Endocrine-disrupting chemicals: Mainstream recognition of health effects and implications for the practicing internist

Abstract

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. While the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to limit known hazardous exposures coupled with proactive screening of new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances—chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Introduction

Silent Spring was not a text routinely included in the medical school curriculum of the 1960s, when Rachel Carson warned about the consequences of widespread use of dichlorodiphenyltrichloroethane (DDT).[1] Except for malaria prevention in endemic regions, DDT is rarely used today; however, Carson’s prescient warnings have implications for the present-day internist. Indeed, substantial evidence suggests that pesticides used as DDT replacements contribute to myeloid leukemias and colorectal cancer.[2] While further studies are needed to better characterize the carcinogenicity of newer pesticides, one longitudinal study has associated greater organic food consumption with reduced cancer risk.[3]

Since Carson’s landmark work, roughly one to three thousand new synthetic chemicals have been approved for industrial use annually. Current estimates suggest 300,000 synthetic chemicals are used to create consumer products,[4] and many of these chemicals were introduced without testing for safety, particularly for effects on endocrine systems.[5] In 2009, the Endocrine Society published its first scientific statement describing how a broad suite of actively used chemicals impaired endocrine function with consequences for neurodevelopment, metabolism, reproduction, and carcinogenesis.⁶ This was soon followed by a World Health Organization joint report with the United Nations Environment Programme (UNEP) that identified EDCs as a global public health issue.⁷ A second Endocrine Society scientific statement followed in 2015,⁸ and the Strategic Alliance for International Chemicals Management—the global multi-sectoral and multi-stakeholder policy framework hosted by UNEP—“welcomed” the WHO-UNEP report, acknowledging only disagreement from the chemical and pesticide industry.⁹

The Endocrine Society defines EDCs as “exogenous chemical[s], or mixture[s] of chemicals, that interfere…with any aspect of hormone action.” ¹⁰ To date, the US Food and Drug Administration has identified more than 1800 chemicals that disrupt at least one of three endocrine pathways (estrogen, androgen, and thyroid).¹¹ The actual number of EDCs is likely to be much higher, as very few chemicals have been tested for endocrine disruption, and as other receptors and the broader suite of human hormones are considered. We now appreciate that receptor binding is but one path by which hormone action can be interfered. Indeed, a recent analysis identified 10 key characteristics of EDCs, ¹² with some mechanisms such as epigenetic effects on the endocrine system only recently coming under interrogation (Figure 1). ¹³

Figure 1.

Endocrine-Disrupting Chemicals (EDCs): Sources, Mechanisms, and Impacts. This figure summarizes the realms in which EDC exposures occur, categories of EDCs and representative compounds, key characteristics by which EDCs disrupt endocrine function, and health impacts associated with EDC exposures. EDCs, endocrine-disrupting chemicals; PAHs, polycyclic aromatic hydrocarbons; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; and PFASs, per/polyfluoroalkyl substances. Created with BioRender.com.

The early evidence documenting effects of endocrine-disrupting chemicals (EDCs) linked pregnancy-associated exposures with neurodevelopmental disabilities in exposed children. ¹⁴ Subsequent studies documented consequences of early life exposures that included obesity and diabetes ¹⁵ as well as alterations in male ¹⁶ and female ¹⁷ reproductive development. While these studies focused upon exposures during early life, substantial evidence has accumulated indicating that the entire lifespan is a window of EDC susceptibility. This perspective focuses on effects that have been identified as a result of adult EDC exposure. Furthermore, it describes safe and simple steps people can take to limit their exposures.

