Hormonal Injustice: Environmental Toxicants as Drivers of Endocrine Health Disparities.

Projected to afflict 783 million adults by 2045, global diabetes prevalence has increased dramatically over recent decades. 10 In the United States alone, 37.3 million people have diabetes; however, the disease burden is not uniform. 11 Diabetes prevalence is markedly lower among non-Hispanic Whites compared with all other minority racial/ethnic groups. Critically, racial/ethnic minorities also suffer from higher diabetes-associated morbidity and mortality. 12 Marked diabetes disparities are also noted by socioeconomic status (SES). 13 In 2017, US adult obesity prevalence reached an astonishing 41.9%. 14 Prevalence was highest among Hispanics/Latinos and non-Hispanic Blacks. Across all groups, prevalence increases with lower educational attainment. Although associations between obesity rates and SES remain somewhat murky, SES seems to predict body fat distribution, with those of lower SES accumulating fat more centrally, a characteristic associated with various metabolic comorbidities. 13 Drivers of obesity disparities include differences in food availability arising from variations in the retail food environment that concentrate poor-quality resources in more disadvantaged areas, 15 and neighborhood insecurity and a lack of green spaces 16 ; more recently, chemical exposures have been implicated. 17 Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by alcohol-independent hepatic fat accumulation associated with inflammation, fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. By 2030, approximately 100.9 million US adults are projected to be afflicted by NAFLD. 18 Importantly, NAFLD prevalence and complications exhibit notable disparities, with the greatest disease burden among Hispanics/Latinos. 19 Although men are disproportionately affected, evidence indicates that women may have higher rates of NAFLD-related complications. 20 NAFLD disparities are also noted based on SES, with low-income populations experiencing greater prevalence, disease progression, and complications. 21 Globally, 200 million people are affected by thyroid diseases, 22 with incidence increasing with age, iodine deficiency, and radiation exposure. 23 Thyroid nodules are more prevalent in women than men, with White individuals disproportionately affected. 24 Importantly, epidemiologic evidence links thyroid nodules with the metabolic syndrome. While this association is observed in both sexes, women are at greater risk of developing thyroid nodules than men with the same metabolic disturbances. 25 Although diagnostic bias may confound the associations, thyroid cancer is more prevalent among Whites, with socioeconomic factors predicting survival. 25 , 26 Despite this, evidence suggests that Black patients have lower survival rates regardless of screening or SES. 27 In addition to disparities in thyroid cancer, Blacks are more likely to develop thyrotoxicosis than Whites, 28 with disparities also present for hypothyroidism. Among those with subclinical hypothyroidism and comorbid congestive heart failure, Blacks have higher mortality rates than non-Blacks. 29 Racial/ethnic and socioeconomic disparities characterize women’s health from menarche to menopause. For example, Hispanic/Latina and Black individuals reach menarche at younger ages than their White counterparts. 30 Furthermore, early onset of menarche is associated with fibroid tumors and increased risk for breast and ovarian cancer. 31 Among women with fibroids, racial minorities with lower SES had greater fibroid severity and decreased health-related quality of life. 32 In addition to earlier menarche, Black women reach menopause earlier than White women, and they experience longer menopausal transitions. 33 Polycystic ovarian syndrome (PCOS) is an endocrine disorder characterized by ovarian cysts, menstrual irregularities, hyperandrogenism, infertility, and metabolic dysfunction. Women of lower SES are at greater risk of developing PCOS, and Black women with PCOS are more likely to develop metabolic complications. 34 Among men, reproductive disparities are also notable. Compared with Whites, Black individuals were significantly more likely to have lower sperm volume and concentration with fewer motile sperm. 35 These issues are likely exacerbated by the fact that Black populations are disproportionately burdened by metabolic disorders, which also negatively affect spermatogenic activity and semen quality. 36 Disruptions in adrenal function adversely affect health and development in myriad ways. Compared with White men, Black men are more likely to exhibit dysregulated cortisol secretion patterns, which are linked to multiple adverse health outcomes. 37 Furthermore, conditions of excess cortisol production are more prevalent among women. 38 Primary hyperaldosteronism, the most common cause of secondary hypertension, is more common in Black populations. 39 Androgen excess is linked to PCOS and other reproductive disorders in men and women, with prevalence varying by race/ethnicity and SES. Collectively, the available evidence points to race/ethnicity-, gender-, and income-based disparities across a spectrum of endocrine disorders; achieving health equity requires identifying and addressing the drivers of these differences.

