethylstilbestrol (DES) on offspring is the “classic and tragic example” of endocrine disruption, according to Bourguignon. The potent synthetic estrogen, prescribed to pregnant women in the 1940s to prevent miscarriage, was linked to unusual vaginal cancer in their daughters in the 1970s.

“Only by accident can you demonstrate endocrine disruptions epidemiologically in humans,” Bourguignon said. “The long time lag between exposure and effect is making our business as clinical investigators difficult.”

Epidemiologic research in the past few years represents an important historical shift in the study of EDCs, Gore said.

“This will begin to have a real influence on the field from a clinical perspective because it will guide us in telling us what is commonly found in our bodies and what chemicals are related to the disease states,” Gore said.

Prevalence and vulnerability

Eating processed foods, applying lotions or cosmetics, using certain shampoos and antibacterial soaps, and breathing household pest killers and air fresheners are common routes for EDC exposure, according to Gore.

“When you think about the ubiquity of chemical exposures that just relate to our day-to-day life, it isn’t possible to avoid them,” Gore said.

EDCs even find their way to parts of the world where they are not being used. Some get transported by air and water currents. Others build up in the food chain when an animal species feeds in one part of the world and nests in another, where humans eating the animals then become exposed.

The Endocrine Society together with the International POPs Elimination Network (IPEN), a global network of more than 700 public interest, nongovernmental organizations in 116 countries, released a guide in December to highlight the international nature of exposures to EDCs and persistent organic pollutants (POPs).

“When countries around the world are grappling with infectious diseases and toxic exposures through occupational or industrial situations, our hope is they will also remember we need to consider the daily kinds of exposures everyone has,” Gore, the lead author, said.

Pregnancy, infancy and puberty are the most vulnerable and, therefore, the most clinically concerning periods for EDC exposure, experts agree.

“It’s now accepted that, in the womb, we are exposed to more than 100 different synthetic chemicals from the environment,” Bourguignon said.

In a study ever on human amniotic fluid, published in Epidemiology, Ivell and colleagues investigated the effect of phthalates, used to make plastics more flexible, on fetal testes using tens of thousands of samples in a bank set up by scientists in Denmark.

“The fetus is not nearly as protected as we’d like to think it is,” Ivell said. “In the first trimester, when the fetus is still small but the organs are developing to take up their final state, anything the mother is exposed to can upset the rapid growth of these tiny organs and cause disruption.”

A clear relationship between the load of phthalate compounds within the amniotic fluid and the testes was demonstrated, with the reduction in some hormones produced in direct proportion to exposure.

“It only requires subtle nudges by chemicals to upset the system,” Ivell said. “If you upset the testes, you’re also upsetting its ability to make its own androgens, including testosterone, which are important for the development of other organs.”

Ivell said “knock-on effects” could manifest as increasing incidence of conditions such as cryptorchidism, hypospadias and other genital malformations. Disturbing androgen metabolism could negatively influence skeletal, muscle and brain development.

Autistic behaviors were associated with gestational exposure to EDCs in the Health Outcomes and Measures of the Environment (HOME) Study published in Environmental Health Perspectives involving 175 pregnant women and their offspring, according to Braun and colleagues.

Harley and colleagues linked anxiety, depression and hyperactivity to both gestational and early life BPA exposure in a study of 292 children published in Environmental Research that examined mothers’ urine during pregnancy, children’s urine at age 5 years and behavior assessments at age 7 years.

Clinicians can look to epidemiology to observe relationships between EDCs and numerous conditions, Bourguignon said, including testicular, breast and prostate cancers, along with obesity, diabetes and metabolic syndrome.

In a review published in Endocrine Reviews, Lee and colleagues summarized epidemiologic results on POPs, with evidence suggesting that background exposure to chemical mixtures is more likely responsible for increased type 2 diabetes risk than a few specific chemicals.

Distinct plasma POP profiles between metabolically healthy and metabolically abnormal obese phenotypes were demonstrated in a cross-sectional study of 76 patients with obesity by Gauthier and colleagues published in The Journal of Clinical Endocrinology & Metabolism.

“The effects are reversible in experiments in mice; when we stop chemical exposure, insulin resistance disappears,” Nadal said. “However, when we expose pregnant mice, the offspring are programmed to have metabolic alterations and to be more predisposed to diabetes and obesity. These are likely epigenetic changes that can last for the whole life.”

Endocrinologists now recognize the severity of consequences potentially stemming from alterations in DNA, particularly during early life, trumping a previous belief in the adjustment capacity of human physiology, Bourguignon said.

“Epigenetics makes possible that environmental influences on our body’s chemicals, our gene expression, is transmitted to our offspring,” Bourguignon said. “Those chemical changes could be transmitted to the next generations.”

