Issue: January 2010
January 01, 2010
10 min read

Endocrine-disrupting chemicals: experts debate health threats

Issue: January 2010
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Recent research on potential health threats posed by endocrine-disrupting chemicals has caused some discussion in the endocrine community.

Defined as chemicals that interfere with hormone biosynthesis, metabolism and action, EDCs are found in everything, from the obvious — pesticides and building materials — to the less obvious — fabrics used for clothes, furniture, food and beverage containers.

EDCs have been linked to having a negative effect on reproductive health, thyroid, diabetes, obesity, metabolism and increased risk for breast and prostate cancer. Despite being used in these products for more than six decades, there are little data on the full extent of their damage.

Andrea C. Gore, PhD
Andrea C. Gore, PhD, is senior author of the Endocrine Society’s scientific statement on endocrine-disrupting chemicals.

Photo courtesy of: Andrea C. Gore, PhD

In June, the Endocrine Society released Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, in conjunction with its annual meeting, to bring attention to the field of endocrine disruption.

“Any level of exposure — even infinitesimally small — poses a risk,” Andrea C. Gore, PhD, professor of pharmacology and toxicology at the University of Texas at Austin, told Endocrine Today.

Common EDCs in the environment include dichloro-diphenyl-trichloroethane (DDT), a synthetic pesticide banned for agriculture use worldwide; polychlorinated biphenyls (PCBs), a class of chlorinated compounds used as industrial coolants and lubricants; and bisphenol A (BPA), a plasticizer found in water and baby bottles, food containers, dental materials and the linings of metal food cans, to name a few.

“The properties of these substances are particularly well-suited for study by endocrinologists because they so often activate or antagonize hormone receptors,” Gore, senior author of the statement, and colleagues wrote. “There is no endocrine system that is immune to these substances because of the shared properties of the chemicals and the similarities of the receptors and enzymes involved in the synthesis, release and degradation of hormones.”

Endocrine Today interviewed experts in the field about this hot topic, specifically the dangers of EDC exposure, where the current research and regulation is and how — if at all — these chemicals can be avoided.

Unknown threat

James Lundblad, MD, PhD, chief of endocrinology at Oregon Health & Science University, Portland, said the true threat of EDCs is unknown.

To date, no chemical in use has been thoroughly tested for its endocrine-disrupting effects, according to the Endocrine Disruption Exchange, an organization focused on human health and environmental problems caused by endocrine-disruptors.

EDCs are thought to exert endocrine effects primarily through receptors such as the nuclear hormone receptors, but also through interactions with receptors for neurotransmitters and other small molecule receptors.

The suggestion of harm comes from human epidemiological studies and a large number of in vivo experiments in rodents and primates demonstrating biological effects consistent with the pathophysiology suggested for human disorders, Lundblad said.

James Lundblad, MD, PhD
James Lundblad

In June, researchers presented data from several studies looking at EDCs, particularly BPA, at the Endocrine Society’s 91st Annual Meeting. One study linked BPA exposure in utero to epigenetic changes and altered developmental programming. In another study, researchers reported that low doses of BPA promoted arrhythmogenesis and altered calcium handling in the heart.

Several classes of EDCs act as antiandrogens and thyroid hormone receptor agonists or antagonists, and, recently, androgenic EDCs have been identified, according to information in the Endocrine Society statement.

“It is believed that disorders associated with these compounds may occur following exposure during critical periods of development: in utero, in early childhood or during puberty,” Lundblad said. Exposure of an adult to an EDC may have different consequences from exposure to a developing fetus or infant.

“The real danger might be that we do not have a firm grasp on the actual risks of exposure to EDCs, nor do we have firm data on the levels that are dangerous,” Lundblad said. “We are hampered in assessing the real risk by a lack of definitive evidence demonstrating harm in humans.”

Frederick S. vom Saal, PhD
Frederick S. vom Saal

One major problem is determining all of the sources of the EDCs of concern, Frederick S. vom Saal, PhD, of the division of biological sciences at the University of Missouri, told Endocrine Today.

Lundblad said although many think of exposure to EDCs as a consequence of environmental contamination by industrial chemicals such as BPA, there is also exposure from a variety of natural substances with endocrine activities; for example, phytoestrogens found in soy-based food products.

“Since these compounds are ubiquitous in the environment and the deleterious effects may appear in humans only many years following exposure, we have difficulty ascribing cause–and–effect,” Lundblad said. ”So although we have little direct evidence for harm in humans, we should not conclude these compounds are harmless, at any level.”

Available, recent data

One chemical under scrutiny is BPA. “More research has been conducted on low doses of BPA than any other chemical being used in products that people come in contact with every day,” vom Saal said.

Hundreds of published studies in laboratory animals reported adverse effects of BPA at doses previously predicted to not cause any effects, he said. These include prostate and mammary gland hyperplasia and preneoplastic lesions; changes in brain structure; chemistry and behavior such as loss of normal gender differences; uterine fibroids, ovarian cysts and oocyte chromosome abnormalities; sperm count decline; metabolic abnormalities, including obesity and insulin and glucose dysregulation; abnormal heart and liver function; and immune dysfunction.

