The metabolic syndrome (MetS) constitutes a growing problem of a serious public health and health care concern not only because of its increase in the population in recent years, but also because it’s a major risk factor for cardiovascular diseases, which is the leading cause of death in the United States and worldwide [1,2]. Age-adjusted prevalence of the MetS in the U.S. adult population has grown from below 24% in 1988–1994 to 34% in 2003–2006 [3,4]. The MetS is a clustering of metabolism-related disorders and conditions that may share common pathophysiological mechanisms: including glucose intolerance/insulin resistance, abdominal obesity, dyslipidemia, and high blood pressure—hypertension (HTN) [5,6]. Insulin resistance and obesity play the central role in the pathophysiology of the MetS. A formalized clinical definition of the MetS includes having any three of the following five criteria: waist circumference over 40 inches (men) or over 35 inches (women); fasting glucose 100 or higher mg/dL or currently on medication for an elevated glucose level; triglycerides 150 or higher mg/dL or currently on medication for hypertriglyceridemia; high-density lipoprotein (HDL) cholesterol below 40 mg/dL (men) or below 50 mg/dL (women) or currently on medication for low HDL cholesterol level; systolic blood pressure over 130 mm Hg or diastolic blood pressure over 85 mm Hg or currently on medication for HTN [7].

The MetS increases risk of myocardial infarction (heart attack) and stroke; it is also associated with an increased cardiovascular disease mortality and all-cause mortality [8,9].

Persistent organic pollutants (POP) are a group of organic compounds that are highly resistant to chemical, photolytic, and biological degradation. These lipophilic compounds are persistent in the environment and human body. POP include polychlorinated biphenyls (PCB), polychlorinated dibenzo-p-dioxins [e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)], polychlorinated dibenzofurans, and persistent pesticides, such as dichlorodiphenyltrichloroethane (DDT) [10]. PCBs were manufactured in the U.S. from 1929 through 1976 for a variety of industrial purposes as determined by the compounds’ low electrical and thermal conductivity. PCBs were used in dielectric fluids in capacitors and transformers; they have also been used in plasticizers, adhesives, paints, pesticide extenders, hydraulic fluids, flame retardants and dyes for carbonless copy paper [11,12]. Inadequate manufacturing control, flaws in waste management, old electrical equipment disposal, and garbage incineration are among sources of environmental contamination with POP [13]. POP are known carcinogens and endocrine disruptors; they have neurotoxicity and immunotoxicity properties and can cause birth defects [12,14].

Recent cell studies reported that POP can interfere with insulin signaling pathway and induce insulin resistance [15,16]. Results from a limited number of studies are indicative of serum levels of POP being associated with MetS prevalence [17,18]. This prompted us to investigate MetS-associated hospitalizations in relation to environmental contamination with POP. We hypothesized that residency in areas containing environmental sources of POP will be associated with an increase in MetS-associated hospitalization rates.

In this study we found that residence in zip codes containing or abutting environmental sources of POP is associated with a statistically significant 39.2% increase in MetS-related hospitalizations compared to residents of non-POP zip codes. To our knowledge, this is the first study investigating the association between the presumed environmental exposure to POP based on residence near to a POP hazardous waste site and MetS employing hospitalization rate as the outcome of interest.

We chose to focus on this outcome for two reasons. Firstly, while an increased MetS-related hospitalization rate does not prove a causal effect of POP, it is reasonable to expect that the hypothesized association between POP and MetS does exist. Our previous studies using hospitalization in relation to residence near to POP sites have reported elevated risk of diabetes [26], hypertension [22], and cardiovascular [27] and cerebrovascular disease [28,29]. In addition, studies in which PCBs and pesticides were measured in serum have demonstrated statistically significant relations between exposure and diabetes [30,31], obesity [32], hyperlipidemia [33] and hypertension [34], each one component of MetS. Secondly, the concept of the environmental burden of disease is important from the public health and health care perspectives [35,36], and hospital utilization is an essential component of this concept.

Our results are consistent with findings from other population-based studies of exposure to POP and MetS, or MetS components, that were conduced using different approaches. Chang et al. (2011) investigated insulin resistance in non-diabetic adults residing near a deserted pentachlorophenol factory that generated polychlorinated dibenzo-p-dioxins and furans as byproducts. They found a statistically significant positive association between serum dioxin levels and homeostasis model assessment—insulin resistance (HOMA-IR; higher values indicative of insulin resistance), fasting glucose, systolic and diastolic blood pressure, waist circumference, and HDL cholesterol level [37].

Cranmer et al. (2000) studied association between environmental residential exposure to TCDD and insulin levels in 69 subjects with normal glucose tolerance test who lived within 25 miles of a Superfund site in Arkansas [38]. The source of TCDD contamination was a plant where the TCDD-containing component of Agent Orange was manufactured and from which TCDD spread into the environment due to lack of adequate production control and waste disposal. High blood TCDD levels were found to be associated with higher levels of both fasting insulin and insulin at 30, 60, and 120 minutes after oral glucose load.