Clinical guidance

Epigenome and transgenerational effects are among the topics to be found in the upcoming edition of Jameson & Degreuts Endocrinology, under the chapter “Endocrine-Disrupting Chemicals and Human Disease.”

The first-ever clinical guidance on EDCs, along with human health impact, hormone action considerations, mechanisms, and disease trends will also be covered in the chapter, co-written by Zoeller.

“This gives broad ideas about what experts are recommending physicians be aware of,” Zoeller said.

From a practice standpoint, Zoeller said endocrinologists must recognize that EDCs are not subspecialty-specific.

“These molecules don’t obey silos. We can’t expect chemicals in the environment to produce diseases that are going to be typical,” Zoeller said. “These kinds of chemicals can contribute to disease in a way that we don’t study. The mosaic effect that is produced by some of these chemicals will trick us.”

From a diagnostic standpoint, no common tests for EDCs are available.

“Exposures can be measured through blood and urine samples, amniocentesis, umbilical cord blood or placenta,” Gore said. “However, there is no common, easy and affordable method.”

Certain EDCs are already on the radar, but the various chemical classes could contain dozens to hundreds. “We can only identify and measure known chemicals,” Gore said.

Gore is now working on the second Scientific Statement of the Endocrine Society on EDCs, anticipated for release in late 2015, building on the first statement from 2009.

Among the priorities is determining mechanisms for EDC effects.

“More research on targets is needed,” Gore said. The focus to-date has been on estrogen, androgen and thyroid hormone receptors, but other types of signaling systems that EDCs act upon are just beginning to be studied.

Boosting translation from in vitro cell line and tissue work to animal models, to make stronger connections to humans, is another focus.

“There needs to be more research on large animals with longer life spans and longer reproductive cycles,” Gore said. Sheep and nonhuman primates are being used more often.

With new chemicals continually in development, the scientific statement will underscore the need for expeditious research and identification of EDCs.

The authors are also emphasizing education for the public, policymakers and media alike.

“Professionals are also consumers, and we are also citizens,” Bourguignon said. “It is important that we urge our authorities to make decisions about the production and release of EDCs in the environment. Ultimately, what drives policymakers is what is coming from citizens.”

Yet, we need to be careful to avoid being overly alarmist, Gore said.

“We’re never going to move into a chemical-free world,” Gore said. “We need to acknowledge that and do certain things to try to minimize exposures.”

The surge of news surrounding EDCs can sound “hyperbolic,” Zoeller said. But he noted concerns must not be dismissed.

“We need to be careful in our rejection of the concern people have for endocrine disruptors because we don’t see overt birth defects, death or direct disease,” Zoeller said.

Neither panic nor rejection will best serve public health, Bourguignon said. The global community must remain grounded and engaged.

“Fear does not help when it can paralyze. Information does help when it can mobilize toward action, protection and further research,” Bourguignon said. “If we don’t talk about EDCs, there will be no action and no protection. We should go beyond fear.” – by Allegra Tiver

For more information:
  • Bae S, et al. Hypertension. 2014;doi:10.1161/HYPERTENSIONAHA.114.04261.
  • Braun JM, et al. Environ Health Perspect. 2014;doi:10.1289/ehp.1307261.
  • Buck Louis GM, et al. Fertil Steril. 2014;doi:10.1016/j.fertnstert.2014.01.022.
  • Diamanti-Kandarakis E, et al. Endocr Rev. 2009;doi:10.1210/er.2009-0002.
  • Gauthier MS, et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-3935.
  • Gore AC, et al. Introduction to Endocrine Disrupting Chemicals. Endocrine Society/IPEN; December 2014. Available at: www.endocrine.org. Accessed Feb. 13, 2015.
  • Gore AC, et al. Endocr Rev. 2014;doi:10.1210/er.2013-1122.
  • Grinder NM, et al. PLoS One. 2015;doi:10.1371/journal.pone.0116057.
  • Harley KG, et al. Environ Res. 2013;doi:10.1016/j.envres.2013.06.004.
  • Jensen MS, et al. Epidemiology. 2015;doi:10.1097/EDE.0000000000000198.
  • Krstevska-Konstantinova M, et al. Hum Reprod. 2001;16:1020-1026.
  • Lee DH, et al. Endocr Rev. 2014;doi:10.1210/er.2013-1084.
  • Schug TT, et al. Reprod Toxicol. 2013;doi:10.1016/j.reprotox.2013.05.010.
  • Zoeller RT, et al. Endocrinology. 2012;doi:10.1210/en.2012-1422.
  • Zoeller RT, et al. Environ Health. 2014;doi:10.1186/1476-069X-13-118.