Endocrine Today reported in December 2008 that BPA was shown to have negative effects on reproduction and was found to be present in the blood of 93% of women and 81% of men undergoing their first cycle of in vitro fertilization. Researchers at the University of California, San Francisco, measured serum BPA levels in 44 women and 31 men undergoing IVF cycles (mean age, 35.8 years). The mean BPA level was 4.2 ng/mL in women and 2.2 ng/mL in men.

Researchers at the same facility also reported variable effects of BPA on several genes involved in estrogen metabolism. The study suggested that BPA may potentially trigger decidualization of endometrial stroma, even in the absence of decidualization stimuli from the surrounding environment.

In November, results of a two-year study commissioned by the nonprofit Environmental Working Group (EWG) indicated as many as 232 chemicals in newborns of minority descent. Moreover, nine of 10 randomly selected samples of cord blood tested positive for BPA. Other chemicals found in the newborns included tetrabromobisphenol A, galaxolide, tonalide and perfluorobutanoic acid. Although the study was small, the results are significant, the EWG said.

Fast Facts

Myriad of potentially dangerous EDCs

Some focus should be shifted to the myriad of other potentially dangerous EDCs, according to Gore.

“The recent attention on BPA is justified, but we also need to be aware that most pesticides and fungicides have some endocrine-disrupting activity,” Gore said. “Poultry and cattle may receive hormones in feed or injections, and this should be reduced. Some of the ‘old’ EDCs such as PCBs, dioxin and DDT are still persistent in the environment, even though they are banned.”

Reinhold Hutz, PhD, professor in the department of biological sciences and a researcher at the National Institute of Environmental Health Science’s (NIEHS) Children’s Environmental Health Sciences Core Center, University of Wisconsin-Milwaukee, said EDCs such as PCBs and dioxin have been known to affect the reproductive axis.

“These types of molecules can alter the way estrogens bind to their receptors or the way estrogens are synthesized in the body, and thereby may exert effects on brain function, cardiovascular function, fertility, osteoporosis and so on,” Hutz said.

The results of a recent NIEHS-funded study suggested that the plasticizing agent di-(2-ethylhexyl) phthalate (DEHP) may interfere with the hormonally controlled signaling that initiates birth. Women at the upper range of exposure to DEHP were found to have a two-day longer gestation length than women at the lower range of exposure. The results, published in the April issue of the American Journal of Epidemiology, also showed that highly exposed women had higher odds for cesarean section delivery and delivery at 41 weeks of gestation or later and decreased odds for preterm delivery.

The NIEHS describes phthalates as chemicals used in a range of products — including food and beverage containers, pharmaceutical pills and nutritional supplements, gelling agents, personal care products, medical devices, detergents, children’s toys and nail polish.

Another NIEHS-funded study reported that exposure to dioxins during pregnancy harms rapidly growing and dividing epithelial cells in breast tissue, which researchers at University of Rochester Medical Center reported may explain why some women have trouble breast-feeding. Using laboratory mice, the researchers showed that early administration of dioxin caused mammary cells to stop proliferating as early as six days into the pregnancy and continued until mid-pregnancy. The results were published in Toxicological Sciences.

New research has also shown that PCBs, which were banned 30 years ago, may alter in utero neonatal brain development. Researchers at the University of California Davis provided evidence in three separate studies of how low-level exposure to PCBs altered the normal development of brain cells. According to the NIEHS, these findings could help explain the relationship between PCB exposure and neurodevelopmental and behavioral disorders. These findings were published in Toxicology and Applied Pharmacology.

Level of exposure

The question seems to be: How much exposure to EDCs is too much?

Because EDCs are in substances all around us — both naturally occurring and man-made — reducing exposure is difficult, especially because any level of exposure can be considered risky, Jason A. Wexler, MD, endocrinologist at Washington Hospital Center, in Washington, D.C., told Endocrine Today.

Jason A. Wexler, MD
Jason A. Wexler

“In other words, there is no safe level,” Gore said.

She cited strong scientific evidence for very low-dose effects of EDCs on endocrine and reproductive functions.

“Low doses are the most pertinent when exposure occurs to developing organisms,” Gore said. “In some cases, these organisms normally have no exposure to some hormones — and exposure to tiny amounts of an endocrine disruptor changes the way these organisms will develop and potentially predispose them to develop a disease later in life.”

Lundblad referenced evidence from in vitro studies that demonstrate endocrine effects “well below concentrations expected from affinities for suspected receptor targets.”

“It is thought that low levels of exposure may be more likely to cause problems than higher exposure levels, and it is possible that exceedingly small exposures could lead to endocrine problems later in life,” Wexler said.

Issues key to understanding the mechanisms of action and consequences of exposure to EDCs include:

  • Age at exposure;
  • Latency from exposure;
  • Dose response dynamics; and
  • Long-term latent effects

“It may be that age at exposure, length of exposure, route of exposure and the particular cocktail of compounds that people are exposed to in life are more important than the specific amount of exposure,” Wexler said.

