There are many types of polychlorinated dibenzodioxins (PCDDs), or dioxins. This page focuses on 2,3,7,8 tetrachlorodibenzo-p-dioxin (known as TCDD or dioxin) in particular. Polychlorinated dibenzofurans (PCDFs) are related chemicals. These compounds are persistent organic pollutants (POPs). Some other persistent organic pollutants act like dioxin, and are called "dioxin-like compounds." For information on studies relating to other persistent organic pollutants, or combinations of POPs, see the POPs page or the PCBs page.
The primary source of exposure to dioxins and dioxin-like compounds in developed countries is via food, especially meat, milk, dairy, eggs, and fish, which together make up 93% of total exposure. Inhalation, drinking water, vegetable oils, and other sources only constitute a small percentage of overall exposure (Lorber et al. 2009). The U.S. Environmental Protection Agency has concluded that "safe" levels of dioxin exposure are 300-600 times lower than current average daily exposure levels, in part due to dioxin's potential effects on the immune system (Gogal and Holladay 2008).
Studies of people exposed to high levels of dioxin (TCDD) have sometimes found increased rates of type 2 diabetes. For example:
What about people exposed to lower, "background" levels of dioxin, as are generally found in the environment and in most people?
To investigate this question, Longnecker and Michalek (2000) studied the association of dioxin levels with diabetes in members of the Air Force study who were not exposed to Agent Orange. The dioxin levels in these vets were similar to those seen in the general U.S. population. They found that men with higher background dioxin levels did indeed have a higher prevalence of diabetes, as well as higher levels of insulin and glucose after a glucose tolerance test (signs of type 2 diabetes). Pretty much the same thing was found in Japan, where levels of dioxin in incinerator workers were associated with diabetes, but the diabetes rates and dioxin levels were similar to those in the general population (Yamamoto et al. 2015).
Another study analyzed tissue samples from the same Air Force veterans, from both vets exposed to TCDD and from vets who were not exposed. They found strong evidence that a change occurred in the tissues of vets exposed to Agent Orange that could contribute to diabetes development. They identified certain markers that were correlated to both dioxin levels and fasting glucose levels. Interestingly, the same change and correlation was also seen in the tissues of vets who were not exposed to Agent Orange. This finding implies that dioxin may be hazardous at current levels of exposure to the general public (Fujiyoshi et al. 2006).
A meta-analysis of studies on dioxin and diabetes finds that among people with low level dioxin exposures, there is an association between dioxin and diabetes. Among people with high level exposures, the association is not clear (Goodman et al. 2015). Thus the effects of dioxin may be more critical at low levels of exposure.
In a study that compared people with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance, those with type 2 had the higher levels of dioxin ("dioxin equivalents"), and the highest AhR activity. (AhR activity is associated with exposure to certain persistent organic pollutants, especially dioxin and dioxin-like compounds). In those without diabetes, AhR activity was associated with fasting glucose and insulin levels, as well as higher insulin resistance (Roh et al. 2014).
A study of people without diabetes living near a Superfund site in Arkansas found that people with higher levels of dioxin (TCDD) in their bodies had higher levels of insulin after a glucose tolerance test. This study suggests that high levels of dioxin may increase insulin resistance (Cranmer et al. 2000). Another study of the Operation Ranch Hand Vietnam vets found that high dioxin (TCDD) levels may promote insulin resistance, but that the effect was small (Kern et al. 2004). A Taiwanese study found that people with higher levels of dioxin (PCDD/F) had higher levels of insulin resistance. The people in this study lived near a contaminated site (Chang et al. 2010). A subsequent study by the same authors found that men with the highest dioxin levels as well as abdominal obesity had 5-fold increased insulin resistance levels than those with the lowest levels (both were individually associated with higher insulin resistance as well, but the effect was greatest when combined) (Chang et al. 2016).
Dioxin has been shown to stimulate insulin secretion by rat beta cells (Kim et al. 2009). The authors suggest that dioxin may therefore contribute to the risk of developing diabetes by causing continuous insulin release, followed by beta cell dysfunction. Other studies have found that dioxin exposure impaired insulin secretion from rodent beta cells (Kurita et al. 2009, Novelli et al. 2005), and, at higher doses, even killed them (Piaggi et al. 2007). Hectors et al. (2011) review the effects of chemicals on beta cells, and find that other chemicals have also been found to increase as well as decrease insulin secretion. The effect may depend on dose, the animal or cells used in the experiment, or other factors. Dioxin's ability to affect beta cells may have importance for diabetes development.
A more recent study confirms that dioxin is highly toxic to pancreatic beta cells, and that a substance in green tea is protective against it (Martino et al. 2013).
A study found that dioxin interferes with the ability of mouse fat cells to take up glucose, perhaps a mechanism that can explain how dioxin exposure could lead to insulin resistance in humans. The study aimed to determine how dioxin might cause dysfunction of the metabolism. Dioxin interfered with the development of fat cells, affected gene expression, and may interfere with insulin signaling (Hsu et al. 2010). Another study found that dioxin increases insulin resistance during active periods but not during rest periods, in mice (Takuma et al. 2015). However, dioxin has also been found to decrease insulin resistance in animals (Fried et al. 2010). Dioxin's effects my depend on dosage, timing, species, and other factors.
Dioxin is an endocrine (hormone) disruptor because it interferes with the endocrine system (Hotchkiss et al. 2008). The mechanisms probably involve the AhR receptor; animal studies show that the AhR affects glucose tolerance and insulin resistance (Wang et al. 2011). Animal studies also show that the AhR is involved in numerous effects on glucose and fats in mice-- and that these effects did not occur in mice without the AhR (Zhang et al. 2015). A similar finding is shown for mice with and without AhR and exposed to a high-fat diet in that AhR deficient mice were protected from the harmful effects of the diet (Xu et al. 2015).
Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life.
Mice exposed to dioxin in the womb and while nursing were then given either a high-fat or low-fat diet and compared to unexposed controls. The control mice who ate a high fat diet developed obesity and some other signs of metabolic syndrome. The dioxin-exposed mice, however, did not develop these or other symptoms, but instead reduced the risk of metabolic problems (Sugai et al. 2014).
Another study that looked at what happened to the offspring when pregnant/lactating mice were exposed to low levels of dioxin (levels generally encountered by humans). The effects differed by gender, but there were effects on the immune system and body weight (van Esterik et al. 2015).
Dioxin can mess with the immune system, we know that. We just don't quite know what it does, or how it does it. It is likely, however, that dioxin's effects on the immune system are related to its AhR activity. The AhR controls or influences many aspects of the immune system (Quintana and Sherr 2013).
Dioxin is known to suppress the immune system of animals and possibly humans (Baccarelli et al. 2002). Dioxin exposure can also expand the population of regulatory T cells that are protective against autoimmunity, and animal studies indeed show that arrests the development of various autoimmune conditions (Quintana and Sherr 2013), including type 1 diabetes in mice (Kerkvliet et al.2009).
Since the AhR has so much influence on the immune system, it might. For example, dioxin can also expand the populations of inflammatory cells that promote autoimmunity. Dioxin could, under various conditions, either promote or ameliorate autoimmunity (Quintana and Sherr 2013). Timing of exposure may be important; adult exposure is generally found to suppress the immune system, while prenatal exposure may promote autoimmunity. The effects also depend on the dose, genetic background, and route of exposure (pers. comm., Dr. Boule, 2014).
In a review, Gogal and Holladay (2008) find that current evidence supports the hypothesis that exposure to dioxin in utero may predispose a person to autoimmune disease later in life. How? Perhaps by interfering with the development of the immune system, especially in the thymus (see the autoimmunity page for more on the thymus and immune system development). Other authors also find that low dose exposure to TCDD in the womb causes autoimmunity, and that an infant's thymus is more susceptible to these effects than an adult's thymus (Ishimaru et al. 2009).
When mice not genetically prone to autoimmune disease were treated prenatally with TCDD during immune system development, they had immune dysregulation that included autoantibody production, and suggested an increased risk for later autoimmune disease. These findings suggest that developmental exposure to TCDD may increase the risk of autoimmune disease (Mustafa et al. 2008). The same authors have found that prenatal TCDD exposure worsens autoimmune disease progression in genetically prone mice as well (Mustafa et al. 2011a). These authors found changes in numerous immune system cells in mice after developmental dioxin exposure, many dependent on sex. This latter finding suggests possible interactions with hormones; the health effects of dioxins may not appear until times of hormonal shifts such as puberty. They also found that prenatal dioxin exposure leads to more autoimmune symptoms later in life (Mustafa et al. 2011b).
Prenatal exposure to dioxin has also been shown to affect T cell response to infection, and since type 1 diabetes (and other autoimmune diseases) are influenced by T cells, its development may be altered by early dioxin exposure (Boule et al. 2014; Winans et al. 2015). For an article describing the Boule et al. study, see Focusing on the AhR: A Potential Mechanism for Immune Effects of Prenatal Exposures, published in Environmental Health Perspectives (Konkel 2014). Further research by the same authors found that developmental exposure of autoimmune-prone mice to AhR activation accelerated disease, accompanied by increased T cell populations (Boule et al. 2015).
Other authors propose that the AhR receptor can be both friend and foe, depending on conditions of exposure. Pollutants that bind the AhR for long periods of time, for example, may promote autoimmunity (Julliard et al. 2014).
In mice treated with a chemical to give them a type 1-like diabetes, TCDD affects the gut microbiome and liver in detrimental ways (Lefever et al. 2016).
Veterans exposed to dioxin via Agent Orange have higher rates of neuropathy-- nerve damage often associated with diabetes-- than those who were less exposed (Michalek et al. 2001). The VA recognizes peripheral neuropathy as related to Agent Orange exposure, if the disease appeared within one year of exposure.
People with type 2 diabetes who have nephropathy -- kidney disease often associated with diabetes-- have higher levels of AhR activity in their blood than people with type 2 who do not have kidney abnormalities (Kim et al. 2013).
In a group of workers exposed to high levels of dioxin in the former Czechoslovakia, 40 years after the exposure, many suffer from high levels of cholesterol and triglycerides, hardening of the arteries, high blood pressure, and heart disease, in addition to neurological damage of the brain (Pelclová et al. 2002, Pelclová et al. 2009).
Exposure to high levels of dioxin appears to increase the risk of developing type 2 diabetes, and possibly exposure to low levels as well. There is contradictory evidence of how dioxin affects beta cells and autoimmunity. Perhaps these contradictions depend on the timing of exposure, with developmental exposures increasing the risk of autoimmunity, and later life exposures decreasing it. It is not clear how dioxin would affect the development of type 1 diabetes, but its role should be studied.
A review of the role of dioxin in diabetes concludes that: "In the last few decades, a considerable body of epidemiological evidence has been accumulated, whose conclusions strongly suggest that exposure to dioxin and other POPs can be considered as a new risk factor for diabetes in humans in addition to the traditional lifestyle-related factors, such as excess of energy intake and a lack of exercise... an increasing number of experimental evidence clearly indicates that pancreatic beta cells can be considered a relevant and sensitive target of dioxin cytotoxicity, throwing some light on the underlying biological mechanisms." (De Tata 2014).
To download or see a list of all the references cited on this page, see the collection Dioxin and diabetes/obesity in PubMed.