Multiple social and structural determinants of health undoubtedly contribute to the marked racial/ethnic-, gender-, and socioeconomic-based disparities in endocrine health; however, the contribution of environmental injustice is vastly underappreciated. Indeed, those groups disproportionately burdened by endocrine disorders are often exposed to higher levels of various EDCs, including PCBs, phthalates, bisphenols, OC pesticides, air pollutants, PFASs, toxic metals/metalloids, and BFRs. Furthermore, the contribution of disparate exposures to health disparities is likely underestimated because of a paucity of data examining the adverse effects of combined EDC exposures. As such, health equity requires interventions to address environmental injustice. Such approaches must include a complementary array of individual action and public policy, 127 the latter of which is inadequately used. 128 Based on the Developmental Origins of Health and Disease hypothesis that posits long-term health risks imposed by stressors during sensitive developmental windows (including EDC exposures), it is essential that interventions be targeted to those most vulnerable, including pregnant mothers and infants, among others. However, it is also critical to recognize that EDC exposures and their disproportionate burden on low income and communities of color is a systemic problem for which individual action is insufficient. Rather, policy interventions are required, including robust efforts to identify EDCs before they enter commerce, eliminate EDCs already in use, mitigate contaminated sites, and develop socially just policies that end the discriminatory siting of polluting industries. Vigorously pursued, such efforts have the potential to improve endocrine health equity while reducing the burden of disease for everyone.

A wide spectrum of endocrine disorders are characterized by health disparities, including metabolic, 1 thyroid, 2 and reproductive disorders. 3 Although metabolic disease prevalence has increased across sociodemographic groups, minority racial/ethnic groups carry a greater disease burden. 4 This difference is exacerbated by educational and socioeconomic disparities, 5 reduced access to resources, and systemic oppression. 6 Evidence indicates that vulnerable populations are disproportionately exposed to various environmental toxicants, including multiple endocrine-disrupting chemicals (EDCs). 7 An analysis of EDC exposures and disease burden across racial/ethnic groups noted higher exposures among non-Hispanic Blacks and Mexican Americans relative to non-Hispanic Whites. 8 Furthermore, per capita EDC-associated health care costs are higher among people of color. Of $340 billion in US health care costs associated with EDCs, Black and Mexican American communities accounted for 31.4% of total expenditures while only comprising 26.1% of the population. 8 The disproportionate burden of hazardous chemical exposures borne by vulnerable communities is an environmental justice crisis with multigenerational consequences. 9 This review highlights key data linking EDC exposures to endocrine health disparities.

