A call for stronger EDC regulations as more studies establish links to human health
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The past 10 years have seen rapid growth in research on how endocrine-disrupting chemicals affect humans.
In February, the Endocrine Society partnered with the International Pollutants Elimination Network to publish a 112-page report on the state of endocrine-disrupting chemicals, commonly known as EDCs. The report acknowledges that the amount of science published on EDCs has greatly increased in recent years and states that studies have attributed more than 24% of human diseases and disorders to environmental factors, including EDCs.
“The basic science information has grown enormously,” Andrea C. Gore, PhD, professor of pharmacology and toxicology and the Vacek Chair in Pharmacology at the University of Texas at Austin and lead author on the Endocrine Society’s report, told Healio | Endocrine Today. “What was most important over those years was a better understanding of mechanisms and a broader understanding of which endocrine systems are being affected by EDCs.”
A lot of early EDC research focused on how the chemicals affected sex and thyroid hormones, according to Michele A. La Merrill, PhD, MPH, professor of environmental toxicology at the University of California, Davis, and a co-author on the Endocrine Society report. In recent years, EDC research has expanded into other endocrinology subspecialties and has led researchers to make further connections with adverse effects.
“There’s been an expansion of research into other areas, in particular looking at the endocrinology of obesity and diabetes, which are highly prevalent,” La Merrill told Healio | Endocrine Today. “They have been examined for a role of EDCs, and those studies are easier to conduct in humans than, for example, a study on reproductive health.”
Investigating links between EDCs and metabolic disorders has been a focus for Robert Sargis, MD, PhD, associate professor of medicine in the division of endocrinology, diabetes and metabolism at the University of Illinois Chicago College of Medicine and a co-author on the Endocrine Society’s EDC report. Sargis described EDCs as an underappreciated environmental determinant of health and as one of several factors that may increase a person’s risk for diabetes, obesity and other metabolic diseases.
“While a single chemical may be the driver of metabolic disease in a minority of patients, it’s the diversity of chemical exposures that likely drives risk for most,” Sargis told Healio | Endocrine Today. “When we think about how to stem the tide of metabolic disease, we work on lifestyle intervention, we work on addressing the obesogenic environment by making it easier to be physically active and by making sure there’s access to healthy foods, but we also need to address the environmental determinants of health that remain woefully neglected.”
More studies on EDCs in larger sample populations has led to a stronger consensus among scientists, physicians and medical societies that many chemicals are tied to adverse health outcomes, according to Gore. The challenge for researchers and providers is now shifting toward understanding the real-world clinical impact of EDCs, making the public aware of the risks chemicals pose and advocating for regulation that can help limit human exposure.
Progress in research
Conducting studies on EDCs presents several challenges. One is the difficulty of determining whether a chemical is causing a specific disease.
“We know from basic endocrinology how sensitive the human body and all animals are to both natural hormones and substances that disrupt hormones,” Gore said. “Sometimes, we don’t even have the technology to measure the levels of certain compounds on the human body, so we have to draw inferences.”
One of the biggest challenges with assessing the effects of EDCs is that the endocrine system involves the interplay of multiple organs, according to Sargis.
“There’s so much inter-organ and inter-tissue cross talk that it makes it difficult to extrapolate out from a cell culture model or even sophisticated cell culture systems that involve multiple tissues, to fully capture everything that happens in an organism,” Sargis said.
In addition, some chemicals have nonlinear, dose-response effects, and those effects found in humans may differ from what scientists observe in animal studies, according to Elizabeth N. Pearce, MD, MSc, professor of medicine in the section of endocrinology, diabetes and nutrition at Boston University Chobanian & Avedisian School of Medicine and a Healio | Endocrine Today Editorial Board Member.
Although animal studies have limitations, they play a crucial role linking EDCs with adverse health outcomes, according to Sargis. In recent years, research has shifted more toward human studies such as population-based research. The use of blood, urine and tissue samples collected in large-scale databases and study cohorts gives researchers the ability to determine exposures to a certain class of EDCs and potentially link them to a variety of endocrine disorders.
Pearce, whose focus is on thyroid disease, said during the past decade, researchers have identified numerous chemicals that have negative effects on nearly every aspect of thyroid hormone function. In a study published in Environmental International in 2020, researchers assessed data from 726 mothers and 465 neonates that were part of the Project Viva cohort in Boston. Mothers exposed to higher levels of perfluoroalkyl and polyfluoroalkyl substances (PFAS) had lower free thyroxine and gave birth to infants with lower free T4 levels. Other studies have also tied higher perchlorate exposure to lower levels of free T4.
