Solvents and TCE
Links Between Trichloroethylene and Diabetes/Obesity
There are almost no studies on the solvent trichloroethylene (TCE) and diabetes or obesity, but some studies on TCE and autoimmunity.
A consensus on the immune system impacts of TCE has not yet been reached (Ordaz et al. 2017). It is possible, however, that TCE might influence the progression of autoimmune diseases, which could be relevant for type 1 diabetes.
Trichloroethylene (TCE) is an industrial solvent and environmental contaminant, commonly found in hazardous waste sites. Exposure can occur via drinking water, food, or air, or in occupational settings (Blossom et al. 2007). The U.S. government estimates that 9-34% of drinking water in this country contains TCE, and in some communities, TCE contamination in drinking water is quite high. TCE can enter the body by ingesting contaminated water, and from showering in it, both by absorption through the skin or via inhalation (Keil et al. 2009). It may be an endocrine disruptor (Tachachartvanich et al. 2018).
Type 1 Diabetes and Autoimmunity
TCE has long been suspected of contributing to the development of autoimmune disease because of studies that have shown associations between TCE exposure (through drinking water or occupationally) and various autoimmune diseases, including systemic lupus erythematous (SLE) and scleroderma. People living in areas with TCE-contaminated drinking water have been found to have signs of autoimmunity or autoimmune disease (Keil et al. 2009).
A U.S. EPA risk assessment review of TCE concluded that, "Recent evidence from studies in both humans and experimental animals point to the involvement of TCE exposure in autoimmune disease," among other health effects (Chiu et al. 2013). Human evidence find that people occupationally exposed to TCE--even at low levels--have immune system changes (Lee et al. 2019).
In workers exposed to TCE, TCE was associated with epigenetic alterations in genes important in the development of autoimmune diseases (Phillips et al. 2019).
A meta-analysis of 33 human studies found that there was an association between exposure to solvents (including TCE and others) and autoimmune diseases (Barragán-Martínez et al. 2012). Unfortunately, the authors did not include type 1 diabetes as part of this study (perhaps because they were under the mistaken impression that type 1 usually occurs in children, not adults, or perhaps because there were no studies on solvents and diabetes, I don't know why not).
Exposure During Development
Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life.
Studies from Woburn, Massachusetts (of A Civil Action fame), have found that children exposed to TCE in utero had a higher incidence of leukemia and recurrent infections than those unexposed. An old study of family members of these children found damage to their immune systems, including increased incidence of autoantibodies (Byers et al. 1988).
Webinar on TCE and Autoimmunity
Listen to Dr. Blossom discuss her research on TCE and autoimmunity on this webinar, Environmental Contributors to Autoimmune Disease: Mechanisms, Impacts, and Chemicals of Concern, sponsored by the Collaborative on Health and the Environment (2019).
Over 20 years ago, TCE was found to induce autoimmunity in animals (Khan et al. 1995). Subsequent studies have confirmed that TCE can promote autoimmunity in genetically susceptible mice, using different doses and routes of exposure (e.g., Gilbert et al. 2006; Wang et al. 2007, Blossom et al. 2004). The effects of TCE exposure can also depend on the strain of mouse. Interestingly, Keil et al. (2009) found that at low doses, TCE did not contribute to the progression of autoimmune disease in genetically susceptible mice, but did lead to increased markers of autoimmunity in mice that were not genetically prone to autoimmune disease. In addition, mice exposed to both TCE and mercury developed signs of autoimmune disease before mice exposed to either chemical alone (Gilbert et al. 2011).
Researchers are working to identify the mechanisms by which TCE may contribute to autoimmunity. TCE can induce oxidative stress in conjunction with the induction and exacerbation of autoimmunity in animals (Wang et al. 2020; Wang et al. 2018; Wang et al. 2007). TCE's autoimmunity-promoting effects can be reduced by antioxidants (Banergee et al. 2020). TCE exposure may also involve inflammation (Gilbert et al. 2006; Blossom et al. 2007). Cooper et al. (2009) summarizes some possible mechanisms through which TCE could affect autoimmunity, including via inflammation and oxidative stress. Also, animals exposed to TCE have been found to have changes in gene expression (Baccarelli and Bollati 2009). TCE affects immune cells in ways that promote autoimmunity (Li et al. 2018; Wang et al. 2019).