Disclosures:
  • Jean-Pierre Bourguignon, MD, PhD, can be reached at CHU Sart Tilman, B4000 Liège, Belgium; email: jpbourguignon@ulg.ac.be.
  • Andrea C. Gore, PhD, can be reached at the University of Texas, College of Pharmacy, 107 W. Dean Keeton St., Stop C0875, Room BME 3.510, Austin, TX, 78712; email: andrea.gore@austin.utexas.edu.
  • Richard Ivell, PhD, can be reached at the Schools of Biosciences and Veterinary Medicine and Science, University of Nottingham, UK, LE12 5RD, UK; email: Richard.Ivell@nottingham.ac.uk.
  • Angel Nadal, PhD, can be reached at the Institute of Bioengineering and CIBERDEM, Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; email: nadal@umh.es.
  • R. Thomas Zoeller, PhD, can be reached at Biology Department, University of Massachusetts Amherst, 611 N. Pleasant St., Amherst, MA  01003; email: tzoeller@bio.umass.edu.
  • Bourguignon, Gore, Ivell, Nadal and Zoeller report no relevant financial disclosures.

POINTCOUNTER

Should endocrinologists be discussing endocrine-disrupting hormones with their patients?

POINT

As a pediatric endocrinologist, I am often asked about EDCs by patients. Pubertal development, including concerns about precocious puberty or early normal puberty, raises questions from families the most.

I discuss EDCs with these families because there is evidence suggesting that pure lavender oil and tea tree oil, commonly found in skin care products, are associated with gynecomastia in prepubertal boys and in other models. When a young girl presents with premature breast development, I always ask about these exposures.

A strong connection is also seen between paternal use of certain androgen-containing creams and premature pubarche or hirsutism. When I see children with early pubic hair or atypical polycystic ovary syndrome, I always ask about household androgen exposure.

Louise Greenspan

Generally, I let patients ask me about endocrine disruptors, but for those two chief complaints — premature breast development and premature pubarche — I ask about these main exposures because the evidence is so strong linking the exposure to the negative health outcome. For many other chemicals, relationships are more challenging to pinpoint, due to the latency of effect and dose variability. Obtaining a patient’s history is important, because the etiology of the chief complaint can spontaneously surface. If EDC exposures are significant, it helps me with my workup and evaluation.

Asking the question elicits the counseling. Many people now know the dangers of exposures, but most people do not. Depending on their particular view on EDCs, parents can get very anxious; it’s our role to remind them that it is not possible to eliminate every single chemical, but efforts can be made to prevent known exposures. Not knowing the exact relationships between EDCs and subsequent health effects presents a critical challenge to counseling. A lot of hypotheses are being tested, but we don’t always have direct links. Although the unknown may hinder our ability to counsel, we have to use the precautionary principle.

The human clinical side of EDCs is an area that requires continued research, but there are inherent challenges to doing this. We have to live with uncertainty a little bit for now.

Louise Greenspan, MD, Kaiser Permanente, San Francisco Associate Clinical Professor, UCSF School of Medicine. Disclosure: Greenspan reports no relevant financial disclosures.

COUNTER

Generally, I don’t talk about EDCs with patients, but occasionally, I do. They are not really pertinent to my patients; even though I specialize in the reproductive system.

There is evidence that various chemicals, both natural and manmade, are absorbed into the human body and could potentially be endocrine disruptors. We create about 10,000 chemicals per year and hardly test any of them.

To determine their clinical importance we have to look at three areas: Does it get into our bodies? Is it a biologically active substance, either intrinsically, or convertible to something that binds to a hormone receptor? Is it a potent competitor to the hormones we make ourselves?

Human beings, both males and females, are flooded with estrogens compared to the amount found in an endocrine disruptor, and there are estrogens in our foods. We have estrogens coursing through our bodies from eating uncooked soy — a heck of a lot more than we get from plastic.

Stanley Korenman

In nature, fish eggs and tadpoles have receptors but don’t have a substantial amount of endogenous hormones, so EDCs in the water they inhabit can have biological effects. This activity depends not only on the presence of a chemical, but also on its competitive ability to affect function.

For obstetricians who see women before and during pregnancy, at a time when they are being warned about everything they are ingesting, a statement about EDC exposure would be sensible because absorption into the fetus is different from hormone concentrations in the mother.

But overall, everyone is overly frightened. People will only eat tuna twice a month because they worry about mercury exposure. Society is afraid of bacteria on the kitchen counter, which is crazy — humans evolved to live in dirt 200,000 years ago. Bringing up EDCs with patients is just going to make them scared about something that doesn’t really affect them.