Although various social and structural determinants of health contribute to disparities in endocrine health, less appreciated are the contributions of differential exposures to EDCs. The Endocrine Society defines EDCs as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action.” More than 500 EDCs have been identified, including polychlorinated biphenyls (PCBs), bisphenols, phthalates, organochlorine (OC) pesticides, per/polyfluoroalkyl substances (PFASs), metals/metalloids, flame retardants, and air pollutants, among others. Critically, exposure to these chemicals is not uniform across populations. Rather certain groups are disproportionately exposed, including various minority racial/ethnic groups, with noted gender-based disparities. 8 , 40 , 41 Those with low incomes or of lower SES are also disproportionately exposed. 42 These exposure disparities are driven by multiple social factors, including dietary patterns, consumer product usage, living conditions, labor practices, and geography, 41 all of which are driven by current and historical policies influenced by racist and classist power structures. Thus, environmental injustice drives exposure disparities. The following highlights key literature regarding notable EDC exposure disparities and adverse endocrine health effects ( Fig. 1 , Table 1 ). PCBs are a class of persistent organic pollutants (POPs) historically used for a multitude of industrial applications. Although PCB production was banned in the US in 1979, they persist in the environment because of their long half-lives and continued leaching from older consumer products and industrial waste facilities. Their hydrophobicity and chemical stability results in accumulation in the fatty tissue of animals over time through consumption of contaminated food or prey, resulting in biomagnification at higher trophic levels of the food system. Consequently, human exposure continues through air, soil, food, and water sources. Following exposure, PCBs are associated with multiple adverse endocrine health effects. PCBs mimic the structure of thyroxine and interfere with thyroid hormone homeostasis. 43 PCBs are also associated with metabolic dysfunction in human studies. 44 , 45 Specifically, a 2014 meta-analysis revealed that individuals exposed to the highest levels of PCBs had a two-fold higher risk of diabetes. 46 In cellular and animal models, PCBs alter insulin release and insulin sensitivity, among other effects, resulting in a diabetic phenotype. 47 Both epidemiologic and preclinical data also link PCBs with NAFLD. 48 PCB exposure is not homogenous across racial/ethnic groups. Among US adults, Black individuals have significantly higher blood PCB levels than all other racial/ethnic groups, whereas among adolescents and young adults, Pacific Islanders and Native Americans have the highest levels. 49 This disparity may be particularly important in the United States where PCB levels are generally higher in US-born individuals than immigrants. 50 It is postulated that these PCB exposure patterns are primarily driven by dietary consumption and past exposures, but more evidence is needed. 49 Lastly, occupation and housing are associated with higher PCB levels, and there are noted income-based disparities as well. 51 , 52 Phthalates are a family of nonpersistent phthalic acid esters with short half-lives but numerous exposure sources. Often classified by their molecular weight, low-molecular-weight phthalates are commonly used in personal care products and solvents, whereas high-molecular-weight phthalates serve as plasticizers in medical equipment and food packaging. 53 These compounds leach from products, leading to exposure via ingestion, dermal contact, or inhalation. Although phthalates are nonpersistent pollutants, continuous and repeated exposure can promote adverse health effects. In women, phthalates are associated with ovarian and uterine dysfunction, contributing to the development of PCOS, uterine fibroids, and endometriosis through direct estrogenic effects. 54 During pregnancy, maternal phthalate exposure is associated with placental disruption, pregnancy loss, and greater risk of preterm birth. 55 Phthalates also disrupt male sex steroid signaling, including antagonism of androgen receptor signaling. Consequently, phthalates are linked to hypospadias and male infertility. 56 Moreover, via interactions with various nuclear receptors, phthalates promote diabetogenic and obesogenic effects. 43 , 44 Indeed, numerous epidemiologic studies associate phthalates and phthalate metabolites with increased diabetes risk. 57 Lastly, phthalates disrupt enzymes involved in adrenal hormone production. 58 Women are disproportionately expose to phthalates, likely a consequence of their greater use of personal care products. Among women, Black and Mexican American women have higher levels of almost all phthalates and phthalate metabolites. 59 This may be the case because beauty products directly marketed to women of color contain higher levels of phthalates and other chemicals. 