Abstract and Introduction
Abstract
Objective: In this systematic review we evaluated the evidence on the association between dioxin exposure and cardiovascular disease (CVD) mortality in humans.
Data Sources and Extraction: We conducted a PubMed search in December 2007 and considered all English-language epidemiologic studies and their citations regarding dioxin exposure and CVD mortality. To focus on dioxins, we excluded cohorts that were either primarily exposed to polychlorinated biphenyls or from the leather and perfume industries, which include other cardiotoxic coexposures.
Data Synthesis: We included results from 12 cohorts in the review. Ten cohorts were occupationally exposed. We divided analyses according to two well-recognized criteria of epidemiologic study quality: the accuracy of the exposure assessment, and whether the exposed population was compared with an internal or an external (e.g., general population) reference group. Analyses using internal comparisons with accurate exposure assessments are the highest quality because they minimize both exposure misclassification and confounding due to workers being healthier than the general population ("healthy worker effect") . The studies in the highest-quality group found consistent and significant dose-related increases in ischemic heart disease (IHD) mortality and more modest associations with all-CVD mortality. Their primary limitation was a lack of adjustment for potential confounding by the major risk factors for CVD.
Conclusions: The results of this systematic review suggest that dioxin exposure is associated with mortality from both IHD and all CVD, although more strongly with the former. However, it is not possible to determine the potential bias, if any, from confounding by other risk factors for CVD.
Introduction
Dioxins, a class of environmental pollutants resulting from the production and combustion of chlorinated compounds, have been shown to cause cardiovascular toxicity in animals (Dalton et al. 2001; Jokinen et al. 2003; Kopf et al. 2007; Lind et al. 2004). Although a number of epidemiologic studies have examined the association of dioxin exposure with cardiovascular disease (CVD) morbidity or mortality, we found no published systematic reviews on this topic, possibly because dioxin epidemiology research has focused primarily on the association with various cancers [International Agency for Research on Cancer (IARC) 1997; National Academy of Sciences 2007]. In this review we focus on CVD mortality. Given the large worldwide burden of CVD, the potential role of dioxin exposure as a preventable risk factor could be of substantial public health and clinical interest, especially in the context of recent reports of elevated environmental dioxin levels in China (Leung et al. 2007; Li et al. 2007, 2008) and ubiquitous low levels worldwide (Schecter et al. 2006).
Definition of "Dioxin." The term "dioxin" refers to a diverse group of structurally related, environmentally persistent chemicals that exert toxic effects through a common pathway mediated by the aryl hydrocarbon receptor (Van den Berg et al. 1998, 2006). Dioxins include several types of polyhalogenated aromatic hydrocarbons: polychlorinated dibenzofurans (PCDFs); some types of polychlorinated biphenyls (PCBs); and polychlorinated dibenzo-p-dioxins (PCDDs), including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent member of this class of chemicals. Although "dioxin" is also sometimes used to refer to TCDD alone, in this review we use the broader definition.
Animal and Laboratory Evidence. Although studies have demonstrated that the fetal mammalian heart is a sensitive target of TCDD-induced teratogenicity (Thackaberry et al. 2005), only in the past few years have toxicologic studies demonstrated cardiovascular effects after exposure to dioxins in adult rats and mice. These effects did not seem to occur as a result of overt toxicity. Chronic exposure of rats to either TCDD or PCB-126, the most potent of the dioxin-like PCBs, led to a dose-dependent increased incidence of degenerative cardiovascular lesions, including cardiomyopathy and chronic active arteritis (Jokinen et al. 2003). PCB-126 also increased heart weight, serum cholesterol levels, and blood pressure in rats (Lind et al. 2004). Adult mice exposed subchronically to TCDD developed increased blood pressure and heart weight, as well as elevated markers of oxidative stress (Kopf et al., in press). Increased blood pressure and triglyceride levels were also observed after an acute high dose of TCDD in mice (Dalton et al. 2001). ApoE–/– mice exposed to subchronic doses of TCDD also developed earlier and more severe atherosclerotic lesions (Dalton et al. 2001). Some of these changes may be due to altered gene expression, inflammation, and oxidative stress (Arzuaga et al. 2007; Lund et al. 2005), whereas others may relate to direct affects on cardiomyocytes involving dioxin perturbation of key calcium signaling pathways leading to abnormal depolarization (Xie et al. 2006). Recent evidence that TCDD causes mitochondrial dysfunction in cell culture (Biswas et al. 2008) may suggest an additional mechanism for the effect of dioxin on the cardiovascular system. Such molecular, physiologic, and morphologic effects in rodent models all provide biological plausibility to the association observed in epidemiologic studies between exposure to dioxins and CVD mortality.