As dangerous as specific compounds may be on their own, Hutz said there must be more research done on the mixtures of these molecules as well.

This is a confounding variable that “human populations are exposed to complex mixtures of these contaminants, and they may elicit additive or synergistic combinatorial effects,” Lundblad said.

“Is the combination greater than the individual parts?” Hutz asked.

Endocrine Society statement

The Endocrine Society statement outlines the public health concerns of exposure to EDCs and proposes a series of recommendations for revising current policy and generating new policy on EDCs.

The organization is concerned that the public may be placed at risk for exposure to EDCs because critical information about potential health effects of EDCs is being overlooked in the development of federal guidelines and regulations, according to the society.

Recommendations for improved awareness include enhancing research and advocating involvement of stakeholders in communicating and implementing changes in public policy and awareness (see second chart ).

“The Endocrine Society does not support alarmist action but does think the American public should have all the facts and should be protected from potential harm,” R. Thomas Zoeller, PhD, a member of the writing group that drafted the position statement, said in a press release. “It is clear that more integrated research into this critical health issue is needed to inform effective risk assessment and development of meaningful policy.”

In November, the American Medical Association’s House of Delegates adopted a resolution calling on the AMA to work with the federal government to enact new federal policies to decrease the public’s exposure to EDCs. This measure was advanced by the Endocrine Society, American Society for Reproductive Medicine and American College of Obstetricians and Gynecologists.

Chemical Idenitfies as Endocrine-Disrupters:

• Polychlorinated biphenyls • Chlorpyrifos
• Polybrominated biphenyls • Dichlorodiphenyltrichloroethane
• Dioxins • Vinclozolin
• Bisphenol A • Diethylstilbestrol
• Phthalates • Phytoestrogens such as genistein and coumestrol
• Methoxychlor

Endocrine Society Recommendations for Research and Practice Regarding EDCs

• Centralized regulatory oversight of EDCs, ie, regulations pass through a single office to ensure coordination among agencies. • An overall precautionary approach for the formulation of EDC policy until conclusive scientific evidence exists to prove or disprove the effects of EDCs.
• Policies based on comprehensive data on both low- and high-level exposures. • A public awareness campaign developed by the federal government to inform the public of the risks and potential risks related to the presence of EDCs in the environment.
• Policies developed and revised by a collaborative group of endocrinologists, toxicologists, epidemiologists and policymakers to identify knowledge gaps and research directions. • Further research into EDCs, including the development of high-throughput assays that would allow the testing of many chemicals for EDCs activity at a full range of concentrations.

Source: The Endocrine Society

Regulation of EDCs

Over the past decade, the U.S. Environmental Protection Agency has worked to develop the Endocrine Disruptors Screening Program (EDSP), a formal system of screens and tests that could be used to recognize potential EDCs in the environment. According to the Endocrine Society’s position statement on EDCs, although the EDSP has yet to be finalized, “recent basic and clinical research into EDCs has provided significant new information about the mechanisms of EDCs on human health that could require modifications to the plan.” They said they fear that if the EDSP is taken in its current form, it will already be outdated.

The society also pushed for reform of the Toxic Substances Control Act (TSCA), which regulates the introduction of new or already existing chemicals, as it claims the bill does not ensure adequate requirements for testing of chemicals for potential EDC activity and effects.

“The TSCA is being revised by Congress, and unless the new law contains some method to determine what chemicals are being used in products, it will continue to be impossible to know how to avoid exposure to EDCs,” vom Saal said.

In August 2008, the FDA released a draft report claiming that BPA remains safe in food contact materials. However, in late October 2008, a subcommittee of the FDA’s science board raised questions about whether the FDA’s review had adequately investigated the most recent research available on BPA. According to the FDA website, results of this review were expected on Nov. 30; as of press time, these results were not made public.

“We need to put pressure on the regulators of chemicals,” Gore said.

According to vom Saal, there has been a huge gulf between the scientific community and regulatory agencies regarding EDCs.

“Legislation and regulation of production will have the greatest impact, but the strength of the science will drive the political will to accomplish this,” Lundblad said.

“Right now, the idea is that something is safe until proven unsafe. We need to use the precautionary principle, in which we assume something is unsafe unless proven otherwise,” Gore said. – by Angelo Milone

Is enough being done by government agencies in the prevention of EDC exposure?

For more information:

  • Bromer JG. OR33-4. Presented at: the Endocrine Society’s 91st Annual Meeting; June 10-13, 2009; Washington, D.C.
  • Diamanti-Kandrakis E. Endocrine Reviews. 2009;30:293-342.
  • Environmental Working Group. Cord blood report: toxic chemicals in minority newborns. 2009. Accessed on: Dec. 10, 2009.
  • Grun F. Endocrinology. 2006;147:S50-S55.
  • Hutz RJ. Tren Reprod Bio. 2006;2:1-11.
  • Stout DM. Environ Sci Technol. 2009;43(12):4294-4300.
  • The Endocrine Disruption Exchange.
  • Wang HS. OR33-3. Presented at: The Endocrine Society’s 91st Annual Meeting; June 10-13, 2009; Washington, D.C.