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Diabetes Care 1

Daniel Ruiz,1 Marisol Becerra,2 Disparities in Environmental Jyotsna S. Jagai,3 Kerry Ard,2 and Exposures to Endocrine- Robert M. Sargis4 Disrupting Chemicals and Risk in Vulnerable Populations https://doi.org/10.2337/dc16-2765

Burgeoning epidemiological, animal, and cellular data link environmental endocrine- disrupting chemicals (EDCs) to metabolic dysfunction. Disproportionate exposure to diabetes-associated EDCs may be an underappreciated contributor to disparities in metabolic disease risk. The burden of diabetes is not uniformly borne by American society; rather, this disease disproportionately affects certain populations, including African Americans, Latinos, and low-income individuals. The purpose of this study was to review the evidence linking unequal exposures to EDCs with racial, ethnic, and socioeconomic diabetes disparities in the U.S.; discuss social forces promoting these disparities; and explore potential interventions. Articles examining the links between chemical exposures and metabolic disease were extracted from the U.S. National REVIEW Library of Medicine for the period of 1966 to 3 December 2016. EDCs associated with diabetes in the literature were then searched for evidence of racial, ethnic, and socioeconomic exposure disparities. Among Latinos, African Americans, and low- income individuals, numerous studies have reported significantly higher exposures to diabetogenic EDCs, including polychlorinated , organochlorine pesti- cides, multiple chemical constituents of air , , and . This review reveals that unequal exposure to EDCs may be a novel contributor to 1Committee on Molecular Metabolism and Nu- diabetes disparities. Efforts to reduce the individual and societal burden of diabetes trition, University of Chicago, Chicago, IL should include educating clinicians on environmental exposures that may increase 2College of Food, Agriculture and Environmental disease risk, strategies to reduce those exposures, and social policies to address Sciences, School of Environment and Natural Re- sources, Ohio State University, Columbus, OH environmental inequality as a novel source of diabetes disparities. 3Environmental and Occupational Health Sci- ences Division, School of , Univer- sity of Illinois at Chicago, Chicago, IL Diabetes is a complex and devastating metabolic disease that arises from impairments 4 in insulin production and/or action with consequential derangements in global energy Division of Endocrinology, Diabetes, and Me- tabolism, Department of Medicine, University metabolism. In the U.S., diabetes is the leading cause of adult blindness, kidney failure, of Illinois at Chicago, Chicago, IL and nontraumatic amputations; moreover, it is a central driver of cardiovascular dis- Corresponding author: Robert M. Sargis, rsargis@ ease, the leading cause of death among people with diabetes. Diabetes disproportion- uic.edu. ately afflicts African Americans, Latinos, and low-income individuals. Compared with Received 27 December 2016 and accepted 23 non-Hispanic whites, the risk of developing diabetes is estimated to be 66% higher for September 2017. Hispanics and 77% higher for African Americans (1). Indeed, 17.9% of African Americans This article contains Supplementary Data online and 20.5% of Mexican Americans have diabetes compared with only 9.1% of non- at http://care.diabetesjournals.org/lookup/ Hispanic whites, and these disparities in diabetes prevalence have been amplified suppl/doi:10.2337/dc16-2765/-/DC1. over the past decade (2). Furthermore, age-adjusted diabetes mortality rates are © 2017 by the American Diabetes Association. significantly higher among Hispanics and non-Hispanic blacks than non-Hispanic whites Readers may use this article as long as the work is properly cited, the use is educational and not (3). Understanding the complete array of factors that contribute to racial and ethnic for profit, and the work is not altered. More infor- differences in the pathogenesis of metabolic disease is critical for addressing the mation is available at http://www.diabetesjournals disproportionate burden of diabetes in communities of color. .org/content/license. Diabetes Care Publish Ahead of Print, published online November 15, 2017 2 Environmental Inequality and Diabetes Risk Diabetes Care

Although physical inactivity and caloric various chemical constituents of air pol- the hypothesis that PCBs are metabolic excess undoubtedly are risk factors, lution, bisphenol A (BPA), and phtha- disease risk factors. For example, residen- emerging evidence implicates environ- lates (Table 1); moreover, exposure to tial proximity to PCB-contaminated waste mental endocrine-disrupting chemicals these EDCs is higher among African Amer- sites is associated with higher diabetes (EDCs) as contributors to the diabetes ep- icans, Latinos, and low-income individuals hospitalization rates (46). Among female idemic. The Endocrine Society defines an (Supplementary Table 1). These unequal residents of Anniston, serum PCB levels EDC as an exogenous chemical or mixture exposures raise the possibility that EDCs were significantly associated with diabe- of chemicals that interferes with any as- are underappreciated contributors to di- tes (47), whereas in a separate study pect of action (4). Of note, the abetes disparities. with 25 years of follow-up, women with dramatic rise in U.S. diabetes rates corre- higher PCB levels exhibited increased di- lates closely with synthetic chemical pro- PCBs abetes incidence (incidence density ratio duction (5), and these associations are Introduced in the U.S. in the 1930s for a 2.33 [95% CI 1.25–4.34]) (10). Similarly, now supported by epidemiological, ani- variety of industrial purposes, PCBs are women exposed to PCB-laced rice bran mal, and cellular data that demonstrate a class of synthetic compounds where oil during the Yucheng poisoning event that EDCs can interfere with insulin secre- various combinations of atoms in Taiwan also had an increased risk tion and action as well as with other path- on the (C12H10) structure are of developing diabetes (odds ratio [OR] ways that regulate glucose homeostasis. substituted with , resulting in 2.1 [95% CI 1.1–4.5]), with markedly Despite a history of environmental pollu- 209 congeners designated by a unique higher risk among those who developed tion disproportionately affecting commu- number reflecting the extent and position , a cutaneous manifestation of nities of color in the U.S. (6), the potential of their chlorination (e.g., PCB 153). Al- dioxin-like PCB exposure (OR 5.5 [95% CI contribution of environmental toxicants though banned by the U.S. Environmental 2.1–13.4]) (11). A meta-analysis that to racial and ethnic differences in diabe- Protection Agency in 1977, PCBs remain pooled data from the Nurses’ Health tes risk is underappreciated. detectable in tissues as a result Study (NHS) with six prospective studies The issue of environmental injustice of their environmental and biologi- showed that total PCBs were associated first entered widespread consciousness in cal persistence (37). Higher PCB expo- with incident diabetes (OR 1.70 [95% CI 1982 when residents of the predomi- sures among African Americans have 1.28–2.27]) (13). Further supporting nantly African American community of been documented since the 1960s (38) these prospective links between PCB ex- Warren County, North Carolina, made (Supplementary Table 1). Ongoing human posure and diabetes are data from cohort national news by laying themselves across exposure to PCBs is due to the legacy of studies, including the Prospective Investi- a rural road to prevent encroaching trucks contamination in food, including certain gation of the Vasculature in Uppsala Se- from dumping dirt laden with polychlori- fish (39); however, additional exposure niors (PIVUS) (16) and a group followed nated biphenyls (PCBs) in their community sources include leaching from contami- for nearly 20 years (15). Finally, although (6). This media attention prompted em- nated industrial sites and indoor con- not reaching statistical significance, a pirical examination of the community’s struction materials (40,41). PCB waste is study of Swedish women suggested that claim that facilities were being found in and toxic waste sites higher levels of PCB 153 were similarly disproportionately sited in low-income that are concentrated in neighborhoods associated with increased rates of type 2 communities and communities of color. of color (6). Although catfish consump- diabetes diagnosed after .6 years of This research has grown substantially tion has been suggested as the main con- follow-up (OR 1.6 [95% CI 0.61–4.0]) (14). since the 1980s, with the majority of evi- tributor to increased PCB levels in African Collectively, these data suggest an associ- dence showing racial and socioeconomic Americans (42), the historical siting of ation between PCBs and diabetes risk, es- disparities in exposures to myriad environ- PCB production and disposal sites in pre- pecially among women; however, some mental (6). In addition to higher dominantly black communities is likely a discrepant findings exist in the literature. exposure to air pollution nationwide (7), significant additional contributor to in- In a study of sport fish con- unequal exposures among people of color creased contamination of locally sourced sumers, PCB 118 and total PCBs were not are also rooted in patterns of occupation, foods. One example of this phenomenon is associated with diabetes (12), and in a housing conditions, and neighborhood in- Anniston, Alabama, a PCB manufacturing Flemish study that adjusted for correlated frastructure (8,9). This article reviews the city from 1929 to 1971. African Americans exposures, PCBs showed a negative asso- state of the evidence linking ethnic, racial, not only lived closer to a former ciation with self-reported diabetes (18). and socioeconomic disparities in pollut- PCB manufacturing plant but also had Despite these discrepancies, a meta- ant exposure in the U.S. to EDCs linked PCB levels three times higher than analysis of both cross-sectional and pro- to diabetes. whites living in Anniston (43). Consump- spective studies published before March tion of local fish and livestock were the 2014 showed that in aggregate, total UNEQUAL ENVIRONMENTAL strongest predictors of higher serum PCB PCBs are associated with increased dia- EXPOSURES AND DIABETES RISK levels among African Americans (44), betes risk (relative risk [RR] 2.39 [95% CI Scientific evidence linking EDCs with the whereas consumption of local dairy prod- 1.86–3.08]) (17). Taken within the context development of diabetes and other meta- ucts and near another PCB- of animal and cellular data demonstrat- bolic disorders continues to grow. Of note, contaminated Superfund site also predicted ing that PCBs alter metabolic function exposures to several toxicants have been higher cord PCB levels in infants (45). (Supplementary Table 2), this evidence prospectively linked to diabetes risk, includ- A large body of evidence, including pro- collectively suggests that PCBs contribute ing PCBs, organochlorine (OC) , spective epidemiological studies, supports to diabetes risk and disparities. care.diabetesjournals.org