Obesity, Diabetes, and Cardiovascular Disease

There are now more than 50 chemical “obesogens.” ¹⁸ A fungicide used in marine paints and now a known contaminant of many plastic containers, tributyltin is arguably the first and prototypical obesogen with a well-characterized mechanism of action—activation of peroxisome proliferator-activated receptor-γ signaling—through which it promotes adipogenesis and increases adipose mass. ¹⁹ Furthermore, in experimental models, tributyltin’s metabolic effects have been shown to be epigenetically transmitted across multiple unexposed generations. ²⁰

Adult exposures to synthetic chemicals are also known to increase weight gain and contribute to diabetes independent of well-known risks such as caloric excess and physical inactivity. Serum levels of per- and polyfluoroalkyl substances (PFAS) used in nonstick cooking materials and oil- and water-resistant clothing were shown to augment weight regain after a successful weight loss intervention, possibly due to reductions in resting metabolic rate. ²¹ In the Diabetes Prevention Program trial, total PFAS was associated with increased weight gain in the control group. ²² Studies from multiple countries have also identified increases in incident diabetes in association with antecedent measures of serum PFAS. ^23–25 Bisphenols used in aluminum can linings and thermal paper receipts such as bisphenol A (BPA) and one of its emerging replacements, bisphenol S (BPS), have been associated with incident diabetes in a nested case-control study within a large representative French cohort.²⁶

The cardiovascular consequences of these exposures are also substantial. BPA is known to reduce levels of the cardioprotective adipokine adiponectin ²⁷ and promote oxidative stress, ^28–31 a major mechanism underlying atherosclerosis and cardiovascular events. In human studies, BPA has been associated with greater carotid intimal media thickness, ³² severity of coronary artery disease on angiography,³³ and reduced heart rate variability.³⁴ Linking national representative surveys from Americans to death records, Bao et al. identified substantially increased risk for all-cause and cardiovascular, but not cancer, mortality among those with higher urinary BPA levels.³⁵ Phthalates are EDCs known to antagonize testosterone action,³⁶ and concerns have been raised about consequential cardiovascular risks given that low testosterone is a marker for or predictor of mortality.³⁷ Furthermore, phthalates are potent inducers of oxidative stress,^38,39 and thus may augment cardiovascular disease risk in both sexes. Indeed, linkage of urinary phthalate levels with death records revealed increases in cardiovascular mortality, independent of the increase observed with phthalates, in both sexes, suggesting approximately 90,761–107,283 preventable deaths annually in the US. ⁴⁰

Male Reproduction

In animals, the distance from the anus to the genital tubercle has been identified as a sensitive biomarker of androgen action. ^41,42 In males, this anogenital distance (AGD) is typically measured from the center of the anus to the anterior base of the penis (anopenile distance), or from the center of the anus to the posterior base of the scrotum (anoscrotal distance). During a “masculine programming window”⁴³ corresponding to weeks 8–14 of gestation in humans, perineal growth and caudal migration of the tubercle in rodents relies upon androgen function, and can be disrupted by antiandrogens.⁴⁴

Shortened AGD in boys due to antiandrogenic phthalate exposure is among the best described effects on reproductive development with independent observations from two birth cohorts, The Infant Development and Environment Study (TIDES)⁴⁵ and the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study,⁴⁶ which showed decreased anogenital distance in boys born to mothers with higher urinary levels of antiandrogenic phthalates in the first trimester of pregnancy.

Minipuberty in infancy can also be influential in shaping AGD, ^47,48 and studies suggest that AGD in animals tracks thereafter to adulthood. ⁴⁹ Shortened adult AGD is strongly predictive of sperm count, with each 1cm increase in AGD associated with a 4.3 million increase in sperm density per mL, strongly predicting reproductive potential. ⁵⁰ A study of young adults from the general population confirmed these associations (with a doubling of risk for subfertile sperm count in the lowest 10 percentile of AGD), noting the absence of an association of AGD with contemporaneously measured sex hormones or testicular size. Together, these studies suggest a strong but intermediate link of prenatal phthalate exposure with reductions in sperm count, with AGD as an intermediate biomarker. ⁵¹ This is consistent with the concept of the testicular dysgenesis syndrome originally described by Skakkebaek, ⁵² in which cryptorchidism, hypospadias, and testicular cancer can arise out of decreased production of testosterone and the neohormone insulin-like factor 3 during a susceptible window of male reproductive development.⁵³