60 Marketing strategies perpetuate European beauty standards among minority populations, leading to disproportionate use of skin lighteners, hair relaxers/straighteners, and odor reduction products known to contain EDCs. 60 Similarly, inexpensive building materials, fast food, and consumer products are more likely to contain a variety of EDCs, including phthalates, placing those of low SES at greater risk of exposure. 61 , 62 Bisphenols, such as bisphenol A (BPA), are found in numerous consumer products, including the linings of food containers, plastics, thermal paper, and preservatives. 63 Like phthalates, bisphenols are nonpersistent pollutants; however, humans are continuously exposed. BPA is a well-studied EDC that disrupts multiple signaling cascades, including estrogen receptors, growth factor receptors, and other pathways implicated in diabetes, cardiovascular disease, and cancer. 64 As a xenoestrogen, BPA is linked to multiple reproductive disorders, including PCOS, cryptorchidism, and male infertility. 56 , 65 Because of BPA’s disruption of metabolic pathways, human and preclinical studies have linked BPA exposure with increased metabolic disease risk, including obesity and diabetes. 44 , 66 The latter findings are supported by robust in vivo and in vitro data demonstrating BPA’s capacity to perturb metabolic homeostasis. 64 Additionally, BPA is implicated in adrenal dysfunction through targeting of enzymes involved in the synthesis of glucocorticoids, mineralocorticoids, and androgens. 58 Across the general population, women and those with lower incomes have greater BPA exposure. 67 Women of color, especially Black women in the United States, have higher BPA levels. 68 , 69 Furthermore, low-income families and those that received emergency food assistance have higher levels of BPA independent of other sociodemographic factors. 70 , 71 Historically used throughout the world, OC pesticides are POPs that were banned in the United States in the 1970s. Despite their toxicity, several OC pesticides are still used in developing countries, including dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane, aldrin, and dieldrin. 72 Because of their persistence and biomagnification, OC pesticides continue to contaminate soil, water, air, and fatty meat and fish. 73 US biomonitoring data indicate near universal exposure to OC pesticides, such as DDT and its metabolites. 74 Many studies have linked OC pesticides with endocrine dysfunction, including disruptions in thyroid hormone function and an increased risk of thyroid cancer. 75 – 77 OC pesticides are also associated with other endocrine-related cancers, including prostate and breast. 78 , 79 Levels of multiple OC pesticides are associated with diabetes and obesity. 46 , 80 – 82 Lastly, because of its lipophilicity, DDT accumulates in adrenal glands. 58 Prospective studies show that OC pesticide levels are higher among Black and Asian women compared with White women. 83 , 84 Furthermore, recently immigrated Hispanics/Latinos have higher levels of OC pesticides than longer-term US residents of the same race/ethnicity, suggesting important international exposure disparities. 7 , 50 Importantly, OC pesticide exposures vary based on occupation and income, with agricultural work an important exposure source. 85 Air pollution includes atmospheric contamination by a wide array of chemical, biologic, and physical agents. The most common air pollutants include fine particulate matter less than 10 μm and less than 2.5 μm in size (PM 10 and PM 2.5 , respectively), ozone, and nitrogen dioxide (NO 2 ), among others. Although outdoor air pollution is more widely appreciated, indoor air pollution is increasingly recognized to adversely impact health. Many studies have linked various air pollutants to endocrine disorders. Indeed, elevated PM and NO 2 exposures are associated with dysregulated glucose homeostasis and increased diabetes risk. 86 , 87 Additionally, air pollution is implicated in the progression of childhood and adult obesity. 88 , 89 This metabolic dysfunction is likely further exacerbated by associations between PM and other conditions, such as chronic liver disease. 90 Lastly, although more evidence is needed, air pollution has been linked to male infertility, including reduced sperm motility and impaired gametogenesis. 91 , 92 Critically, air quality varies geographically. Minority communities are disproportionately situated in areas with higher levels of multiple air pollutants, with exposures amplified by low-income status. 93 , 94 Additionally, minority communities are more likely to live in geographic areas with higher levels of traffic-related air pollution, which contributes significantly to NO 2 exposure and more toxic forms of PM. 95 , 96 Black and Hispanic/Latino communities have been noted to have some of the highest air pollution exposures. 97 With the implementation of federal environmental policies, absolute air quality in the US has improved since 1990; however, racial/ethnic exposure disparities persist under the influence of income inequality and historical discriminatory policies. 