Table 1—Prospective studies documenting associations between EDC exposure and diabetes risk Reference Population Outcome and comparison Effect estimate (95% CI) PCBs Vasiliu et al., 2006 (10) 1,384 subjects without diabetes in the Michigan Incident diabetes in women with the highest vs. lowest IDR: 2.33 (1.25–4.34)* polybrominated biphenyls cohort followed serum PCB levels for 25 years Wang et al., 2008 (11) 378 subjects and 370 matched referents from Incident diabetes in women who consumed OR: 2.1 (1.1–4.5)*; Chloracne OR: 5.5 (2.1–13.4)* the Yucheng poisoning in Taiwan in the 1970s laced with PCBs as well as a subgroup who developed chloracne, a manifestation of dioxin-like PCB exposure Turyk et al., 2009 (12) 471 Great Lakes sport fish consumers without diabetes Incident diabetes among the highest vs. lowest tertile Total PCBs IRR: 1.8 (0.6–5.0); PCB 118 IRR: 1.3 followed from 1994/1995 to 2005 of PCB levels (0.5–3.0) Wu et al., 2013 (13) Two case-control studies of women without diabetes Incident diabetes after pooling of data and comparing Pooled OR: 1.70 (1.28–2.27)* from the NHS and a meta-analysis of pooled data highest PCB exposure group with the referent with six additional prospective studies Rignell-Hydbom et al., 2009 (14) Case-control study of women age 50–59 years in Incident diabetes in 39 patients and matched control OR: 1.6 (0.61–4.0) southern Sweden subjects after $6 years of follow-up comparing the highest quartile of PCB levels with the referent Lee et al., 2010 (15) 90 patients and control subjects in a nested case-control Incident diabetes comparing second sextile or quartile PCB sum OR: 5.3*; PCB 187 OR: 2.8 (1.1–7.4)* study followed for ;18 years with the referent for a summary measure of 16 POPs, including 12 PCBs as well as individual PCBs Lee et al., 2011 (16) 725 participants from the PIVUS study Incident diabetes comparing a summary measure Quintile 2 OR: 4.5 (0.9–23.5); Quintile 3 OR: of 14 PCBs across quintiles with the referent 5.1 (1.0–26.0); Quintile 4 OR: 8.8 (1.8–42.7)*; Quintile 5 OR: 7.5 (1.4–38.8)*; Ptrend , 0.01 Song et al., 2016 (17) Meta-analysis of 13 cross-sectional and 8 prospective Pooled diabetes risk in the highest vs. lowest exposure RR: 2.39 (1.86–3.08)* studies published before 8 March 2014 examining groups for PCBs links between PCBs and diabetes risk OC pesticides Wu et al., 2013 (13) Two case-control studies of women without diabetes Incident diabetes comparing highest tertile of plasma NHS OR: 3.14 (1.28–7.67)*; Pooled OR: from the NHS and a meta-analysis of pooled data HCB levels in NHS and highest to lowest exposure 2.00 (1.13–3.53)* with six additional prospective studies group in pooled prospective studies Turyk et al., 2009 (12) 471 Great Lakes sport fish consumers without diabetes Incident diabetes comparing tertiles of serum DDE levels Tertile 2 IRR: 5.5 (1.2–25.1)*; Tertile 3 IRR: followed from 1994/1995 to 2005 with the referent 7.1 (1.6–31.9)* Rignell-Hydbom et al., 2009 (14) Case-control study of women age50–59 years in southern Incident diabetes in 39 patients and matched control OR: 5.5 (1.2–25)* Sweden subjects after $6 years of follow-up comparing the highest quartile of DDE levels with the referent Lee et al., 2010 (15) 90 patients and control subjects in a nested case-control Incident diabetes comparing second sextile with the Sum OR: 5.4 (1.6–18.4)*; Trans-nonachlor OR: study followed for ;18 years referent for summary measure of 16 POPs (including 4.3 (1.5–12.6)* 3 OC pesticides) or second quartile with the referent for trans-nonachlor Lee et al., 2011 (16) 725 participants from the PIVUS study Incident diabetes comparing quintiles of OC pesticides or Quintile 5 sum OC pesticides OR: 3.4 (1.0–11.7); summary measure of three OC pesticides with the Ptrend 5 0.03; Quintile 4 trans-nonachlor OR:

referent 4.2 (1.3–13.3)*; Ptrend 5 0.03 3 Associates and Ruiz Van Larebeke et al., 2015 (18) 973 participants of the Flemish Environment and Risk of incident diabetes calculated for a doubling Doubled HCB OR: 1.61 (1.07–2.42)*; 90th vs. 10th Health Survey of serum or comparing 90th percentile with 10th percentile HCB OR: 6.27*; Doubled DDE OR: 1.66 percentile of levels for HCB (men and women) or DDE (1.09–2.53)*; 90th vs. 10th percentile DDE OR: (men only) 5.39*