However, multiple studies suggest that later-life exposure to EDCs can impair sperm concentration, motility, and morphology. These studies are generally cross-sectional and do not contain additional information on in utero and early life exposures. Despite these limitations, phthalates have been reported to have negative associations with one or more semen quality parameters, ¹⁵ with similar disruptions also reported for BPA, ⁵⁴ BPS, ⁵⁵ organophosphate pesticides, ^56–58 and PFAS. ^59,60 A modest number of studies have also identified increased risks for reproductive cancer. Occupational exposure to persistent pesticides has been associated with prostate cancer. ^61,62 Maternal levels of brominated flame retardants have been associated with testicular cancer in their sons. ^16,63 While further study is needed, PFAS exposure has been linked to kidney and testicular cancer as well as potentially prostate cancer. ⁶⁴

Female Reproduction

Buck Louis et al. described an analogous ovarian dysgenesis syndrome in 2007. ⁶⁵ Similar to the testicular dysgenesis syndrome, disruptions of the developing reproductive tract—including the ovary, fallopian tubes, and uterus—occur in utero; however, external phenotypes are not readily appreciated. The clinical manifestations are equally significant even if their documentation is delayed.

Epidemiologic evidence of EDC effects on female reproduction has chiefly been based on measures of adult exposure, and data have somewhat lagged behind studies of male reproductive effects. Phthalates ⁶⁶ and PFAS ⁶⁷ have been associated with endometriosis, and case-control studies have implicated PFAS and bisphenols with increased risk for polycystic ovarian syndrome. ^68–75 The effects of BPA are perhaps not surprising in light of concordant laboratory evidence of its ovarian toxicity. ⁷⁶

Multiple studies have also shown EDCs to contribute to breast cancer risk. In the Child Health and Development Studies, prenatal exposure to N-ethyl-perfluorooctane sulfonamidoacetic acid was associated with breast cancer in daughters. ⁷⁷ Other studies have revealed associations of adult PFAS exposure with newly incident breast cancers. ^78,79 Pesticide exposure studies have also revealed increases in cancer risk, but none are based on biological specimens; evidence for phthalates is similarly limited. ¹⁵

Disparities in EDC Exposures

Many endocrine disorders are characterized by marked disparities in disease prevalence, complications, and/or mortality—including metabolic, thyroid, and reproductive disorders. ^80–84 In most instances, Black, Hispanic/Latinx, Indigenous, and low-income communities are disproportionately burdened. While recognition of the social/structural determinants of health (SDoH) has improved our understanding of the origins of these disparities, SDoH discussions often focus on educational attainment, economic opportunity, healthy food and activity ecosystems, and access to health care, ⁸⁵ without substantial regard for disparities in exposures to EDCs. This is a missed opportunity as minoritized and low-income communities are known to be disproportionately exposed to a variety of toxicants linked to endocrine dysfunction, including polychlorinated biphenyls (PCBs), phthalates, bisphenols, organochlorine pesticides, air pollution, PFAS, toxic metals, and brominated flame retardants (reviewed in ref. ⁸⁶). The drivers of these disparities are myriad but include neighborhood segregation, racialized labor and beauty practices, grandfathering clauses for industrial sites, suburbanization, and urban disinvestment, all of which are rooted in intersectional systems of oppression. ^87,88 While the bases of these exposure disparities have deep historical roots and are nurtured by current systems of power, unlike genetics, environments are modifiable; thus, improving environmental health has the potential to mitigate endocrine health disparities.

Disease Burden and Costs due to EDCs

Expert panels organized by the Endocrine Society conservatively estimated the costs of adult diseases (Table 1) in the European Union attributable to EDCs. ^89,90 Teresa Attina et al. expanded these to the US in 2016, ⁹¹ and Julia Malits et al. expanded these to Canada in 2022. ⁹² Trasande et al. have also estimated cardiovascular mortality due to phthalates, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the US alone. ⁴⁰ Vladislav Obsekov et al. estimated PFAS costs in the United States. ⁹³ Moreover, minoritized populations disproportionately account for EDC-associated healthcare costs. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. ⁹⁴ Critically, these are conservative estimates for several reasons, including: they are limited to a subset of chemicals in plastic materials that contribute to disease and disability; they are limited to a subset of diseases due to the few chemicals studied; and the cost estimates represent a subset of the entire costs due to the disease studied. Despite these limitations, EDC-associated healthcare costs are substantial.