There is a lot of fear that chemicals in the environment are reducing sperm count and may relate to why girls are entering puberty earlier. That’s not demonstrated for specific molecules, and we can’t hide from chemical exposure no matter how we try or where we live.

Stanley Korenman, MD, Professor, Medicine, Endocrinology, Diabetes Metabolism and Hypertension; Regulatory Program Director, CTSI Associate Dean for Ethics, David Geffen School of Medicine at UCLA. Disclosure: Korenman reports no relevant financial disclosures.

With updated scientific and policy statements expected this year, the use of endocrine-disrupting chemicals is at the center of impassioned discussions among citizens, scientists and policymakers worldwide. Mounting evidence for the health consequences of these ubiquitous compounds is inciting public concern, but proof of their harm to humans has been difficult to demonstrate.

Experts argue that chemical testing methods are antiquated, and a clear definition for the toxic substances remains a debate — just one of many unfolding as consumers live with uncertainty and clinicians practice in unknowns.

“No one is exposed to one single chemical. All of us are experiencing mixtures,” Jean-Pierre Bourguignon, MD, PhD, co-chair of the Endocrine Society Global and European EDC Policy Task Forces and head of pediatric endocrinology at University Hospital Center, Liège, Belgium, told Endocrine Today. “When it comes to finding out how one chemical in this complex mixture has been possibly responsible for this or that disorder, the task is difficult.”

Testing and regulation

A statement of principles from the Endocrine Society published in Endocrinology in 2012 defined an endocrine-disrupting chemical (EDC) as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action.”

After a resolution by the European Union Parliament in March 2013 that identified concerns regarding the use of EDCs, the EU Commission initiated a public consultation to explore what definition criteria should be used.

Jean-Pierre Bourguignon, MD, PhD, co-chair of the Endocrine Society’s European EDC Policy Task Force, said clinicians can look to epidemiology to observe relationships between endocrine-disrupting chemicals and numerous conditions, including testicular, breast and prostate cancers, along with obesity, diabetes and metabolic syndrome.

Photo by Jean-Louis Wertz.

 

“The international community is looking at this carefully,” Andrea C. Gore, PhD, a neuroendocrinologist at the University of Texas, Austin, told Endocrine Today. “It is time to take some significant steps as far as regulatory policy. The EU is ahead of the U.S. in making genuine efforts.”

Chemical production has increased exponentially in recent years. Using data from the toxic chemical registry, Gore and colleagues detailed the sharp increase in chemicals — from approximately 120,000 in 1988 to 250,000 in 2008 — in a paper published in Endocrine Reviews.

Not all are endocrine disruptors, but many have not been tested.

R. Thomas Zoeller, PhD, co-chair of the Endocrine Society Global and European EDC Policy Task Forces, and member of the U.N. Environment Programme (UNEP) Advisory Group on EDCs, of the University of Massachusetts, said mechanisms of action of these agents are not being adequately identified by the Environmental Protection Agency and the FDA.

The agencies’ testing methods are weak, Zoeller told Endocrine Today.

“The way the system is set up, you need to see absence of evidence for adverse effect rather than safety,” Zoeller said.

“The methods they’re using today are no different than the methods they’ve been using since the 1970s,” he said. “The assays are largely based on organ weight. That’s not a specific or sensitive endpoint.”

Zoeller said “the single biggest problem” is assessing toxicity in a way that does not work for EDCs.

“The concept of viewing chemicals that interact with the endocrine system from a baseline of understanding how the endocrine system works is actually controversial,” Zoeller said.

Endocrinology perspective needed

In the classical toxicology approach to endocrine disruption, researchers attempt to determine thresholds below which no effect would occur.

R. Thomas Zoeller

“Endocrine science has demonstrated during the past decade that the relationship between EDCs and effect was not a simple linear relation that would allow for the line-of-thought that ‘dose equals poison,’” Bourguignon said.

A series of papers published in Toxicology argued that EDC risk assessment is under the purview of toxicologists and spurred a “vocal response” from endocrinologists, Zoeller said.

Tapping expertise from both arenas would be the ideal way to responsibly develop and test chemicals, Gore said.

“If knowledgeable chemists work with people who are knowledgeable about hormone action, that could result in an important kind of partnership where the chemicals, as they get developed, are being tested in a way that is likely to reveal an endocrine-acting activity.”

PAGE BREAK

The Strategic Approach to International Chemicals Management (SAICM), a chemical safety policy framework organized by UNEP with contributions from WHO, is working on the global front to achieve, by 2020, sound management of chemicals to minimize adverse effects on health and the environment.

Stakeholders from industry and policymakers from nations and nongovernmental organizations convened in December in Geneva for a second meeting of the SAICM Open-ended Working Group, where they discussed initiatives to identify potential EDCs and safer alternatives.

