Two common flavoring chemicals in e-cigarettes can damage lung cells

Known for its buttery aroma, diacetyl is a popular flavorant in the food industry. In the early 2000s, studies revealed an association between the compound and bronchiolitis obliterans, or “popcorn lung,” a disease first observed in workers at popcorn factories that causes dry cough and wheezing. According to a 2012 report from the US Flavor and Extract Manufacturers Association, several workplace safety organizations have published voluntary occupational exposure guidelines for diacetyl and, in one case, for its close analog 2,3-pentanedione. Some organizations also recommended that the chemicals carry a warning label explaining that inhaling fumes containing the compounds could be harmful.

Diacetyl is also the most common of several hundred flavoring chemicals used in e-cigarettes, and a 2016 study of 51 e-cigarette products found that more than half contained 2,3-pentanedione. Now, a multidisciplinary team of researchers at the Harvard T. H. Chan School of Public Health and the University of Pennsylvania has evaluated the effect of the two flavoring chemicals on human bronchial epithelial cells in culture and proposed a possible mechanism for how they could impair lung function (Sci. Rep. 2019, DOI: 10.1038/s41598-018-37913-9).

Public health researchers studying e-cigarettes have found that flavorings contribute to the devices’ appeal to young users. From 2011 to 2015, e-cigarette use in U.S. high school students grew 900%, leading the US surgeon general to declare e-cigarette use among youths and young adults a major public health concern since most products contain addictive nicotine that can be harmful to developing brains. In an effort to reduce e-cigarette use among young people, in November 2018 US Food and Drug Administration commissioner Scott Gottlieb proposed policies to restrict the sale of flavored e-cigarette products (not including mint, menthol, or tobacco flavors) to stores at which customers must present ID to enter.

Still, flavorants in e-cigarettes are widespread, and few studies have investigated the health impacts of these compounds on e-cigarette users.

The new study focuses on diacetyl and 2,3-pentanedione’s effects on epithelial cells. These cells line the lungs’ airways and keep them clear, says geneticist and study coauthor Quan Lu of Harvard. They exist in three forms: ciliated, goblet, and basal cells. The hairlike ciliated cells work with mucus-producing goblet cells to sweep away dust and pathogens from airways. Basal cells can turn into either of the other types of epithelial cell.

The researchers treated all three types of epithelial cells with a solution of diacetyl, 2,3-pentanedione or a blank solution. Exposure to the flavor chemicals led to a decrease in the number of ciliated cells, compared with exposure to the blank solution. Using a method called RNA-seq, the team monitored levels of the cells’ RNAs, allowing them to see which genes changed their expression after exposure to the flavor chemicals. Many of the genes with lower expression levels after exposure were involved in ciliogenesis—the pathway in which basal cells turn into ciliated cells. Having fewer ciliated cells along the airways means that the lungs have less protection against foreign bodies that can cause inflammation. This work provides a possible mechanism for how these chemicals are causing damage in the lungs, Lu says.

The researchers plan to test a wider pool of flavoring chemicals and also develop a laboratory set-up to expose cells to aerosolized flavorants, which would better mimic how the cells are exposed to the compounds in the lungs.

Maciej L. Goniewicz of the Roswell Park Comprehensive Cancer Center, who studies the toxicity of flavoring compounds in e-cigarettes, says controlled cellular studies like this one are important because they allow scientists to investigate the impact of single chemicals, which can be challenging to do in human studies. However, it can be difficult to extrapolate these results to human health, he says. When evaluating the health risks of e-cigarette flavorants, Goniewicz adds that it’s important to keep in mind that their risks are relative. For examples, smoking cigarettes exposes people to thousands of chemicals, so it’s possible that even with some toxicity from flavorants, e-cigarettes may still be less risky than traditional ones. Weighing those risks will be up to regulators, he says, but they’ll need more data to do so.