Table 1.

Disease Burden and Costs of EDC Exposures in Adults.

Exposure	Life stage of exposure	Outcome	US		Canada		EU
			Disease Burden	Economic Cost (USD)	Disease Burden	Economic Cost (USD)	Disease Burden	Economic Cost (USD)
Phthalates	Adult	Obesity	5900 cases	$1.7 billion	2093 cases	$684.8 million	53,900 cases	$20.8 billion
	Adult	Type 2 Diabetes	1300 cases	$91.4 million	225 cases	$25.8 million	20,500 cases	$807.2 million
	Adult Females	Endometriosis	86,000 cases	$47.0 billion	10,151 cases	$5.7 billion	145,000 cases	$1.7 billion
	Adult Males	Male infertility	240,100 cases	$2.5 billion	1395 cases	$17.0 million	618,000 cases	$6.3 billion
	Adults	Cardiovascular mortality	90,800 cases	$39.9 billion	Not quantified yet.
PFAS	Adult	Obesity	4,294,379 Cases	$17 billion
	Adult	Kidney cancer	142 cases	$184 million
	Adults	Couple Infertility	593–26,160 cases	$37.6 million -$1.7 billion
	Adult Females	Hypothyroidism	14,572 cases	$1.3–5.2 billion
	Adult Females	Type II Diabetes	1728 cases	$140 million
	Adult Females	Endometriosis	696–18,062 cases	$397 million - $10.2 billion
	Adult Females	Polycystic ovarian syndrome	7209–7505 cases	$10.5–10.9 million
	Adult females	Breast cancer	421–3095 cases	$555 million-$4.1 billion

Healthcare as a Vector of EDC Exposure

Healthcare facilities also use many products that increase the risk of EDC exposures. ⁹⁵ Phthalates, for example, are abundant in polyvinylchloride-based medical devices such as blood bags, nutrition pockets, tubing, umbilical venous catheters or disposable gloves, where they can account for up to 40% of the final product. ⁹⁶ They are also used to make coatings for oral medications and in flooring. Bisphenols are used in polycarbonate-based medical tubing, hemodialysis equipment, newborn incubators, syringes, and nebulizers.⁹⁷ Parabens are used in medications and intravenous catheters for their antimicrobial properties. ⁹⁸ Exposures are likely the greatest per unit body weight in neonatal intensive care units, where non-invasive respiratory support and feeding tubes were identified as the most significant drivers of phthalate exposure. ⁹⁹ While modern healthcare has transformed human health and acknowledging that in some instances the removal of select EDCs from medical devices may augment risk, ⁹⁸ the lack of knowledge of medical care as a vector of exposure undermines core principles of medical ethics. ¹⁰⁰ Importantly, given the magnitude of plastic waste generated by modern healthcare systems, addressing EDCs in healthcare is likely to have broader benefits on health.

Unfortunately, health care providers know little about EDCs and seldom offer steps to patients to limit exposure.^101–104 Given that disparities in EDC exposure are well documented,^105,106 collaborative efforts are needed between scientists and healthcare organizations to develop products that improve provider knowledge about EDCs and support the use of safer alternatives in medical devices and other equipment. Healthcare providers are well positioned to communicate safe and simple steps to limit exposures; however, knowledge about environmental exposures remains limited, and health care providers still have modest self-efficacy in managing common exposures and communicating advice for prevention.^{101,103,107,108}

Addressing Gaps in Knowledge

There are particularly large gaps in the adult epidemiologic literature that would serve to advance our understanding of EDCs and their contribution to adult chronic disease. Large national and international biobank consortia (e.g., All of Us, UK Biobank Cohort) have not measured chemical exposures in sera or urine to evaluate later life vulnerabilities to these conditions. Some notable exceptions include the Nurses’ Study ¹⁰⁹ and the Study of Women’s Health Across the Nation, ¹¹⁰ but even in these samples, the researchers found limited statistical power to examine the potential effects. These cohorts have also included more women than men, which may limit their capacity to discern effects that are likely to be sexually dimorphic. Fewer still have provided mechanistic insights by examining hormone levels or leveraging multi-omic approaches to confirm or corroborate observed effects. Further work is needed to empower large-scale studies to fully interrogate the environmental drivers of disease risk in diverse populations.