This followed the assembly of the European EDC Policy Task Force by the Endocrine Society in April 2014 in Brussels to ensure endocrine principles are incorporated into global policies.

European EDC Policy Task Force member Richard Ivell, PhD, of the University of Nottingham, United Kingdom, said the group is continually working to advise authorities as the EU decides how to regulate the compounds moving forward. But the decisions are not easy ones.

“You don’t want to be massively heavy on industry; these chemicals are useful substances, and they obviously earn money,” Ivell told Endocrine Today. “But equally, we have got to make sure the public is safe.”

In the United States, a proof-of-concept collaboration among the National Toxicology Program, National Institute of Environmental Health Sciences and the FDA — the Consortium Linking Academic and Regulatory Insight of Bisphenol A Toxicity (CLARITY-BPA) — aims to enhance the translation of scientific findings to regulation.

Endocrinologists remain the missing link in these decisions.

“When scientific studies are evaluated by expert committees, endocrinologists are rarely a part of those,” Zoeller said. “There is a weakness in the way endocrinology and basic science gets incorporated into safety consideration because the expertise required isn’t on board.”

Evidence, research and limitations

Known for its presence in plastic water bottles and food-container linings, bisphenol A (BPA) has focused the EDC debates of the past few years. The chemical has already been banned in the United States, among other countries, from use in baby bottles and children’s cups and is targeted by some for broader prohibition.

“BPA winds up being a poster child because it’s a molecule that fits into the receptors of estrogen, androgen and thyroid hormone,” Zoeller said, noting he does not know of any other molecule that reaches all three.

A U.S. ban on the pesticide DDT in 1972 raised public awareness to the dangers of EDCs, followed by a ban on polychlorinated biphenyls (PCBs), used in industrial and commercial applications as plasticizers and in pigments, in 1979.

Studies have since elucidated the harmful effects of both chemicals in humans.

Bourguignon and colleagues demonstrated precocious puberty resulting from transient DDT exposure in a study published in Human Reproduction involving 145 patients, with higher levels of a DDT derivative detected in plasma of foreign adopted girls who were exposed vs. native Belgium girls.

Buck Louis and colleagues linked a subset of persistent environmental chemicals with reduced fecundity in a cohort study of 501 couples published in Fertility and Sterility, with the strongest associations in men and women with PCB exposure.

Consuming soy milk from BPA-lined cans vs. glass bottles sent systolic blood pressure up by approximately 4.5 mm Hg and urinary BPA concentrations by more than 1,600%, in a randomized trial of 60 participants conducted by Bae and Hong and published in Hypertension.

“This study is impressive because it’s an intervention study; it’s like doing an experiment in a person,” Angel Nadal, PhD, a cell physiologist at Miguel Hernandez University of Elche in Alicante, Spain, and spokesman for the Endocrine Society, told Endocrine Today.

“These results are particularly important because they show a rapid effect,” he said. “If it is having an effect in a manner of minutes, there is no time for metabolism.”

PAGE BREAK

In a cross-sectional survey of National Health and Nutrition Examination Survey data from 1999 to 2008 (n = 31,575 women) published in PLOS ONE, Grinder and colleagues documented an association between EDCs and earlier age at menopause; 15 chemicals warranted closer evaluation due to persistence and potential detrimental effects on ovarian function.

Findings in humans are limited compared with those from animal studies.

“The field has been hampered with a lack of real clinical evidence,” Gore said. “It would not be good science or ethical to give people a chemical and see what happens. Exposure studies can only be done in animals.”

Research on endocrine disruptors in rodents is highly translatable to humans, Gore said, noting the two species have 100% identical estrogen, androgen and progestin steroid hormones.

In studies on brain development published in Molecular Endocrinology and Endocrinology, Gore and colleagues showed that a short, 2-day window of low-level EDC exposure in utero changed gene expression and brain protein throughout the life cycle.

“We’ve looked at the outcomes in early life stages, during puberty and early adulthood, but we’ve also looked at the aging brain and found that there are significant changes in the brains of animals at ages comparable to humans in their 60s and 70s,” Gore said.

Andrea C. Gore

Attempting to relate chemical exposure to endocrine diseases in humans that may take decades to manifest is challenging.

“Determining exposures is not easy, and trying to get at causality is almost impossible,” Gore said.

The effect of diethylstilbestrol (DES) on offspring is the “classic and tragic example” of endocrine disruption, according to Bourguignon. The potent synthetic estrogen, prescribed to pregnant women in the 1940s to prevent miscarriage, was linked to unusual vaginal cancer in their daughters in the 1970s.

“Only by accident can you demonstrate endocrine disruptions epidemiologically in humans,” Bourguignon said. “The long time lag between exposure and effect is making our business as clinical investigators difficult.”