Continued on p. 4 niomna nqaiyadDaee Risk Diabetes and Inequality Environmental 4

Table 1—Continued Reference Population Outcome and comparison Effect estimate (95% CI)

Starling et al., 2014 (19) 13,637 women from the Agricultural Health Study Incident diabetes for ever use of the OC pesticidedieldrin HR: 1.99 (1.12–3.54)* Song et al., 2016 (17) Meta-analysis of 11 cross-sectional and 6 prospective Pooled diabetes risk in the highest vs. lowest exposure RR: 2.30 (1.81–2.93)* studies published before 8 March 2014 examining groups for pesticides links among various pesticides and diabetes risk Chemical constituents of air pollution Brook et al., 2016 (20) 65adultswithmetabolicsyndromeand insulin resistance Change in HOMA-IR per SD increase in personal-level Day 4 black : 0.18 (0.01–0.36)*; Day 5 black from the Air Pollution and Cardiometabolic Diseases black carbon or PM2.5 exposure during the fourth and carbon: 0.22 (0.04–0.39)*; Day 4 PM2.5 : China Study fifth days of assessment 0.18 (0.02–0.34)*; Day 5 PM2.5 : 0.22 (0.08–0.36)* Weinmayr et al., 2015 (21) 3,607 individuals from the Heinz Nixdorf Recall Study Incident diabetes relative IQR increase in PM10,PM2.5 , PM10 RR: 1.20 (1.01–1.42)*; PM2.5 RR: 1.08 (0.89– in Germany followed for an average of 5.1 years traffic-specificPM10,andtraffic-specificPM2.5 as well as 1.29); TrafficPM10 RR: 1.11 (0.99–1.23); Traffic comparison of living ,100 m vs. 200 m from a busy PM2.5 RR: 1.10 (0.99–1.23); ,100 m RR: 1.37 road (1.04–1.81)* To et al., 2015 (22) 29,549 women from the Canadian National Breast Change in diabetes prevalence per 10 mg/m3 increase in PRR: 1.28 (1.16–1.41)* Screening Study PM2.5 exposure Park et al., 2015 (23) 5,839 subjects in the Multi-Ethnic Study of Prevalent and incident diabetes risk per IQR increase in Prevalent DM PM2.5 OR: 1.09 (1.00–1.17)*; Prevalent Atherosclerosis Cohort residential concentrations of PM2.5 or NOx DM NOx OR: 1.18 (1.01–1.38)*; Incident DM PM2.5 HR: 1.02 (0.95–1.10); Incident DM NOx HR: 1.00 (0.86–1.16) Pope et al., 2015 (24) 669,046 participants from the American Cancer Society Risk of diabetes-associated death on death certificates HR: 1.13 (1.02–1.26)* 3 Cancer Prevention Study II per 10 mg/m increase in PM2.5 Brook et al., 2013 (25) 2.1 million adults from the 1991 Canadian Census Diabetes-associated mortality per 10 m/m3 increase in HR: 1.49 (1.37–1.62)* Mortality Follow-up Study PM2.5 Thiering et al., 2013 (26) Fasting blood from 397 10-year-old children in two Change in HOMA-IR per 2-SD increase in ambient NO2 NO2:17.0%(5.0–30.3%)*; PM10:18.7%(2.9–36.9%)*; prospective German birth cohort studies and PM10 and for every 500 m to nearest major road Road proximity: 7.2% (0.8–14.0%)* 3 Coogan et al., 2012 (27) 3,992 black women living in Los Angeles followed for Incident diabetes per IQR increase in NOx or 10 mg/m NOx IRR: 1.25 (1.07–1.46)*; PM2.5 IRR: 1.63 10 years increase in PM2.5 (0.78–3.44) Coogan et al., 2016 (28) 43,003 participants in the Black Women’s Health Study Incident diabetes per IQR increase in NO2 by using both Land use HR: 0.96 (0.88–1.06); Dispersion HR: 0.94 followed from 1995 to 2011 land use repression and dispersion models (0.80–1.10) Kramer¨ et al., 2010 (29) 1,775 women without diabetes age 54–55 followed Incident diabetes per IQR increase in exposure on the Monitored PM10 HR: 1.16 (0.81–1.65); Monitored NO2 for 16 years in West Germany basis of data from monitoring stations, emission HR: 1.34 (1.02–1.76)*; Inventory traffic PM HR: 1.15 inventories, or land use regression models as well as (1.04–1.27)*; Inventory trafficNO2 HR: 1.15 (1.04– distance from busy road (,100 m) relative to 1.27)*;LandusesootHR:1.27(1.09–1.48)*; Land education status use NO2 HR: 1.42 (1.16–1.73)*; ,100 m/low education HR: 2.54 (1.31–4.91)*; ,100 m/high education HR: 0.92 (0.58–1.47) Schneider et al., 2008 (30) 22 people with type 2 diabetes living in North Carolina Changes in vascular parameters per 10 m/m3 increase in Lag 0 FMD: 217.3 (234.6 to 0.0)*; Lag 1 SAEI: 217.0 PM2.5 accounting for lag period (in days) (227.5 to 26.4)*; Lag 3 SAEI: 215.1 (229.3 to 20.9)* O’Donnell et al., 2011 (31) 9,202 patients hospitalized with ischemic stroke Risk of ischemic stroke among patients with diabetes per 11% (1–22%)* 3 10 mg/m increase in PM2.5 m 3 – Brook et al., 2013 (32) 25 healthy adults from rural Michigan brought Change in HOMA-IR per 10 g/m increase in PM2.5 0.7 (0.1 1.3)* Care Diabetes to an urban location for 5 consecutive days Continued on p. 5 care.diabetesjournals.org Ruiz and Associates 5

OC Pesticides OC pesticides were extensively used in

3.69) theU.S.untilthe1970swhenmost – were banned because of their environ- 3.49)*; – mental persistence and to hu- 5.95)*; NHS II – mans and wildlife; however, several OC 3.85)* – 3.3%)*; Prepubertal pesticides and their metabolites are still 2 measurable in the U.S. population. Levels

2.30); NHS butyl phthalates of these compounds are greater in Mex- – 29 to

2 ican Americans and African Americans 1.38); NHS II OR: 2.08 (1.17

– compared with whites (Supplementary 41%)* 1.68); NHS total phthalates OR: 0.87 17% ( – 30.04)* 2.72)* 2.25) 1.87)* 2 – – Table 1). The prolonged use of OC pesti- – – Effect estimate (95% CI) cides outside of the U.S. for agricultural 1.53); NHS II DEHP OR: 1.91 (1.04