Opportunities for Clinical Interventions and Prevention: PFAS and Beyond

In 2022, the National Academies of Science, Engineering, and Medicine published “Guidance on PFAS Exposure, Testing, and Clinical Follow-Up,” the first clinical guidelines on an EDC.¹¹¹ These guidelines are a milestone that bring the internist into the world of environmental health. In addition to providing extensive background on PFAS contamination and potential adverse health effects, the guidelines empower clinicians with robust, actionable guidance to identify and mitigate risk. The guidelines are focused upon a subset of potential PFAS effects for which the committee found sufficient evidence for increased risk (i.e., reductions in birthweight, dyslipidemia, kidney cancer, and reduced antibody responses) while also commenting on areas with limited suggestive evidence (i.e., breast cancer, pregnancy-induced hypertension, liver enzyme elevations, testicular cancer, thyroid dysfunction, and ulcerative colitis). Key recommendations of the guidelines include:

• 4–1: “Clinicians advising patients on PFAS exposure reduction should begin with a conversation aimed at first determining how they might be exposed…and what exposures they are interested in reducing.”

• 4–2: “If patients are exposed occupationally…clinicians should consult with occupational health and safety professionals…to determine the most feasible ways to reduce that exposure.”

• 4–3: “Clinicians should advise patients with elevated PFAS in their drinking water that they can filter their water to reduce their exposure.”

• 4–4: “In areas with known PFAS contamination, clinicians should advise patients that PFAS can be present in fish, wildlife, meat, and dairy products and direct them to local consumption advisories.”

• 4–5: “Clinicians should direct patients interested in learning more about PFAS to authoritative sources for information on how PFAS exposure occurs and what mitigating actions they can take.”

• 4–6: “When clinicians are counseling parents of infants of PFAS exposure, they should discuss infant feeding and steps that can be taken to lower sources of PFAS exposure. The benefits of breastfeeding are well known; the AAP, the AAFP, and the ACOG support and recommend breastfeeding for infants, with rare exceptions. Clinicians should explain that PFAS can pass through breast milk from a mother to her baby. PFAS may also be present in other foods, such as water used to reconstitute formula and infant food, and potentially in packaged formula and baby food. It is not yet clear what types and levels of exposure to PFAS are of concern for child health and development.”

• 4–7: “Federal environmental health agencies should conduct research to evaluate PFAS transfer to and concentration in breast milk and formula to generate data that can help parents and clinicians make shared, informed decisions about breastfeeding.”

The guidelines identify who should be tested, how PFAS levels should be interpreted with regard to health risks, and how those risks should be monitored in adults and children. A cornerstone of all environmental health interventions, exposure reduction strategies are highlighted (included in Table 2) as are potential therapeutic approaches such as the use of bile acid sequestrants or phlebotomy, although further evidence is likely needed to advocate for broad use of these approaches. Critically, these guidelines highlight many of the key principles of modern environmental health practice: patient education, clinician engagement, shared decision-making, community engagement, patient/community/clinician advocacy, and system-wide policy development and implementation that focuses on human health.

Table 2:

Transforming Clinical Care to Reduce EDC Exposures^*

Advising Patients
Context	Intervention
Reducing EDC Exposures from Food and Beverages Potential Exposure Reductions: pesticides, PFASs, bisphenols, phthalates, PCBs, and toxic metals	• Choose organic foods that are preferably locally grown, and fresh or frozen foods. • Avoid canned, processed, and fast foods. • Avoid take-out containers and other food packaging. • Avoid microwave popcorn and greasy foods wrapped in paper. • Consume a diverse, fiber-rich diet. • Trim fat from meat and skin from fish. Cook meat and fish on a rack to allow the fat to drain. • Consult local guidance regarding safe sport fish consumption. • Ensure adequate intake of calcium, iron, and iodine as well as other essential vitamins and minerals. • Store food in glass, stainless steel, or porcelain containers. • Avoid heating foods in plastic containers. • Consider testing your water and filtering your drinking water using an activated carbon or reverse osmosis filtration system. • Determine whether a lead service line provides water to your home and pursue local programs to replace it. • Reduce use of plastic containers. • Avoid polyvinyl chloride (PVC), polystyrene, and polycarbonate plastics (in U.S. recycling, numbers 3, 6, and 7).
Personal and Home Care Practices to Reduce EDC Exposures Potential Exposure Reductions: flame retardants (PBDEs and OPFRs), pesticides, triclosan, fragrances, bisphenols, phthalates, particulate matter, PAHs, parabens, PFASs, and toxic metals	• Regularly clean floors and remove dust using a damp cloth or mop. • Eliminate or drastically reduce use of household chemicals, including cleaning supplies, pesticides, and solvents. • Wash hands regularly using fragrance- and antibiotic-free soaps. • Minimize use of products packaged or stored in plastics. • Minimize handling of receipts. • Choose electrical appliances and lawncare equipment. • Use cast iron, stainless steel, glass, and enamel instead of nonstick cookware. • Increase indoor ventilation and air filtration. • Forbid smoking indoors. • Do not burn trash or yard waste. • Read product labels and avoid items containing parabens, bisphenols, and phthalates. • Avoid cosmetics with synthetic fragrances, phthalates, or toxic metals. Choose instead those labeled as “no synthetic fragrance,” “scented with essential oils,” or “phthalate-free.” • Avoid stain-resistant carpets and upholstery as well as stain-resistant treatments. • Use nylon or silk dental floss that is uncoated or coated in natural wax.
Travel, Transportation, and Activity Choices to Limit EDC Exposures Potential Exposure Reductions: particulate matter, ozone, nitrogen oxides, PAHs, and toxic metals	• Monitor air quality and avoid outdoor activities when air pollutions levels are high. • Schedule outdoor activities, including exercise, away from busy roads and at low traffic times. • Choose efficient modes and routes of travel that limit time spent in traffic. • Choose active modes of transportation, including walking, cycling, and public transportation.
Educating Patients to be Environmental Health Advocates
Empowering Patient Advocacy to Improve Environmental Health Potential Exposure Reductions: flame retardants (PBDEs and OPFRs), parabens, phthalates, bisphenols, pesticides, PFASs, particulate matter, ozone, nitrogen oxides, PAHs, toxic metals, and others	• Encourage local school districts to reduce school bus emissions, including the introduction of “No Idling Zones.” • Demand local water utilities test for PFAS and other EDCs and encourage the establishment of more health-protective drinking water limits. • Urge local political officials to pursue sustainable development, including renewable energy, walkability, bike lanes, and expanded access to public transportation. Ensure that such policies are rooted in social equity. • Ask state legislators to set up statewide water and blood testing programs to monitor for EDCs. • Encourage local municipalities to expand green spaces and increase tree planting. • Urge park districts to eliminate synthetic turf fields and the use of pesticides. • Advocate for expanded environmental health education. • Encourage politicians to promote policies that identify and eliminate EDCs, including transparent labeling to empower individual action. • Tell retailers and manufactures you want products made without EDCs and encourage elected officials to support restrictions on EDCs in consumer products. • Join local and national organizations devoted to improving environmental health.
Engaging Clinicians in Environmental Health Practice and Advocacy
Practice Improvement Potential Exposure Reductions: flame retardants (PBDEs and OPFRs), parabens, phthalates, bisphenols, pesticides, PFASs, particulate matter, ozone, nitrogen oxides, PAHs, toxic metals, and others	• Institute clinic and hospital task forces to reduce medical waste and reduce healthcare-associated EDC exposures. • Lobby professional organizations to develop environmental health clinical practice guidelines to help providers advise patients on ways to reduce EDC exposures.
Healthcare Provider Advocacy Potential Exposure Reductions: flame retardants (PBDEs and OPFRs), parabens, phthalates, bisphenols, pesticides, PFASs, particulate matter, ozone, nitrogen oxides, PAHs, toxic metals, and others	• Join professional organizations working to address the health threats of EDCs and become active participants in subgroups devoted to this issue. • Contact political representatives to advocate for policies that expand testing to identify EDCs, quantify human exposures in diverse populations, limit those exposures, and establish regulatory bodies to eliminate EDC exposures. • Encourage policymakers and regulators to develop and implement state and national programs to monitor EDCs in food, water, and human samples.