Epidemiologic research in the past few years represents an important historical shift in the study of EDCs, Gore said.

“This will begin to have a real influence on the field from a clinical perspective because it will guide us in telling us what is commonly found in our bodies and what chemicals are related to the disease states,” Gore said.

Prevalence and vulnerability

Eating processed foods, applying lotions or cosmetics, using certain shampoos and antibacterial soaps, and breathing household pest killers and air fresheners are common routes for EDC exposure, according to Gore.

“When you think about the ubiquity of chemical exposures that just relate to our day-to-day life, it isn’t possible to avoid them,” Gore said.

EDCs even find their way to parts of the world where they are not being used. Some get transported by air and water currents. Others build up in the food chain when an animal species feeds in one part of the world and nests in another, where humans eating the animals then become exposed.

The Endocrine Society together with the International POPs Elimination Network (IPEN), a global network of more than 700 public interest, nongovernmental organizations in 116 countries, released a guide in December to highlight the international nature of exposures to EDCs and persistent organic pollutants (POPs).

“When countries around the world are grappling with infectious diseases and toxic exposures through occupational or industrial situations, our hope is they will also remember we need to consider the daily kinds of exposures everyone has,” Gore, the lead author, said.

Pregnancy, infancy and puberty are the most vulnerable and, therefore, the most clinically concerning periods for EDC exposure, experts agree.

“It’s now accepted that, in the womb, we are exposed to more than 100 different synthetic chemicals from the environment,” Bourguignon said.

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In a study ever on human amniotic fluid, published in Epidemiology, Ivell and colleagues investigated the effect of phthalates, used to make plastics more flexible, on fetal testes using tens of thousands of samples in a bank set up by scientists in Denmark.

“The fetus is not nearly as protected as we’d like to think it is,” Ivell said. “In the first trimester, when the fetus is still small but the organs are developing to take up their final state, anything the mother is exposed to can upset the rapid growth of these tiny organs and cause disruption.”

A clear relationship between the load of phthalate compounds within the amniotic fluid and the testes was demonstrated, with the reduction in some hormones produced in direct proportion to exposure.

“It only requires subtle nudges by chemicals to upset the system,” Ivell said. “If you upset the testes, you’re also upsetting its ability to make its own androgens, including testosterone, which are important for the development of other organs.”

Ivell said “knock-on effects” could manifest as increasing incidence of conditions such as cryptorchidism, hypospadias and other genital malformations. Disturbing androgen metabolism could negatively influence skeletal, muscle and brain development.

Autistic behaviors were associated with gestational exposure to EDCs in the Health Outcomes and Measures of the Environment (HOME) Study published in Environmental Health Perspectives involving 175 pregnant women and their offspring, according to Braun and colleagues.

Harley and colleagues linked anxiety, depression and hyperactivity to both gestational and early life BPA exposure in a study of 292 children published in Environmental Research that examined mothers’ urine during pregnancy, children’s urine at age 5 years and behavior assessments at age 7 years.

Clinicians can look to epidemiology to observe relationships between EDCs and numerous conditions, Bourguignon said, including testicular, breast and prostate cancers, along with obesity, diabetes and metabolic syndrome.

In a review published in Endocrine Reviews, Lee and colleagues summarized epidemiologic results on POPs, with evidence suggesting that background exposure to chemical mixtures is more likely responsible for increased type 2 diabetes risk than a few specific chemicals.

Distinct plasma POP profiles between metabolically healthy and metabolically abnormal obese phenotypes were demonstrated in a cross-sectional study of 76 patients with obesity by Gauthier and colleagues published in The Journal of Clinical Endocrinology & Metabolism.

“The effects are reversible in experiments in mice; when we stop chemical exposure, insulin resistance disappears,” Nadal said. “However, when we expose pregnant mice, the offspring are programmed to have metabolic alterations and to be more predisposed to diabetes and obesity. These are likely epigenetic changes that can last for the whole life.”

Endocrinologists now recognize the severity of consequences potentially stemming from alterations in DNA, particularly during early life, trumping a previous belief in the adjustment capacity of human physiology, Bourguignon said.

“Epigenetics makes possible that environmental influences on our body’s chemicals, our gene expression, is transmitted to our offspring,” Bourguignon said. “Those chemical changes could be transmitted to the next generations.”

Clinical guidance

Epigenome and transgenerational effects are among the topics to be found in the upcoming edition of Jameson & Degreuts Endocrinology, under the chapter “Endocrine-Disrupting Chemicals and Human Disease.”

The first-ever clinical guidance on EDCs, along with human health impact, hormone action considerations, mechanisms, and disease trends will also be covered in the chapter, co-written by Zoeller.