7 , 98 Moreover, lower income status is consistently shown to predict exposure to higher air pollution levels independent of race, ethnicity, or sex. 99 PFASs encompass a diverse family of synthetic chemicals widely used in manufacturing and consumer products, including food packaging, cookware, and outerwear among others. Considered “forever chemicals,” PFASs are another class of POPs with long half-lives that contaminate food, water, soil, and air. Various PFASs are associated with multiple adverse endocrine effects. These include links to diabetes, obesity, NAFLD, and reproductive dysfunction. 100 , 101 Importantly, PFAS exposures vary across populations. Black and Hispanic/Latino populations have been noted to have significantly higher PFAS levels compared with Whites. 102 , 103 Although some studies suggest that PFAS levels have begun to decline, this is not true across all racial/ethnic groups. For example, individuals of Chinese descent were found to have almost no decline in PFAS levels between 1999 and 2011. 104 Beyond race/ethnicity, lower SES and food insecurity are also linked to PFAS exposures, potentially as a consequence of food packaging and chemicals in less expensive personal care products. 103 , 105 A recent report by the National Academies recommends PFAS testing in those likely to have a history of elevated exposures, including those based on occupation and place of residence. 106 Such expanded testing may further illuminate PFAS exposure disparities. Toxic metal/metalloid exposures include organic and inorganic forms of several elements, including arsenic, cadmium, and lead. These elements leach naturally into groundwater via geochemical processes; however, environmental exposures are enhanced via historical and current anthropogenic activities. Climate change also increases exposure to toxic metals/metalloids. Arsenic exposure threatens the health of millions of people worldwide, with exposure occurring through contaminated food and water, tobacco use, and industrial activities among other processes. 107 Cadmium contaminates food, water, and tobacco; it is also found in plastics, dyes, and fertilizers. 108 In addition to occupational contact, lead exposure occurs through lead-containing products, including some cosmetics and jewelry, and via inhalation and ingestion from contaminated foods, lead plumbing, lead-based paints, and the largely historical use of leaded gasoline. 109 Toxic metals/metalloids are linked to multiple acute and chronic adverse health effects through a variety of mechanisms, including oxidative stress, inflammation, and endocrine disruption. 110 Despite similar mechanisms of toxicity, metals/metalloids may uniquely target certain organ systems. With respect to metabolic disease, arsenic and cadmium are noted to disrupt metabolic physiology, promoting the development of insulin resistance and diabetes, with somewhat conflicting evidence regarding their obesogenic properties. 111 Both alone and in combination with other toxic metals, lead is associated with diabetes. 112 These metals are also implicated in other endocrine conditions including thyroid disruption, infertility, and other reproductive disorders. 113 – 115 There are important racial disparities in toxic metal/metalloid exposures. For example, lead is a major public health threat in the US, and there is extensive evidence that Black and Hispanic/Latinx families are more highly exposed, especially those who live in low-income areas. 116 Additionally, in utero and postnatal lead biomarkers are higher in Black children. 117 Regions with higher groundwater arsenic levels tend to be home to greater minority populations, especially Hispanics/Latinxs. 118 Exposures also vary across countries as more recently immigrated individuals have higher toxic metal/metalloid levels than individuals who have lived in the US for longer. 119 Lastly, regardless of race/ethnicity, lower SES is associated with increased risk of heavy metal exposures, including lead, cadmium, and arsenic. 120 Added to consumer products, such as furniture, insulation, plastics, and electronics, flame retardants are synthetic chemicals used to prevent the initiation or spread of fires. 121 The most widely used brominated flame retardants (BFRs) are polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyls. BFRs are persistent pollutants that accumulate in the environment and in human tissue, with contaminated dust the major source of BFR exposures, especially in North America. 122 BFRs are associated with various adverse endocrine health effects, including diabetes, obesity, altered thyroid function, cancer, and reproductive dysfunction. 123 Studies have shown that lower income individuals and low-income housing residents had higher exposures to PBDEs, especially children. 124 , 125 There are also significant gender disparities in BFR exposures. Among young adults in China, women had PBDE levels three-times higher than those of men. 122 Racial/ethnic disparities in BFR exposures are also noted, with Black and Hispanic/Latinx populations having the highest PBDE exposures. 126