– purposes or vector control is believed to contribute to higher levels in Latino pop- girls: 20% (2.5 NHS II butyl phthalates OR: 3.16 (1.68 total phthalates OR: 2.14 (1.19 OR: 0.91 (0.50– (0.49 * ulations (37,48,49). Indeed, on the basis of RR: 1.48 (0.98 Pubertal boys: NHS DEHP OR: 1.34 (0.77 RR: 1.45 (1.13 OR: 6.65 (1.47 OR: 1.89 (1.31 NHS OR: 0.81 (0.48 National Health and Nutrition Examina- tion Survey data, people born outside prevalence rate ratio; SAEI, small-artery elasticity index. the U.S. are more likely to be exposed to OC pesticides (50). However, the over- representation of Mexican Americans in U.S. agriculture may also play a role in exposure disparities (51). In addition, di- rect exposures to OC pesticides before their phaseout may have been passed down to offspring through and cord blood (52), likely resulting in higher body burdens at the start of life Outcome and comparison that persist into adulthood. In concordance with animal and cellu- lar data demonstrating the capacity of groups for BPA index per IQR increase in either in uteropubertal MEP boys levels for or peripubertal DEHPgirls for prepubertal highest with the referent quartilephthalate of levels urinary groups for BPA comparing highest with referent tertileBPA of level urinary quartile of urinary BPA level for each 10-pointin increase a diabetes genetic risk score highest with the referent quartile of urinary BPA levels OC pesticides to disrupt multiple aspects Pooled diabetes risk in the highest vs. lowest exposure Change in insulin secretion as assessed by a C-peptide Incident diabetes after adjusting for BMI comparing Pooled diabetes risk in the highest vs. lowest exposure Incident diabetes risk in highest quartile vs. lowest Incident diabetes after adjusting for BMI comparing of cellular and systemic glucose regula- tion (Supplementary Table 2), epidemio- ow-mediated dilatation; IDR, incidence density ratio; PRR, fl logical studies from various regions of the world have associated OC expo- sure with diabetes and the metabolic syndrome (Table 1). For example, plasma hexachlorobenzene (HCB) was positively associated with incident type 2 diabetes, an effect confirmed in an accompanying meta-analysis (OR 2.00 [95% CI 1.13– Population 3.53]) (13). Among Great Lakes sport ve cross-sectional and prospective fi fish consumers, levels of dichlorodiphe- nyldichloroethylene (DDE), a metabolite of dichlordiphenyltrichloroethane (DDT), were associated with incident diabetes studies published before 8 Marchlinks 2014 between examining phthalates and diabetes risk in Mexico to Environmental Toxicants cohort the NHS and NHS II studies published before 8 Marchlinks 2014 between examining BPA and diabetes risk followed for 4 years the NHS and NHS II (12), whereas a study in Swedish women Meta-analysis of four cross-sectional and prospective 250 childrenof womenenrolledin the Early Life Exposure 971 incident type 2 diabetes case-control pairs from 121 patients with type 2 diabetes followed for 6 years Incident chronic kidney disease in patients with diabetes Meta-analysis of 2,209 middle-aged and elderly subjects without diabetes 971 incident type 2 diabetes case-control pairs from showed that being in the highest quartile of DDE levels relative to the lowest quar- tile was associated with incident diabetes (OR 5.5 [95% CI 1.2–25]) (14). In a nested case-control cohort of individuals fol- lowed for nearly 20 years, the OC pesti- cides trans-nonachlor, oxychlordane, and mirex were nonlinearly associated with Continued

— new-onset diabetes (15). In the PIVUS

0.05. study, trans-nonachlor and a summary in- , Song et al., 2016 (17) Watkins et al., 2016 (36) et al., 2014 (33) Song et al., 2016 (17) Hu et al., 2015 (35) Bi et al., 2016 (34) Sun et al., 2014 (33)

P dex of three OC pesticides also were pos- Data are from studies from* around the world (Supplementary Fig. 1). DM, diabetes; FMD, Phthalates BPA Table 1 Reference itively associated with diabetes at age 6 Environmental Inequality and Diabetes Risk Diabetes Care

