The Human Element

Lion Shahab is a psychologist, neuroscientist and epidemiologist, with a focus on tobacco control: “My interest is in the use of biomarkers as a tool to motivate smoking cessation and investigate the effects of tobacco products and products such as e-cigarettes that are thought to mitigate harms.

“Around 2011, people started approaching our group at University College London about e-cigarettes, which were just taking off at the time,” says Shahab. Based on his previous biomarker work, he secured funding from Cancer Research UK for a study examining biomarkers related to various negative health outcomes in users of e-cigarettes compared with smokers, and those using nicotine replacement therapy, such as gum and patches (1).

A lack of evidence

Shahab says that previous studies provided only limited evidence about the harms of e-cigarettes, with some focusing on biomarkers that have only a tenuous link with long-term health consequences. “For example, people have looked at changes in the inner lining of blood vessels, and claimed that e-cigarettes cause cardiovascular disease. The problem is, you see similar changes when you drink a cup of coffee,” says Shahab. Then there were the usual problems of extrapolating results from in vitro or animal studies into humans – notably, nicotine itself is far more toxic to mice than humans.

It’s also important to note that the risk of a product is not determined solely by its inherent properties, but also by how it is used. Water is safe to drink, but a teaspoon in your lungs could kill you, says Shahab. “There was a widely reported study showing that there is hidden formaldehyde in e-cigarettes – the flaw was that the machine used to generate vapor from the product was at a setting that created “dry puffing” – something that consumers avoid at all costs due to the acrid taste,” Shahab adds (2). Shahab also points to tobacco industry studies in the 1970s showing that adding perforations into the filter lowered toxin levels. In reality, no such benefit materialized, because human smokers covered up the perforations with their fingers and smoked more intensely, in order to get the same nicotine “hit.”

As e-cigarettes have become more sophisticated, there is far more variety in how people use them in terms of temperature, choice of e-liquid, and so on, which makes it difficult to estimate how the aerosols will correlate with actual exposure, says Shahab. “For that reason, my preference is always to study humans.”

The lesser evil

In the Cancer Research UK-funded study the team focused on a panel of exposure biomarkers reliably linked with long-term health outcomes, including tobacco-specific nitrosamines and other carbonyls, and a range of volatiles.

Bioanalysis was carried out at the Centers for Disease Control in the US, using LC and GC-MS/MS to measure nicotine exposure in saliva and urine, respectively. Carbonyls were measured using LC and atmospheric pressure ionization MS/MS, while volatiles were analyzed with UHPLC coupled with electrospray ionization MS/MS.

All the products performed equally well in terms of providing nicotine – but compared to smokers, users of nicotine replacement therapy or e-cigarettes had greatly reduced levels of harmful biomarkers.  “There was a 95 percent reduction in some biomarkers for e-cigarette users versus smokers,” says Shahab. “And that implies that they are likely to have better health outcomes in the long term.”  E-cigarettes are unlikely to be as safe as standard nicotine replacement – inhaling many e-liquid components (including nicotine) into the lungs causes irritation and inflammation – but the study suggests that they are much safer than smoking tobacco.

The unknown

Though Shahab is confident that vaping is less harmful than smoking, the risks are hard to quantify. One problem with tobacco research is that the health effects may take a long time to materialize. “If you look at the prevalence of smoking rates in the UK and US, you see a peak in smoking prevalence in the 1950s and 1960s, and then a peak in lung cancer deaths around 30 years later, so there’s a huge time lag between exposure and associated health consequences,” says Shahab. In addition, while some biomarkers, like NNAL (a nitrosamine metabolite) have been shown in long-term studies to have a close relationship with cancer, for others, the evidence is weaker. Other toxic compounds, like formaldehyde, have no good biomarkers to estimate exposure in humans.

“The other major problem is unknown unknowns”, says Shahab. Research into vaping is informed by earlier research on tobacco cigarettes, but the chemistry is very different.

New technology, new risks?

Shahab’s latest research is looking at long-term users of heat-not-burn products, like BAT’s Glo and IQOS from Phillip Morris International. “Tobacco companies are keen to promote these products, which make use of their existing tobacco supply chains, and they claim that by avoiding combustion, they reduce harms,” he says. “So far the research in this area has almost all been carried out by industry, so there 
is a need for independent verification.”

Shahab stresses the need for long-term studies of heated tobacco products, taking into account less than perfect use. “For example, when a stick is replaced some of the tobacco is often left stuck to the heating elements, and I suspect this could lead to the formation of carcinogens over time – but that’s something that will only become apparent in long-term studies.”