Using the National Health and Nutrition Examination Survey data, Lee et al. (2007) investigated cross-sectional associations between POP and MetS among 721 adults, of whom 175 individuals had MetS [17]. They found that serum concentrations of organochlorine pesticides and dioxin-like polychlorinated biphenyls (PCBs) were positively associated with the prevalence of the MetS. The dose-response relationship between non-dioxin-like PCBs and the MetS was inverted-U-shaped, with the association being the strongest for the two middle quartiles of serum POP levels. Serum levels of other POP investigated in that study (polychlorinated dibenzofurans and polychlorinated dibenzo-p-dioxins) were found to be associated with only one of the MetS components—HTN.

In a study of 160 MetS patients among 1,374 Japanese residents non-occupationally exposed to POP, Uemura et al. (2009) found that body burden levels of polychlorinated dibenzofurans, polychlorinated dibenzo-p-dioxins, and dioxin-like PCBs were statistically significantly associated with the prevalence of the MetS [18].

While the exact pathogenic mechanisms involved in the association between POP and the MetS have not been established with certainty, results from a number of studies indicate that insulin resistance and changes in gene regulation caused by POP play the major role. POP can increase secretion of tumor necrosis factor alpha (TNF-α), which plays an essential role in development of insulin resistance. The insulin resistance-inducing effect of TNF-α is established [39–41]. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to stimulate TNF-α and inhibit glucose transport in adipose cells (adipocytes) [15,42]. TCDD interferes with the insulin signaling pathway by decreasing the expression levels of insulin receptors and glucose transporter GLUT-4 that results in inhibiting insulin-stimulated glucose uptake [16]. The underlying mechanism of the insulin resistance-inducing effect of TCDD is stimulation of TNF-α production [16]. TNF-α substantially decreases GLUT-4 [43]. TNF-α activates nuclear factor kappa B (NF-κB)—an obligatory mediator of the changes in gene expression induced by TNF-α, including GLUT-4. This pathway leads to development of insulin resistance [44].

The role of the TNF-α → NF-κB → GLUT4 pathway in POP-induced glucose intolerance was also demonstrated in a study of United States Air Force veterans of the Vietnam War who were involved with spraying the Agent Orange herbicide that was contaminated with TCDD. Fujiyoshi et al. (2006) investigated the NF-κB:GLUT4 ratio in the exposed veterans, as compared to the veterans without history of exposure, and found that this ratio is significantly correlated with serum dioxin levels [45]. In another study of the exposed veterans, Michalek et al. (1999) found elevated levels of insulin in non-diabetic veterans [46]. High insulin levels would be expected in the MetS.

Although investigating MetS-associated hospitalization in relation to demographic characteristics was not a goal of our study, these results may be worth a brief discussion. Prevalence of the MetS is known to increase with age [4,47]. Our findings are consistent with this knowledge, in that MetS-associated hospitalization rates increased with age (p for trend < 0.001). While MetS prevalence is higher in men than in women and in Caucasians than in African Americans, gender and racial differences in the MetS components vary substantially [4,48]. While hypertriglyceridemia, HTN, and high fasting glucose are more prevalent in men, abdominal obesity and low HDL cholesterol are more prevalent in women [4]. Abdominal obesity, hypertriglyceridemia, low HDL cholesterol, and high fasting glucose are more prevalent in Caucasians, but HTN is more prevalent in African Americans [4]. In our study, racial and gender differences in MetS-associated hospitalization (higher rates in Caucasians than in African Americans and in men than in women) were not statistically significant. Probably, racial and gender differences appearing in MetS prevalence became smoothed in MetS-associated hospitalization rates because diseases and conditions that do not constitute an immediate threat to patient’s life or risk of permanent and severe disability if not treated promptly may be underrepresented in hospital settings.

Our study is not free from limitations. Exposure status information was available only on a zip code-level (group level), which is a very crude measure of exposure. Group-level measurements are a common limitation intrinsic to ecological and semi-ecological studies. Therefore, the results of such studies cannot be extrapolated to individual level because of ecological fallacy problem [49,50]. It should be noted, however, that ecological design remains valuable for studies investigating population-level processes and effects, such as an extent of public health impact of social processes and outcomes of public health interventions [49,51]. Only data on hospital discharges from State-regulated hospitals were used, as data from Federal hospitals were not available. We also utilized only the ICD-9 code for MetS, not that for the components of the disease. This may have resulted in an underestimation of the true rate of the MetS.

It can be reasonably argued that crude measurement of exposure might have produced a dilution effect, thus weakening the measure of association (underestimation of RR) due to non-differential misclassification. That means that if exposure status was measured more accurately, the true RR obtained in such a study would have been even higher, indicating stronger association between exposure and outcome. Since exposure and outcome status were estimated independently from each other, using independent sources of data, differential misclassification is unlikely in our study.

In conclusion, our findings contribute to the body of evidence supporting the hypothesis of POP constituting an environmental risk factor for the MetS. Further studies of POP exposure and the MetS with individual level measurements of exposure and outcome, including measures of insulin resistance, are warranted. Given the involuntary nature of environmental residential exposure to POP that may affect a substantial portion of population, it is imperative to develop and implement respective public health and environmental health policy interventions aimed at reducing and eliminating POP exposure.