75 years (16). In a Flemish biomonitoring worsening insulin resistance (20). In Ger- the disease. For example, PM2.5 levels program, OC pesticide levels measured in many, long-term exposure to PM10 and modeled for home addresses were linked 2004–2005 were associated with self- NO2 was associated with greater insulin to diabetes on death certificates (24), reported diabetes in 2011; this included resistance in 10-year-old children (26). In whereas a prospective analysis of .2 HCB as well as DDE in men (18). Finally, in addition, several studies have linked poor million adults revealed that a 10 mg/m3 in- the Agricultural Health Study, a large pro- air quality with progression to diabetes. crease in PM2.5 was associated with in- spective cohort of pesticide applicators In one study of individuals without dia- creased diabetes-related mortality (25). and their spouses, the OC pesticide diel- betes followed for 5.1 years, each These findings may be related to adverse drin was associated with incident diabetes interquartile range (IQR) increase in total vascular effects in individuals with diabe- ( ratio [HR] 1.99 [95% CI 1.12–3.54]) PM10 was associated with a 20% in- tes. In 22 patients with type 2 diabetes (19). By compiling data across studies, a creased risk of developing type 2 diabetes living in North Carolina, daily measures meta-analysis comparing the highest to (RR 1.20 [95% CI 1.01–1.42]) (21). of flow-mediated vasodilatation were de- lowest exposure groups demonstrated a Living ,100 m (relative to .200 m) creased in association with PM2.5 levels strong positive correlation between OC from a busy road was associated with a (30). The clinical significance of this find- pesticide exposure and diabetes rates 37% increased risk of developing diabetes ing may be reflectedindatashowing 3 (RR 2.30 [95% CI 1.81–2.93]) (17). (RR 1.37 [95% CI 1.04–1.81]). Further- that each 10 mg/m increase in PM2.5 was more, higher levels of PM2.5,traffic- associated with an 11% increased risk of Traffic-Related Air Pollution and specificPM10, and traffic-specificPM2.5 ischemic stroke in individuals with diabe- Particulate Matter were associated with increased diabetes tes (31). Traffic-related air pollution comprises risk; however, these measures failed to various chemical components, including reach statistical significance. In a study BPA nitric oxides (NOx), ozone, and particulate of black women living in Los Angeles, Cal- BPA is a ubiquitous synthetic chemical matter (PM), which is a mixture of parti- ifornia, followed for 10 years, incident di- used in the manufacturing of polycarbon- cles and classified by their diam- abetes rates were increased for each IQR ate and other commonly used in eter (e.g., ,10 mm[PM10]or,2.5 mm increase in NOx (incidence rate ratio [IRR] consumer products; moreover, BPA is a [PM2.5]). Nationwide studies have shown 1.25 [95% CI 1.07–1.46]), whereas PM2.5 component of sales receipts and epoxy that African Americans and Latinos are was associated with a nonsignificant in- resins lining food and beverage cans as exposed to significantly more PM2.5 crease in incident diabetes (IRR 1.63 well as water pipes. BPA exposure in the (7,53), and ethnic and racial disparities [95% CI 0.78–3.44]) (27). Among woman U.S. population is nearly universal (57). in exposure to traffic-related air pollution without diabetes from the Study of the Although BPA is rapidly cleared from the exceed those between income groups Influence of Air Pollution on Lung, Inflam- body and single measurements may not (54) (Supplementary Table 1). NO2 levels mation, and Aging cohort followed for reflect cumulative exposure (58), African correlate closely with PM2.5,ultrafine par- 16 years, incident diabetes increased by Americans and people with lower in- ticles, and black carbon and thus serve 15–42% per IQR of PM10 or traffic-related comes have higher BPA levels than the as a proxy for traffic-related air pollution air pollution (29). The data from prospec- population at large (Supplementary (55). Exposure to NO2 is 38% higher for tive studies are not, however, uniform. In Table 1). The reasons for these disparities people of color than for non-Hispanic the Multi-Ethnic Study of Atherosclerosis, are not clear, but reduced access to fresh whites and 10% higher for people below NOx was associated with prevalent diabe- food and consequential consumption of the poverty line (54). Among nonwhite tes, and PM2.5 trended toward an associ- processed foods may partly explain these individuals living in poverty, children ation (OR 1.09 [95% CI 1.00–1.17]), but associations (59) because consuming age ,5 years are exposed to 23% higher no air pollution measure was associated foods packaged in or cans in- NO2 concentrations than the rest of the with incident diabetes over 9 years of creases BPA exposure (60). Moreover, population (54). Of note, racial differ- follow-up (23). In a long-term analysis of among individuals with low food security, ences in NO2 exposure are greater in large the Black Women’sHealthStudywithad- BPA levels are higher if they receive emer- metropolitan centers compared with justment for multiple metabolic stressors, gency food assistance, which includes small-to-medium urban areas, likely re- NO2 was not associated with diabetes in- canned foods (61). For example, 6–11- flecting racial and ethnic segregation cidence (28). Despite this heterogeneity, year-old children receiving emergency around traffic corridors in major U.S. cities. epidemiological studies linking various food assistance had BPA levels that Increasing evidence implicates air pol- chemical constituents of air pollution to were 54% higher than age-matched child- lution in glucose dysregulation, including diabetes risk coupled with animal studies ren from more affluent families (61). insulin resistance (56) (Table 1). In a demonstrating that exposures to air pol- Disparities in BPA exposure may con- small, but elegant study of residents of lutants such as PM2.5 and polyaromatic tribute to metabolic disease burden be- rural Michigan, exposure to urban air for hydrocarbons disrupt metabolism and cause increasing evidence associates BPA only 4–5 h daily for 5 consecutive days in- promote inflammation (Supplementary with diabetes. Analyses that explore the creased HOMA insulin resistance (HOMA-IR) Table 2) suggest that differential exposure association between urinary BPA levels 3 for each 10 mg/m increase in PM2.5 (32). to air pollution may augment diabetes risk and metabolic disease are complicated Similarly, in adults with the metabolic in low-income communities of color. by BPA’s rapid excretion (62); moreover, syndrome living in the Beijing metropol- In addition to effects on diabetes de- althoughnodefinitive evidence exists that itan area, variations in black carbon velopment per se, air may also urinary excretion of BPA is influenced by and PM2.5 have been associated with promote adverse outcomes in those with race/ethnicity, lack of adjustment for care.diabetesjournals.org Ruiz and Associates 7

renal function can complicate urinary toys, and building materials, such as poly- Exposure in Mexico to Environmental assessments in population studies (63). vinyl (PVC); low-molecular-weight Toxicants cohort, in utero levels of MEP Despite these caveats, the National phthalates are used in pharmaceuticals, were associated with reduced insulin Toxicology Program concluded that BPA personal care products, and . secretion in pubertal boys (36). In the could exert effects on glucose homeosta- Phthalates are not covalently bound within meta-analysis of Song et al. (17), urinary sis and insulin release on the basis of an- products and, thus, can volatilize or leach concentrations of phthalates were nearly imal and in vitro studies (64). Although out, thereby facilitating absorption significantly associated with diabetes (RR some heterogeneity exists across studies, through dermal contact, ingestion, and 1.48 [95% CI 0.98–2.25]). With supportive the literature that supports this conclu- inhalation. Higher exposure cellular and animal data demonstrating sion demonstrates myriad BPA-induced among people of color and people with that various phthalates have the capacity metabolic disruptions across multiple an- low income have been documented in to promote dysfunction in multiple met- imal and cellular model systems, includ- various studies (Supplementary Table 1), abolic tissues (Supplementary Table 2), ing alterations in body weight regulation, although the sources of these exposure further prospective studies are justified insulin action, and insulin secretion as differences are difficult to discern given to define the relationship between phtha- well as specific disruptions in b-cell, the widespread commercial use of phtha- late exposures and diabetes risk, particu- a-cell, hepatocyte, and adipocyte func- lates. Reduced access to fresh fruits and larly among vulnerable populations. tion and development (Supplementary vegetables and increased consumption of Table 2). This conclusion is further sup- -rich foods in low-income populations LINKING ENVIRONMENTAL ported by limited prospective human may augment exposure differences be- EXPOSURES TO DIABETES RISK studies (Table 1). In data from the NHS, cause certain high-fat foods are a major IN VULNERABLE POPULATIONS extremes of BPA quartiles were associ- source of HMW phthalates (66). Weather- Most studies examining links between ated with incident diabetes after adjust- ing of older construction materials in low- EDCs and diabetes have done so without ing for BMI (OR 2.08 [95% CI 1.17–3.69]) income households may increase inhala- consideration of race, ethnicity, or socio- in NHS II but not NHS (33), suggesting that tional phthalate exposure (67). Further- economic status; however, recent reports age modifies BPA-associated diabetes risk more, purchasing inexpensive products have begun to interrogate these impor- because the mean age in NHS II was 45.6 likely contributes to disproportionate tant interactions. In a cross-sectional years versus 65.6 years in NHS. Alterna- phthalate exposures according to an eval- study investigating the associations be- tively, these differences may have arisen uation of products at dollar stores that tween phthalates and insulin resistance, from period-cohort effects in which the revealed that 32% of PVC-containing an interaction with race demonstrated that extent, diversity, or timing of exposures products exceed phthalate limits estab- Mexican American (P = 0.001) and non- may have been greater or more deleteri- lished for children’s products by the Con- Hispanic black adolescents (P =0.002) ous in NHS II. Furthermore, evidence that sumer Product Safety Commission (68). had significant increments in HOMA-IR the BPA-diabetes association is modified Of note, personal care products and cos- with higher levels of HMW phtha- by a diabetes genetic risk score (34) sug- metics also contribute to phthalate expo- lates or DEHP that were not observed gests that some populations are more sure (69), especially in women, who in non-Hispanic whites (P $ 0.74) (72). sensitive to the diabetogenic effects of typically have the highest concentrations Similarly, in stratified models, HMW BPA. Of note, BPA may exacerbate diabe- of phthalates (70). Indeed, certain femi- phthalates and DEHP were more strongly tes complications because high levels of nine hygiene products were found to be associated with HOMA-IR in adolescents BPA have been associated with a mark- at least partially responsible for higher from households with lower income. In edly increased rate of developing chronic levels of monoethyl phthalate (MEP) in another cross-sectional study, phthalate kidney disease (OR 6.65 [95% CI 1.47– African American women (71). These levels were positively associated with 30.04]) (35). In one meta-analysis that ag- data provide provocative evidence of ra- fasting blood glucose, fasting insulin, or gregated cross-sectional and prospective cial, ethnic, and socioeconomic disparities HOMA-IR; however, the dose-response studies, a comparison of the highest to in phthalate exposure; however, addi- relationship was stronger among African lowest exposure groups demonstrated a tional studies are needed to further illu- Americans and Mexican Americans than positive association between BPA and di- minate the sources of these differences. among whites (73). In the meta-analysis abetes (RR 1.45 [95% CI 1.13–1.87]) Several epidemiologic studies have of Song et al. (17), the impact of PCBs (17), a finding similar to a second, more linked higher phthalate exposure with di- on diabetes risk was higher in nonwhite recent meta-analysis of prevalent diabe- abetes (Table 1). In data from NHS II, total populations (RR 2.91 [95% CI 1.60–5.30]) tes in three cross-sectional studies (OR urinary phthalate metabolites were asso- compared with their white counterparts 1.47 [95% CI 1.21–1.80]) (65). Thus, on ciated with diabetes (33). In this analysis, (RR 1.94 [95% CI 1.42–2.62]); similarly, the basis of reasonable evidence, differ- metabolites of butyl phthalates and associations between OC pesticides and ential BPA exposure may promote diabe- diethylhexyl phthalate (DEHP) were asso- diabetes were stronger in nonwhites (RR tes disparities. ciated with diabetes (OR 3.16 [95% CI 2.64 [95% CI 1.56–4.49]) than in whites 1.68–5.95] and 1.91 [95% CI 1.04–3.49], (RR 1.95 [95% CI 1.40–2.71]). Although Phthalates respectively). Similar to BPA, these asso- these associations are likely partially at- Phthalates are a diverse class of widely ciations may be age-related or a conse- tributable to higher EDC exposures, these used synthetic compounds. High-molecular- quence of period-cohort effects because findings also suggest that African Ameri- weight (HMW) phthalates are mainly similar findings were not observed with cans and Latinos have heightened sensi- used as in food packaging, the older, original NHS. In the Early Life tivity to the diabetogenic effects of niomna nqaiyadDaee Risk Diabetes and Inequality Environmental 8