^*Adapted from references ^{12,111,119,120,124}.

Despite its sole focus on PFAS, the impact of these guidelines is difficult to overstate; however, it is also clear that expansion of clinical guidelines to address other EDCs is urgently needed. In the meantime, an array of intervention studies reveals a path forward for reducing other EDC exposures. Though large-scale intervention studies have not been conducted, small-scale interventions support the feasibility of reducing EDC exposures. Lu et al. reduced organophosphate pesticide metabolites in urine to nondetectable levels through an organic diet intervention.¹¹² Though concerns about the additional costs associated with organic food are appropriate, a more recent dietary intervention similarly reduced pesticide metabolites in a low-income, agricultural population.¹¹³ In young girls, choosing personal care products labelled to be free of phthalates, parabens, triclosan, and benzophenones reduced personal exposure by 27%–44%.¹¹⁴ Another dietary intervention study that replaced diets in a small sample of families with fresh foods reduced urinary levels of phthalate metabolites and bisphenols by 53%–56%.¹¹⁵

Household interventions can also reduce exposure. One study performed a graded comparison of offices, common areas, and classrooms, measuring dust levels of PFAS, polybrominated diphenyl ethers (PBDEs), and organophosphorus esters (OPE), the latter having increasingly replaced PBDEs in electronics and furniture. Rooms with full “healthier” materials had 78% lower dust levels of PFAS, 65% lower OPE levels, and 45% lower PBDE levels than rooms with only partial interventions, adjusted for covariates related to insulation, electronics, and furniture.¹¹⁶ To be clear, not all studies have achieved expected changes in EDC levels. One study reported an increase in urinary phthalate metabolites due to substantial phthalate contamination in the coriander provided to participants.¹¹⁷ Use of a BPA risk score based on characteristics of food containers and packaging did not reduce urinary levels.¹¹⁸ Much more work is needed to formalize clinical guidance for providers to empower them to address patient questions about exposure reduction strategies; however, recognition of exposure sources and burgeoning clinical studies can assist providers in guiding their patients (Table 2).^119,120

Policy Actions to Reduce Exposure

While beneficial, individual actions have limited power to address systemic threats to health; however, current policy interventions also remain inadequate. We refer the reader to a recent review that speaks to severe gaps in the regulation of chemicals in commerce and efforts to limit endocrine-disruptive effects.¹³ In brief, chemicals are not regulated for their endocrine-disrupting effects, and efforts are needed to improve:

• Testing and identification of chemicals that disrupt endocrine systems,

• Evaluating exposures,

• Limiting exposures through regulations, and

• Establishing an International Agency for Research on EDCs

Currently available and validated tests do not cover all endocrine modes of action. For example, US regulations require testing for estrogen agonist activity only for pesticides and drinking water contaminants. Even for estrogen and androgen signaling, the validated tests (e.g., uterotrophic assay) work best for endogenous hormones and are too insensitive for identifying EDCs. Fortunately, sensitive assays exist to test a broad number of nuclear receptors, and assays to examine receptor expression, hormone transport, hormone synthesis, and epigenetic alterations should soon be validated for inclusion in regulatory requirements. Recognizing the need to push a large suite of chemicals through a new, more scientifically up-to-date panel of tests, we suggest in vitro screening using high-throughput platforms followed by in vivo testing using zebrafish or mammalian systems to verify the absence of adverse effects using approaches that account for the integrated, multisystem nature of endocrine physiology. At the very least, such approaches should be applied prospectively to avoid the addition of new adverse exposures. Critically, we also need to regulate chemicals by class, rather than one at a time, as regrettable substitutes have emerged time and again (e.g, diisononylphthalate as a replacement for di-2-ethylhexylphthalate, and BPS for BPA).