“As far as we know, perchlorate only affects the thyroid. We have a well understood mechanism and we can readily measure thyroidal effects,” Pearce said. “However, some other EDCs have mechanisms or health effects which are much more complex.”
Increasing evidence in recent years has tied EDCs to metabolic disorders. Sargis said several studies have linked bisphenol A to metabolic disruption, phthalates to beta-cell disruption, arsenic to increased risk for diabetes and PFAS to hypercholesterolemia.
A study by La Merrill and colleagues published in 2020 found that women whose mothers were exposed to higher levels of the pesticide DDT while pregnant had increased risk for obesity at age 44 to 53 years. The researchers measured DDT in blood samples from mothers who participated in the prospective Child Health and Development Studies birth cohort from 1959 to 1967 and followed up with their daughters during midlife to measure height, weight and waist circumference.
“Some of the strongest evidence of EDCs operating in humans are the studies looking at chemicals as risk factors for obesity,” La Merrill said. “Because pretty much no one conducts a study without asking for height and weight, it’s easy to calculate BMI. That’s facilitated a lot of people being able to [study EDCs and obesity].”
Research into EDCs has expanded beyond endocrinology. A study published in The New England Journal of Medicine in March found adults who had microplastics and nanoplastics in carotid artery plaque had higher risk for myocardial infarction, stroke or death than adults without the microparticles.
EDC regulation lacking in U.S.
The number of studies linking EDCs to adverse health outcomes in humans has progressed, but regulation limiting people’s exposure to chemicals has moved at a slower pace in the U.S.
According to the Endocrine Society report, the European Union adopted criteria for identifying EDCs in biocides and pesticides in 2017 and 2018. In 2022, the European Commission proposed new hazard classes for classifying, labeling and packaging chemicals, including EDCs, to better protect people and the environment.
In the U.S., chemicals are regulated under the Toxic Substances Control Act, according to the Endocrine Society report. However, the U.S. Environmental Protection Agency has reviewed fewer than 10 chemicals since the act was adopted in 1976. The EPA has a program in place to analyze pesticides used on food, but the report states the agency has never identified one as an EDC. Additionally, the report states the FDA does not have requirements in place to test for EDCs in food ingredients and food contact materials.
Researchers said they believe that there are several factors that have limited EDC regulation in the U.S. Among those factors is that U.S. regulators have a narrower view of endocrine disruption, according to La Merrill. She said agencies consider EDCs as chemicals that affect only androgen, estrogen or thyroid hormones.
“When you unnecessarily narrow the true biology, then by extension you’re unnecessarily missing true toxicity,” La Merrill said. “That’s really a concern.”
The FDA has established acceptable daily intake levels for some chemicals. However, those restrictions may not go far enough, according to La Merrill. A study published in Endocrinology in 2023 found female mice exposed to the FDA’s human accepted daily intake levels of two types of parabens were more likely to develop cancer than unexposed mice.
“Revisiting some of the basic assumptions about existing chemicals would be helpful,” La Merrill said. “Parabens are used not just in cosmetics and beauty care products, but are also used as preservatives in foods and medicines. It is under the purview of the FDA to say what’s safe and to control human exposure.”
Gore said one issue holding back regulation in the U.S. is that research done at the FDA follows what are called “good laboratory practices” (GLP), which requires using arbitrarily large sample sizes and has very high costs. Academic labs typically use statistical power analyses to determine how many rodents or tissue culture plates are needed; grant awards are not big enough to meet the GLP threshold. As a result, FDA may not include the results of high-quality academic studies when making regulatory decisions.
“When we’re trying to answer questions about whether a chemical will cause a reproductive problem or change gene expression in the brain, we don’t have enough funding to be able to have sample sizes that are that big and to do the work the way that regulatory bodies do it,” Gore said.
Pearce said she believes that part of the reason the U.S. lacks regulations for EDCs is due to influence from the chemical manufacturers.
“Companies that manufacture these chemicals or create a lot of pollution that’s causing population exposure are often well resourced with a lot of lobbying,” Pearce said. “That has unequivocally played a role.”
Pearce added that restricting or banning a chemical solves only part of the problem. She said companies that manufacture a product with a restricted chemical may replace the chemical with another substance that could also be an endocrine disruptor.
“Some of the substitutes that replace the original chemicals may or may not be any safer, they just may be less tested,” Pearce said.
Raising public awareness
EDC regulation continues to lag in the U.S., but a rise in public awareness could help push for change. Gore credited greater media coverage on EDCs with increasing public awareness. Organizations such as the Endocrine Society have also tried to provide resources for providers so they can increase awareness.