Table 2—Interventional studies that lowered levels of nonpersistent and persistent diabetogenic EDCs in Reference Population Intervention and assessment Results Nonpersistent pollutants Harley et al., 2016 (84) 100 Latina adolescents from the Health and Mean percent change (95% CI) in urinary MEP: 227.4% (239.3 to 213.2)*; Methylparaben: 243.9% Environmental Research on Makeup of Salinas concentrations after 3-day intervention with (261.3 to 218.8)*; Propylparaben: 245.4% (263.7 Adolescents study personal care products devoid of chemicals under to 217.9)*; : 235.7% (253.3 to 211.6)*; study Benzophenone-3: 236.0% (251.0 to 216.4)* Rudel et al., 2011 (85) 10 children and 10 adults from the San Francisco Mean urinary concentrations of BPA and phthalates BPA: 3.7 vs. 1.2 ng/mL; 266%*; MEHP: 7.1 vs. 3.4 ng/mL; Bay Area, California before and during 3-day dietary intervention with 253%*;MEOHP:27vs.12ng/mL;255%*; MEHHP: 57 vs. fresh and organic foods that were not canned or 25 ng/mL; 256%* packaged in plastic Chen et al., 2015 (86) 30 Taiwanese girls with previously recorded high Mean urinary concentrations (mg/g) of creatinine MMP: 10.4 (3.49–29.7) vs. 4.54 (2.97–17.3)*; MEP: 58.6 urinary phthalate metabolite concentrations (95% CI) of eight phthalate metabolites before and (9.08–650) vs. 16.4 (4.66–200)*; MBP: 123 (57.9–482) vs. after 1 week of seven different interventions: hand 84.7 (36.3–236)*; MBzP: 8.52 (1.87–58.2) vs. 4.67 washing, not using plastic containers, not eating (1.25–17.8)*; MEHP: 14.4 (4.34–38.3) vs. 6.95 (3.42–24.7)*; food wrapped in plastic, not microwaving food, not MEOHP: 55.2 (21.2–207) vs. 26.9 (15.5–85.6)*; MEHHP: taking nutritional supplements, reducing the use of 115 (40.3–398) vs. 61.2 (29.1–202)*; MECPP: 124 cosmetics, and reducing the use of personal care (34.7–320) vs. 52.9 (30.1–161)*; SDEHP: 0.98 (0.36–3.21) products (results are for those who were compliant vs. 0.49 (0.27–1.57)* with the intervention) Sathyanarayana et al., 2013 (87) 21 individuals from Seattle, , with high Geometric mean urinary DEHP concentrations DEHP: 283.7 (154.6–520.8) vs. 7,027.5 (4,428.1–11,152.68)* potential for BPA and phthalate exposures (nmol/g creatinine) (95% CI) before and at completion of 5-day intervention with complete dietary replacement with fresh and organic foods prepared without plastics POPs Geusau et al., 1999 (88) 2 female patients with chloracne Fecal excretion of 2,3,7,8-tetrachlorodibenzo- Patient 1: 134 vs. 1,350 ng/day; Patient 2: 29 vs. 240 ng/day p-dioxin before and after a 38-day intervention of dietary supplementation with chips by using five different dosing regimens (15–66 g olestra daily) Jandacek et al., 2014 (89) 23 participants from Anniston, Alabama, with PCB Elimination rate (ng/g lipid/year; mean 6 SEM) of Olestra: 20.00864 6 0.0116 vs. 20.0829 6 0.0357/year*; levels above the national 50th percentile 37 serum PCBs before and after a 1-year double- Placebo: 20.0283 6 0.0096 vs. 20.0413 6 0.0408/year blind placebo-controlled trial of 15 g/day dietary olestra vs. placebo (vegetable oil) Redgrave et al., 2005 (90) 1 obese male patient with diabetes Adiposelevelsofthe PCBmixturearoclor1254before Aroclor 1254: 3,200 vs. 56 mg/kg; Body weight: 101 vs. 83 kg; and after 2 years of dietary supplementation with BMI: 33.0 vs. 27.1 kg/m2;Cholesterol:8.6vs.3.7mmol/L; olestra (16 g/day) Triglycerides:11.8vs.1.4mmol/L;Bloodglucose:17vs. 5.3 mmol/L Arguin et al., 2010 (91) 37 obese men undergoing weight loss trial Plasma concentrations (mg/L) of the OC pesticide Standard treatment: 0.009 6 0.019; Fat-reduced group: b-HCH (mean 6 SD) before and after a 3-month 0.015 6 0.035; Olestra group: 20.009 6 0.034* weight loss intervention; subjects randomized to

standard treatment (n = 13), fat-reduced diet (n = Care Diabetes 14), and olestra-substituted diet (33% of dietary fat) (n =10)