“This gives broad ideas about what experts are recommending physicians be aware of,” Zoeller said.

From a practice standpoint, Zoeller said endocrinologists must recognize that EDCs are not subspecialty-specific.

“These molecules don’t obey silos. We can’t expect chemicals in the environment to produce diseases that are going to be typical,” Zoeller said. “These kinds of chemicals can contribute to disease in a way that we don’t study. The mosaic effect that is produced by some of these chemicals will trick us.”

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From a diagnostic standpoint, no common tests for EDCs are available.

“Exposures can be measured through blood and urine samples, amniocentesis, umbilical cord blood or placenta,” Gore said. “However, there is no common, easy and affordable method.”

Certain EDCs are already on the radar, but the various chemical classes could contain dozens to hundreds. “We can only identify and measure known chemicals,” Gore said.

Gore is now working on the second Scientific Statement of the Endocrine Society on EDCs, anticipated for release in late 2015, building on the first statement from 2009.

Among the priorities is determining mechanisms for EDC effects.

“More research on targets is needed,” Gore said. The focus to-date has been on estrogen, androgen and thyroid hormone receptors, but other types of signaling systems that EDCs act upon are just beginning to be studied.

Boosting translation from in vitro cell line and tissue work to animal models, to make stronger connections to humans, is another focus.

“There needs to be more research on large animals with longer life spans and longer reproductive cycles,” Gore said. Sheep and nonhuman primates are being used more often.

With new chemicals continually in development, the scientific statement will underscore the need for expeditious research and identification of EDCs.

The authors are also emphasizing education for the public, policymakers and media alike.

“Professionals are also consumers, and we are also citizens,” Bourguignon said. “It is important that we urge our authorities to make decisions about the production and release of EDCs in the environment. Ultimately, what drives policymakers is what is coming from citizens.”

Yet, we need to be careful to avoid being overly alarmist, Gore said.

“We’re never going to move into a chemical-free world,” Gore said. “We need to acknowledge that and do certain things to try to minimize exposures.”

The surge of news surrounding EDCs can sound “hyperbolic,” Zoeller said. But he noted concerns must not be dismissed.

“We need to be careful in our rejection of the concern people have for endocrine disruptors because we don’t see overt birth defects, death or direct disease,” Zoeller said.

Neither panic nor rejection will best serve public health, Bourguignon said. The global community must remain grounded and engaged.

“Fear does not help when it can paralyze. Information does help when it can mobilize toward action, protection and further research,” Bourguignon said. “If we don’t talk about EDCs, there will be no action and no protection. We should go beyond fear.” – by Allegra Tiver

For more information:
  • Bae S, et al. Hypertension. 2014;doi:10.1161/HYPERTENSIONAHA.114.04261.
  • Braun JM, et al. Environ Health Perspect. 2014;doi:10.1289/ehp.1307261.
  • Buck Louis GM, et al. Fertil Steril. 2014;doi:10.1016/j.fertnstert.2014.01.022.
  • Diamanti-Kandarakis E, et al. Endocr Rev. 2009;doi:10.1210/er.2009-0002.
  • Gauthier MS, et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-3935.
  • Gore AC, et al. Introduction to Endocrine Disrupting Chemicals. Endocrine Society/IPEN; December 2014. Available at: www.endocrine.org. Accessed Feb. 13, 2015.
  • Gore AC, et al. Endocr Rev. 2014;doi:10.1210/er.2013-1122.
  • Grinder NM, et al. PLoS One. 2015;doi:10.1371/journal.pone.0116057.
  • Harley KG, et al. Environ Res. 2013;doi:10.1016/j.envres.2013.06.004.
  • Jensen MS, et al. Epidemiology. 2015;doi:10.1097/EDE.0000000000000198.
  • Krstevska-Konstantinova M, et al. Hum Reprod. 2001;16:1020-1026.
  • Lee DH, et al. Endocr Rev. 2014;doi:10.1210/er.2013-1084.
  • Schug TT, et al. Reprod Toxicol. 2013;doi:10.1016/j.reprotox.2013.05.010.
  • Zoeller RT, et al. Endocrinology. 2012;doi:10.1210/en.2012-1422.
  • Zoeller RT, et al. Environ Health. 2014;doi:10.1186/1476-069X-13-118.