A lack of clinical guidance on EDCs has potentially kept providers from discussing the chemicals in greater detail with patients, according to Sargis. The National Academies of Sciences, Engineering, and Medicine published one of the first detailed guidance documents on EDCs in 2022 when it released a 280-page guideline focused on PFAS exposure, testing and clinical follow-up. Sargis said the document was a good start for providing information on one common class of EDCs but added that the guidance did not touch on other chemical classes.
“There’s still too much compartmentalization of environmental health separate from clinical practice,” Sargis said.
Providers can help patients by offering ways to reduce EDC exposure at the individual level, according to Pearce. She said people should carefully wash produce to limit exposure to pesticides and other environmental chemicals. Food should be stored and heated in glass or ceramic containers instead of plastic to avoid chemicals leeching into food. Eating fewer processed or canned foods can also help people avoid EDCs.
Beyond food, Pearce suggested washing clothes and cookware before using them for the first time. Regular dusting and house cleaning can prevent EDCs from accumulating in household dust. Families with young children should be aware that older toys may contain EDCs. Pearce also suggested avoiding contact with thermal receipt paper, which contains bisphenol A.
Still, Pearce said, eliminating exposure entirely is almost impossible because EDCs are ubiquitous in the environment.
“What we need is more science and more regulation,” Pearce said. “Some of these exposures in drinking water and air pollution are not things that individual households, hospitals and medical practices can manage.”
The future of EDC research
Many questions regarding EDCs remain.
“There’s been little research on the system that regulates blood pressure,” La Merrill said. “There’s little that’s been done on the hormones that come from our brain that talk to the distal tissues. I’ve never seen anyone do a toxicology study on the pineal gland.”
One of the next steps in research is examining the effects of mixtures of chemicals, according to Sargis.
“Techniques using mass spectrometry to measure multiple chemicals simultaneously give us a sense of exposures across a spectrum of different endocrine disruptors,” Sargis said. “The computational approaches to look at mixtures is evolving rapidly and robustly. In our own studies, we’re starting to look at metal exposures, metal mixtures and how they relate to adverse health outcomes.”
Gore said a greater understanding of the mechanisms of endocrine disruption and how EDCs affect multiple systems is needed to develop interventions for people with high chemical exposures.
“One of the problems with EDCs is they’re not like pharmaceuticals,” Gore said. “They were never designed to bind to a single receptor. They were designed to be in a plastic water bottle or to be used in pesticides. When they get into the body, their structures are often such as that they can interact with multiple different hormone receptors.”
Researchers also plan to examine multigenerational effects of EDCs. Gore said a person’s exposure to EDCs could potentially affect their children and grandchildren.
“We think epigenetic programming is happening within germ cells in a way that is heritable,” Gore said. “There are a number of labs that are trying to understand the mechanisms for that. But there is some evidence that DNA methylation may be involved. The other mechanism is something we’re trying to study in my lab, which is small noncoding RNAs that can affect gene expression.”
Pearce and Sargis both said more studies are needed to examine the effects of EDCs at specific points of one’s life.
“Thyroid disruptors probably matter most early in life, because of the potential adverse effects in neurodevelopment, the fetus and young children,” Pearce said. “Studying effects in pregnant women and young children from an epidemiologic perspective is where our energy needs to be focused.”
Sargis agrees.
“There are additional windows of vulnerability that also need to be studied more,” Sargis said. “Those include more studies during puberty when these big changes are happening. Studies in the elderly or aging populations are important given that resilience or resistance to some of these exposures may be reduced due to physiological changes as well as comorbidities and their treatments.”
- References:
- Gore AC, et al. Endocrine-disrupting chemicals: Threats to human health. https://www.endocrine.org/-/media/endocrine/files/advocacy/edc-report2024finalcompressed.pdf. Published Feb. 26, 2024. Accessed April 16, 2024.
- Guidance on PFAS Exposure, Testing, and Clinical Follow-Up. https://www.nationalacademies.org/our-work/guidance-on-pfas-testing-and-health-outcomes. Published July 28, 2022. Accessed April 16, 2024.
- La Merrill MA, et al. Int J. Obes. 2020;doi:10.1038/s41366-020-0586-7.
- Marfella R, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2309822.
- Preston EV, et al. Environ Int. 2020;doi:10.1016/j.envint.2020.105728.
- Tong JH, et al. Endocrinology. 2023;doi:10.1210/endocr/bqad007.
- For more information:
- Andrea C. Gore, PhD, can be reached at andrea.gore@austin.utexas.edu.
- Michele A. La Merrill, PhD, MPH, can be reached at mlamerrill@ucdavis.edu.
- Elizabeth N. Pearce, MD, MSc, can be reached at elizabeth.pearce@bmc.org.
- Robert Sargis, MD, PhD, can be reached at rsargis@uic.edu.
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