Continued on p. 9 care.diabetesjournals.org Ruiz and Associates 9

environmental contaminants because of by race in major U.S. cities document how

6 potential synergy with other diabetes risk people of color were restricted to low- 6 0.97 factors. wage, hazardous occupations while simul- 1.65*; 6

6 The current literature provides evi- taneously being confined to low-income

57.65* dence that five classes of environmental housing near these industries (76). Similar 6

0.96 vs. 8.18 toxicants are linked to diabetes risk in hu- labor divisions also occurred in agricul-

6 mans, and for each, vulnerable popula- ture (51). Grandfathering clauses allow 1.66 vs. 10.52

4.01*; PCB 180: 20.47 tions are disproportionately exposed. older industrial facilities, often located 6 6 The strength of epidemiological evidence in America’s metropolitan centers, to 0.62*; PCB 118: 6.87

-DDT: 8.31 fi 6 58.40 vs. 338.77 9 for these ve classes varies, with the most opt out of the stricter environmental reg- 6 Results consistent findings observed for the per- ulations required of newer facilities, sistent pollutants (PCBs and OCs), likely thereby clustering industrial toxins within 4.16 vs. 20.68 4.85*; 4,4 reflecting their long biological half-lives, these urban cores (77). Suburbanization 6 6 0.57 vs. 4.00 the stability of their quantitation, and was accompanied by expansion and clus- 6 1.01*; PCB 138: 10.85 -DDE: 344.06 9 the longer time they have been studied. tering of highways near and through 6 -ethyl-5-hydoxyhexyl phthalate; MEHP, mono-2- Among all five classes, however, is pro- neighborhoods of color (79), leading to vocative evidence of diabetes-promoting higher traffic-related air pollution expo- 1.11*; 4,4 vs. 6.79 PCB 153: 21.16 4.99 vs. 20.07 effects as well as disparities in exposure. sure among African Americans and Lati- PCB 74: 4.04 Thus, although further study is required, nos (54). A shifted focus to suburban the unequal burden of environmental risk economic development with consequen- factors in ethnically, racially, and econom- tial disinvestment in inner city neigh- ically segregated neighborhoods of color borhoods has perpetuated a legacy of may contribute to interethnic differences environmental inequality (76). The cumu- in metabolic health. lative effects of these cultural forces enhance exposure to environmental tox- ORIGINS OF DIFFERENTIAL icants among African American, Latino, ENVIRONMENTAL EXPOSURES and low-income communities; addressing Addressing disparities in environmental this history is essential to eliminating dis- SEM) before and after 2 months of

ve PCBs and two OC pesticides (ng/g health necessitates understanding the parities in metabolic health. 6 fi sociological forces that shape society. Intervention and assessment

0.05. Segregation profoundly influences indi- ENVIRONMENTAL HEALTH IN THE

, vidual socioeconomic status, reinforces DIABETES CLINIC P supplementation with 1,000 mg/day ascorbic(vitamin acid C) lipid) (mean unhealthy neighborhood environments, With increasing evidence that pollutants

Blood levels of and modifies individual behaviors (74), promote metabolic dysfunction and likely all of which influence metabolic disease contribute to diabetes disparities, environ- susceptibility. Reduced access to afford- mental health will become an important able healthy foods, as seen in many Afri- component of clinical practice. As such, can American and Latino neighborhoods, physicians need to be acquainted with promotes unhealthy eating habits (59), these data to meaningfully address the con- whereas lack of safety and reduced access cerns of their patients who are increasingly to green space can limit physical activity troubled about these links. In addition, as (75). Thus, the built environment in many these data mature, policies to improve communities of color potentiates two key environmental quality should become com- Population drivers of diabetes risk, namely diet and ponents of comprehensive diabetes pre- exercise. vention and management strategies. Such In addition, historical economic and efforts may have significant benefits. On xohexyl phthalate; MMP, monomethyl phthalate. * political racialization of residential areas the basis of recent intriguing analyses of and the labor force has promoted today’s the PIVUS study, 25% reductions in repre- California racial segregation and the codecline of sentative compounds from several chemi- 15 healthy women from the Area, environmental health in these neighbor- cal classes discussed herein (PCBs, OC hoods (76). Indeed, living in highly segre- pesticides, and phthalates) as well as per- gated metropolitan areas is associated fluoroalkyl substances are predicted to re- with a greater health risk from industrial duce diabetes prevalence in Europe by 13% air pollution, with African Americans at (95% CI 2–22%),withaprojectedcost enhanced risk relative to non-Hispanic savings of V4.51 billion/year (80). Thus, whites (77). Despite improvements in air the identification of patient-specificexpo- Continued -hexachlorocyclohexane; MBP, monobutyl phthalate; MBzP, monobenzyl phth alate; MECPP, mono-2-ethyl-5-carb oxypentyl phthalate; MEHHP, mono-2

— quality over time, African Americans re- sures and implementation of exposure b main exposed to significantly more air reduction strategies may reduce the bur- Guo et al., 2016 (92)

-HCH, pollution than non-Hispanic whites (78). den of diabetes on both the individual b ethylhexyl phthalate; MEOHP, mono-2-ethyl-5-o Reference Table 2 Accounts of the industrial division of labor and society at large. 10 Environmental Inequality and Diabetes Risk Diabetes Care

Identifying Patients With Unique occupational and environmental histories that exacerbate metabolic dysfunction. Diabetes Phenotypes in patients without the classical clinical fea- Aided by the development and implemen- Astute clinicians revolutionized diabetes tures of type 2 diabetes and without a ge- tation of validated clinical questionnaires care by recognizing unique disease pheno- netic explanation, may identify unique to estimate contact with diabetogenic types that were subsequently linked to chemical exposures that promote disease chemicals, informed clinicians may be specific genetic variants and targeted development. Similarly, patients whose able to identify glucose-disrupting expo- therapeutics (i.e., maturity onset diabetes medication needs are greater than antici- suresandofferpatientstargetedinterven- of the young). Similarly, comprehensive pated may have background exposures tions to improve diabetes outcomes.