Regulatory policies across the world use exposure and related risk to judge whether to limit chemicals of concern. However, this approach has extreme limitations, and the disease burden linked to EDCs in adults reveals the failure of a risk-based regulatory paradigm. First, current risk-based paradigms do not account for the non-linear and non-monotonic exposure-response relationships common to many EDCs.¹²¹ Indeed, the risk-based paradigm is largely based on extrapolating from no-adverse effect levels in animals to humans, which cannot be done when non-linear or non-monotonic relationships apply. There is a substantial lag from identifying new exposures to completing studies of human health effects, especially for disease outcomes with longer latencies such as diabetes or cancer. While some risk-based approaches attempt to account for age-related vulnerability, they falsely presume that the population sensitivity can be quantified a priori. Moreover, enhanced sensitivity of individuals to EDCs based on underlying disease states or their treatments remains unaddressed.¹²²

In a hazard-based regulatory environment, chemicals identified as EDCs would simply be removed from use without regard to the exposure required to achieve an adverse effect. There are precedents for a hazard-based regulatory paradigm, especially in Europe for carcinogens; persistent, bioaccumulative and toxic chemicals; and pesticides and biocides which are EDCs. If we persist with a risk-based approach, we need broader and stronger human biomonitoring platforms, particularly to address gaps in exposure assessment in low- and middle-income countries. Such biomonitoring data will also inform educational campaigns about safe and simple steps to limit exposure.

We also suggest the establishment of a new international agency, or a broadening of the International Agency for Research on Cancer (IARC)’s scientific charge, to include endocrine disruption. Established in 1965, IARC was tasked with evaluating the evidence of carcinogenesis due to environmental hazards. Monographs describe three streams of evidence (mechanistic, animal, and epidemiological studies). An autonomous body such as the IARC can bring together diverse experts for international collaborative reports on EDCs, and further support the post-2020 process of the Strategic Alliance for International Chemicals Management.

The Plastics Treaty: An Opportunity to Address EDCs Globally

Plastics are a crucial source of many EDCs, including phthalates, bisphenols, and per- and polyfluoroalkyl substances. In February 2022, the United Nations Environment Assembly announced plans to negotiate an international, legally binding instrument to end plastic pollution. Recent public and media attention to microplastics detected in both wildlife and humans¹²³ has coalesced the policy community around initiatives to reduce the use of single-use plastics. The arguments for this action have often focused on the visible microplastics, despite stronger evidence of human health effects induced by chemicals used as additives in plastics (e.g., phthalates and bisphenols). At the same time, there are substantial gaps in our scientific understanding of the relationships between detectable microplastics in biological specimens and the observed health effects of additive chemicals.

The dialogue around the “circular economy” and pivoting to reusable plastics as a solution to the plastic health crisis fails to address concerns about contamination of reused plastics containing EDCs. There is a need to transition to other materials (e.g., glass and stainless steel). While some suggest bioplastics as potential alternatives, early studies suggest potential endocrine activity that may pose similar risk to synthetic, fossil fuel-based plastics. There also remain gaps in information about the health effects of high-density polyethylene and other plastics that do not use phthalates or bisphenols. The global plastics treaty offers a profound opportunity; however, active engagement from the medical community is required to ensure that limiting the adverse health effects of plastics and their constituent chemicals is prioritized.

Conclusions

Patients are potentially exposed to a host of EDCs associated with cardiometabolic, reproductive, and other disorders that contribute substantially to healthcare expenditures. Moreover, differential exposure to these chemicals is a likely but underrecognized driver of health disparities. The internist can play a critical role in addressing this underlying health threat by working with patients on strategies to reduce their exposures; collaborating across the healthcare system to reduce exposures arising from clinical care; and advocating for local, national, and global policies that identify EDCs and remove them from our environment.