E-cigarette liquids vaporized at higher-than-standard voltage produced significant quantities of formaldehyde-releasing compounds, researchers said, suggesting that power-vaping may be more hazardous than previously supposed.

With a variable-voltage e-cigarette device set to operate at 5 V, 10 puffs produced a mean of 380 mcg (SE 90) of formaldehyde in the form of hemiacetal compounds that release formaldehyde, according to David H. Peyton, PhD, of Portland State University in Oregon, and colleagues.

More than 2% of solvent molecules in aerosol samples produced by "vaping" e-cigarettes converted into hemiacetal compounds known to spontaneously degrade into formaldehyde -- "reaching concentrations higher than concentrations of nicotine," they wrote in a letter published in the Jan. 22 issue of the New England Journal of Medicine.

Action Points This study of electronic cigarettes found high levels of formaldehyde-associated substances in the particulate aerosol.

Be aware that this finding was voltage-dependent and seemed to be restricted to high-voltage e-cigarettes.

No formaldehyde-related compounds were detected when the voltage was set to 3.3 volts. Fixed-voltage commercial e-cigarettes generally operate at 3.7 V, but variable-voltage devices are sold that run at up to 6 V, which produce a stronger vapor more to the liking of some users.

"Many have argued in favor of e-cigarettes because they don't deliver the countless noxious chemicals associated with tobacco combustion. This report doesn't invalidate that argument, but it makes a strong case that "vaping" delivers more than just nicotine," medical toxicologist David Juurlink, MD, PhD, of Sunnybrook Research Institute in Toronto, who was not involved with the research, wrote in an email to MedPage Today.

"[Formaldehyde-releasing agents] are used as preservatives and in other roles because they release formaldehyde over time," Lewis Nelson, MD, a poisoning expert at New York University, also not affiliated with the study, told MedPage Today in an email. "Formaldehyde is definitely considered a carcinogen, although like any chemical that causes cancer, there is a dose and time of exposure relationship with risk."

"This new study shows convincingly that e-cigarette users are drawing more than just nicotine into their lungs. And while it's not nearly as noxious as tobacco smoke, it's not far-fetched to speculate that long-term e-cigarette use might pose a risk of cancer," Juurlink said.

The Study

The chemical reaction happens when propylene glycol and glycerol, known agents in e-cigarette liquid cartridges, are heated in the presence of oxygen.

Peyton -- a pharmaceutical chemist -- and colleagues in other Portland State departments, including computer science and civil and environmental engineering, used a nuclear magnetic resonance spectroscopy tube to analyze the aerosolized liquid output of a variable voltage e-cigarette device, using a commercial e-liquid. The resulting vapors were trapped in the tube.

First, they tested the apparatus on low voltage. At 3.3 volts, the machine performed 10 puffs, at 3 to 4 seconds per puff, of 50 mL of an e-cigarette's liquid cartridge over the course of 5 minutes. Analysis of the vapors collected by the tank showed no "formation of any formaldehyde-releasing agents."

At 5.0 volts, however, measurable quantities of formaldehyde-releasing agents were found in the tube.

The researchers calculated that a person vaping at 3 mL of e-cigarette liquid per day, using a 5-V device, would inhale 14.4 mg (SE 3.3) of formaldehyde daily in the form of formaldehyde-releasing agents.

That's nearly five times the 3 mg of formaldehyde that a pack-a-day smoker of conventional cigarettes would inhale, they estimated.

Peyton and colleagues wrote that these estimates were conservative: not all aerosolized liquid was collected and gas-phase formaldehyde was not measured.

Previous research by Polish researchers led by Leon Kosmider, PharmD, had also indicated that toxic and carcinogenic compounds increase with voltage in e-cigarette vapors.

"Increasing voltage from 3.2 to 4.8 V resulted in a four to more than 200 times increase in formaldehyde, acetaldehyde, and acetone levels," Kosmider and colleagues wrote.

The difference between the two studies is that Peyton's group measured aerosol particles containing formaldehyde-releasing agents, whereas the Polish researchers looked at formaldehyde in the gas phase alone.

Using a formula developed by Canada's Office of Environmental Health Hazard Assessment, Peyton and colleagues calculated that for a person who weighs 70 kg, the incremental lifetime cancer risk from smoking a pack a day is 9×10-4. In contrast, the corresponding risk from the formaldehyde levels found with 5-V vaping in the current study would be some 4.2×10-3, or five times greater.

In Real Life

The key unknown is the actual health risk to humans from inhaled formaldehyde or formaldehyde-releasing agents, either as aerosolized liquid or in gaseous form. The International Agency for Research on Cancer lists formaldehyde as a group 1 carcinogen, primarily on the basis of occupational exposures to liquid formaldehyde.

Juurlink said that there is a considerable amount of scientific literature suggesting that inhaled formaldehyde is a carcinogen in animals. "The data in humans are mixed, but it's a difficult association to study because of the long latency period of cancer and the confounding effects of other exposures, particularly smoking and other occupational toxins."

He added that it's premature to conclude that e-cigarettes constitute a risk factor for cancer. "But it's certainly reasonable to speculate, as the authors have, that they may. If I were a user of e-cigarettes, I'd view this study as a reason to focus on tapering and quitting, rather than using e-cigs in the longer term."

"Deposition of [formaldehyde-releasing agents] in the lung may increase the duration and extent of exposure to formaldehyde," Nelson said. "The data provided in this study are concerning because they highlight the possibility that e-cigarette products, as currently formulated, may increase the exposure of the lung to a potential carcinogen and thereby the risk of developing lung cancer."

"The degree of actual risk, and that compared to cigarette smoking, cannot be answered by this work. Direct assessment of formaldehyde exposure of lung tissue, rather than estimated exposure, is likely the next step towards gaining a better understanding," Nelson added.

The authors reported no relevant financial relationships with industry.