Table 3—Sources of diabetes-promoting EDCs and exposure reduction strategies Chemical Source Exposure Reduction Strategy PCBs Contaminated fish, , and dairy products, including bottom- Consult local guidelines regarding which sport fish are safe feeding freshwater fish that consume PCB-laden sediment to consume; Trim fat from meat and skin from fish and cook on a rack that allows fat to drain away Dusts contaminated with low levels of PCBs can coat the surfaces Wash fruits and vegetables before consumption of fruits and vegetables Contaminated drinking water arising from PCB leaching from Check submersible pumps for failure and, if so, replace toxic waste sites or old submersible pumps containing PCBs pumps and clean the well (development of an oily film or fuel odor in water wells) Older fluorescent lights with or ballasts containing Replace old PCB-containing fluorescent bulbs PCBs Deterioration of old building materials, including some paints Remove deteriorating building materials; Repair damaged and caulking areas with new, safer alternatives OC pesticides Some high-fatmeats and dairy products as well as some fatty fish Trim fat from meat and skin from fish and cook on a rack that allows fat to drain away Dust and contaminated from historical use Regularly clean floors and remove dust with a damp cloth; Wash hands often, especially before eating or preparing food; Wash fruits and vegetables before consumption Air Burning of fossil fuels, including power plants, motorized Checklocalairpollutionforecastsandavoidoutdoorexercise vehicles, lawn care equipment, chemical plants, factories, when pollution levels are high; Avoid exercise near high- refineries, and gas stations traffic areas; Use hand-powered or electric lawn care equipment; Encourage local schools and municipalities to reduce bus emissions by eliminating idling; Plant trees Gas appliances, paints, solvents, tobacco , and household Choose electrical appliances and paints low in volatile chemicals, including cleaning supplies organic compounds; Limit use of household chemicals; Avoid places that permit smoking Combustion of organic materials, including fireplaces, wood Do not burn wood, leaves, or trash stoves, charcoal grills, and leaf burning BPA plastics, including some water and baby bottles, Avoidplasticcontainers designated#7onthebottom;Do not compact discs, impact-resistant safety equipment, and microwave polycarbonate plastic food containers; Opt for medical devices bottles and toys that are labeled BPA- free; Opt for glass, porcelain, or stainless steel containers when possible, especially for hot foods and drinks Epoxy resins coating metal products, such as food cans, bottle Eat fresh and frozen foods while reducing use of canned tops, and water supply pipes foods; Prepare more meals at home and emphasize fresh ingredients Thermal paper, including sales receipts Minimize handling of receipts and thermal paper Some dental sealants and composites Consult dentist about alternative options Phthalates Plastic food and beverage containers Opt for glass, porcelain, or stainless steel containers when possible, especially for hot food and drinks Personal care products, such as perfumes, hair sprays, Read labels and avoid products containing phthalates; deodorants, nail polishes, insect repellants, and most Choose products labeled phthalate-free; Avoid fragrances consumer products containing fragrances, including and opt for cosmetics labeled no synthetic fragrance, shampoos, air fresheners, and laundry detergents scented only with essential oils, or phthalate-free Contaminated food and water Purchase, if possible, organic produce, meat, and dairy products; Avoid food known to be especially high in contaminants; Consider using a water filter Plastic toys; plastic coatings on wires, cables, and other Choose nonplastic alternatives whenever possible, equipment; plastic showercurtains;PVC-containingproducts; especially avoid plastics labeled #3 and #7; Avoid hand- carpeting and vinyl flooring; and medical devices, including me-down plastic toys intravenous bags, tubing, and some extended-release medications care.diabetesjournals.org Ruiz and Associates 11

Reducing Exposures to Nonpersistent p-dioxin in two patients with chloracne important contributor. Although further Pollutants (88). Moreover, olestra was shown to ac- work is required to validate the EDC- For patients exposed to nonpersistent dia- celerate the elimination of 37 noncopla- diabetes link and better quantify exposure betogenic pollutants, practices that in- nar PCBs in 11 individuals from Anniston, disparities, current evidence suggests that crease exposure to diabetogenic toxicants Alabama (89). With regard to the meta- improvements in environmental health offer insights into potential interventions. bolic impact of these changes, one case could reduce diabetes risk and disparities. For example, fast food intake increases study of OC toxicity showed that 2 years As additional data accumulate and the phthalate exposures (81), whereas con- of olestra resulted in weight loss and im- field matures, the practicing diabetologist suming water from polycarbonate bottles provements in glycemic control (90). and endocrinologist will be uniquely posi- (82) or soup from cans (83) increases uri- Whether these metabolic improvements tioned to address exposure to diabeto- nary BPA levels. Built upon this knowl- resulted from the elimination of POPs or genic environmental toxicants as part of edge, clinical trials have attempted to were simply a consequence of weight loss individualized diabetes care plans to re- lower BPA and phthalate levels (Table 2). requires further study. Olestra may not duce disease risk and to improve diabetes In an intervention focused on personal universally lower POP levels, however. In outcomes across the population. care products, attention to product con- subjects who underwent a weight loss tents reduced levels of various chemicals, intervention, olestra decreased levels of b including MEP (84). A trial focused on eat- -hexachlorocyclohexane but did not at- Acknowledgments. The authors gratefully ac- ing food with limited packaging reduced tenuate the expected weight loss– knowledge the constructive feedback of Dr. Louis levels of DEHP and BPA (85), whereas induced rise in other OCs (91). Collec- H. Philipson, Director, Kovler Diabetes Center, hand washing and reduction of the use tively, these findings raise the possibility University of Chicago. The authors also recognize of plastic cups lowered phthalate levels the insights and suggestions of Dr. Victoria Persky, that other agents that interrupt the University of Illinois at Chicago. Because of refer- in children (86). Although these studies enterohepatic circulation of lipophilic tox- ence limits, the authors regret the omission of any are encouraging, challenges in advising icants similarly lower the body burden of other relevant studies. patients remain. For example, avoiding POPs and mitigate their diabetogenic ef- Funding. This work was supported by the Na- packaged and fast foods may be imprac- fects. The glycemic benefits of the bile acid tional Institute of Child Health and Human Devel- tical in individuals with low food security. opment (T32-HD-007009 to D.R.) and the sequestrant colesevelam could partially re- National Institute of Diabetes and Digestive and Moreover, even careful efforts can be flect clearance of metabolism-disrupting Kidney Diseases (P30-DK-092949 to J.S.J.) through confounded by unexpected exposures as chemicals, but this hypothesis requires for- the Chicago Center for Diabetes Translational Re- illustrated by a failed intervention during mal testing. Other approaches to reduce search as well as by the American Diabetes Asso- which DEHP levels rose because of unex- the body burden of diabetogenic EDCs ciation (1-17-JDF-033 to R.M.S.). Duality of Interest. No potential conflicts of in- pectedly high phthalate levels in milk and also have been tried. Supported by cross- terest relevant to this article were reported. ground coriander (87). Collectively, these sectional data suggesting that fruit and Author Contributions. D.R. researched and data suggest that limiting contact with vegetable consumption attenuates the wrotethemanuscript.M.B.researchedandedited plastics and packaging, encouraging PCB-diabetes association (93), a study of themanuscript.J.S.J.contributedtothediscussion hand washing, and increasing awareness 15 healthy women showed that 1,000 and edited the manuscript. K.A. contributed tothe discussion and edited the manuscript. R.M.S. of diabetogenic toxicants can reduce ex- mg/day of ascorbic acid for 2 months researched and wrote the manuscript. R.M.S. is posures; however, these efforts must be reduced levels of six PCBs and two OC the guarantor of this work and, as such, had full supported by regulatory action to ensure pesticides (92). access to all the data in the study and takes adequate labeling of consumer products. Although further work is needed, these responsibility for the integrity of the data and the accuracy of the data analysis. Finally, evidence that insulin sensitivity small intervention trials provide clinicians rapidly shifts with changes in air quality and patients with intriguing evidence that (20,32) suggests that advising patients to therapeutic approaches may be devised References avoid exercise near busy streets or during to mitigate exposures to diabetogenic 1. Centers for Disease Control and Prevention. 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