TCE as well as its metabolites (TCA and DCA) have been found to enhance the activation of immune system T cells, which may affect the development of autoimmunity (Pan et al. 2015).
One study has examined the effects of TCE on NOD (non-obese diabetic) mice, an animal model of type 1 diabetes. Ravel et al. (2005) found that TCE did not accelerate diabetes in NOD mice. To the contrary, TCE showed almost opposite effects than have been found in other strains of mice. The authors conclude that the mechanisms involved in autoimmune disease development are more complex than previously thought, and that people with differing levels of susceptibility may have differing levels of risk to environmental contaminant exposures (see the Of mice, dogs, and men page for more discussion).
A review examined experimental and human studies of the immune-related, especially autoimmune-related, effects of TCE. It found that the consistent findings of the studies and the similarities between studies in mice and humans support the idea that TCE may cause autoimmune disease (Cooper et al. 2009). The health effects of TCE exposure during development (e.g., in utero were not included in this review.
Other solvents, including perchloroethylene, have also been linked to autoimmunity in rodent studies (Wang et al. 2017).
Another chemical, 1,2-dichloroethane (1,2-DCE) sometimes used as a solvent, suppresses glucose production in the liver, in animal studies (Zeng et al. 2018).
Exposure During Development
Developmental exposures to TCE show that TCE affects the development of the immune system. These immune system effects occurred at lower doses than those producing effects in adult animals (Peden-Adams et al. 2006).
Gestational exposure to TCE may induce immune system changes that could contribute to autoimmune disease later in life. A study compared exposure during gestation, and exposure during early life (in mice), to see which had the most profound effects. Certain immune system effects were found in both sets of mice. Some additional changes were found in the mice exposed during gestation, while other changes were found in those exposed early in life. These changes may affect the likelihood of autoimmune disease later in life, but that remains to be determined (Gilbert et al. 2014). A further study by the same authors found that much lower level TCE exposure during development led to autoimmunity in mice, and that ending the exposure during adulthood did not prevent the immunotoxic effects (Gilbert et al. 2017). Even further, these changes are probably driven by epigenetic processes (Byrum et al. 2019).
These authors also found that developmental exposure to TCE affected anti-liver autoantibodies, immune cells in the liver, gut, and spleen, as well as gut bacteria. The exposure also counteracted the effects of a high-fat diet in relation to measures of weight and fatty tissue (Blossom et al. 2018). In fact, mice exposed to TCE during development had changes to the gut and gut bacteria that continued even after the exposure ended (Khare et al. 2018). Young adult female mice developmentally exposed to TCE were more likely to have these changes in the immune system, gut, and liver as compared to male mice (Blossom et al. 2020). Adult female mice exposed to TCE had changes to gut microbiota, plus gut inflammation and a leaky gut, which seem to be a critical pathway by which TCE can trigger autoimmunity (Wang et al. 2021).
Even in mice resistent to autoimmunity, developmental exposure to TCE enhances autoimmune markers (Blossom et al. 2022).
Type 2 Diabetes
The U.S. Agency of Toxic Substances and Disease Registry (ATSDR) monitors groups of people exposed to TCE in drinking water in Michigan, Indiana, Illinois, Pennsylvania, and Arizona. They document some of the health effects found in people exposed to TCE, as compared to others in the general U.S. population. They have found higher levels of diabetes in people exposed to TCE, but did not distinguish between type 1 and type 2 (Davis et al. 2005).
A long-term study of early-life exposure to tetrachloroethylene, a solvent used in dry-cleaning (also known as PERC), did not find any links between exposure and later diabetes, obesity, or cardiovascular diseases (it did find a link with cancer and epilepsy, however) (Aschengrau et al. 2015).
A study of Hispanics/Latinos found that occupational exposure to solvents was associated with high blood pressure, which is one component of metabolic syndrome (the other components were not associated) (Bulka et al. 2017).
In rats, inhalation exposure to TCE decreased LDL cholesterol levels and raised glucose levels (Zamanian et al 2018).
Oil spill dispersants are composed in part of solvents. Women who reported oil spill exposure, particularly loss of use of the coast, were more likely to report gestational diabetes; however, the level of association was similar for pregnancies before and after the spill, so there was not really an association (Harville et al. 2017).