Disclosures:
  • Jean-Pierre Bourguignon, MD, PhD, can be reached at CHU Sart Tilman, B4000 Liège, Belgium; email: jpbourguignon@ulg.ac.be.
  • Andrea C. Gore, PhD, can be reached at the University of Texas, College of Pharmacy, 107 W. Dean Keeton St., Stop C0875, Room BME 3.510, Austin, TX, 78712; email: andrea.gore@austin.utexas.edu.
  • Richard Ivell, PhD, can be reached at the Schools of Biosciences and Veterinary Medicine and Science, University of Nottingham, UK, LE12 5RD, UK; email: Richard.Ivell@nottingham.ac.uk.
  • Angel Nadal, PhD, can be reached at the Institute of Bioengineering and CIBERDEM, Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; email: nadal@umh.es.
  • R. Thomas Zoeller, PhD, can be reached at Biology Department, University of Massachusetts Amherst, 611 N. Pleasant St., Amherst, MA  01003; email: tzoeller@bio.umass.edu.
  • Bourguignon, Gore, Ivell, Nadal and Zoeller report no relevant financial disclosures.
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POINTCOUNTER

Should endocrinologists be discussing endocrine-disrupting hormones with their patients?

POINT

As a pediatric endocrinologist, I am often asked about EDCs by patients. Pubertal development, including concerns about precocious puberty or early normal puberty, raises questions from families the most.

I discuss EDCs with these families because there is evidence suggesting that pure lavender oil and tea tree oil, commonly found in skin care products, are associated with gynecomastia in prepubertal boys and in other models. When a young girl presents with premature breast development, I always ask about these exposures.

A strong connection is also seen between paternal use of certain androgen-containing creams and premature pubarche or hirsutism. When I see children with early pubic hair or atypical polycystic ovary syndrome, I always ask about household androgen exposure.

Louise Greenspan

Generally, I let patients ask me about endocrine disruptors, but for those two chief complaints — premature breast development and premature pubarche — I ask about these main exposures because the evidence is so strong linking the exposure to the negative health outcome. For many other chemicals, relationships are more challenging to pinpoint, due to the latency of effect and dose variability. Obtaining a patient’s history is important, because the etiology of the chief complaint can spontaneously surface. If EDC exposures are significant, it helps me with my workup and evaluation.

Asking the question elicits the counseling. Many people now know the dangers of exposures, but most people do not. Depending on their particular view on EDCs, parents can get very anxious; it’s our role to remind them that it is not possible to eliminate every single chemical, but efforts can be made to prevent known exposures. Not knowing the exact relationships between EDCs and subsequent health effects presents a critical challenge to counseling. A lot of hypotheses are being tested, but we don’t always have direct links. Although the unknown may hinder our ability to counsel, we have to use the precautionary principle.

The human clinical side of EDCs is an area that requires continued research, but there are inherent challenges to doing this. We have to live with uncertainty a little bit for now.

Louise Greenspan, MD, Kaiser Permanente, San Francisco Associate Clinical Professor, UCSF School of Medicine. Disclosure: Greenspan reports no relevant financial disclosures.

COUNTER

Generally, I don’t talk about EDCs with patients, but occasionally, I do. They are not really pertinent to my patients; even though I specialize in the reproductive system.

There is evidence that various chemicals, both natural and manmade, are absorbed into the human body and could potentially be endocrine disruptors. We create about 10,000 chemicals per year and hardly test any of them.

To determine their clinical importance we have to look at three areas: Does it get into our bodies? Is it a biologically active substance, either intrinsically, or convertible to something that binds to a hormone receptor? Is it a potent competitor to the hormones we make ourselves?

Human beings, both males and females, are flooded with estrogens compared to the amount found in an endocrine disruptor, and there are estrogens in our foods. We have estrogens coursing through our bodies from eating uncooked soy — a heck of a lot more than we get from plastic.

Stanley Korenman

In nature, fish eggs and tadpoles have receptors but don’t have a substantial amount of endogenous hormones, so EDCs in the water they inhabit can have biological effects. This activity depends not only on the presence of a chemical, but also on its competitive ability to affect function.

For obstetricians who see women before and during pregnancy, at a time when they are being warned about everything they are ingesting, a statement about EDC exposure would be sensible because absorption into the fetus is different from hormone concentrations in the mother.

But overall, everyone is overly frightened. People will only eat tuna twice a month because they worry about mercury exposure. Society is afraid of bacteria on the kitchen counter, which is crazy — humans evolved to live in dirt 200,000 years ago. Bringing up EDCs with patients is just going to make them scared about something that doesn’t really affect them.

There is a lot of fear that chemicals in the environment are reducing sperm count and may relate to why girls are entering puberty earlier. That’s not demonstrated for specific molecules, and we can’t hide from chemical exposure no matter how we try or where we live.

Stanley Korenman, MD, Professor, Medicine, Endocrinology, Diabetes Metabolism and Hypertension; Regulatory Program Director, CTSI Associate Dean for Ethics, David Geffen School of Medicine at UCLA. Disclosure: Korenman reports no relevant financial disclosures.