Volume 95 Issue 14 | pp. 24-26
Issue Date: April 3, 2017 | Web Date: March 28, 2017

Can tobacco clean up its act?

Emerging tobacco products have cleaner chemistry than cigarettes but regulators remain leery of their benefit—and the companies developing them
Department: Science & Technology
Keywords: toxicology, e-cigarette, heat-not-burn, tobacco, TSNA
Keeping tobacco but kicking combustion could reduce health risks associated with smoking and nicotine use.
Credit: Shutterstock
A photo shows tobacco leaves in an arrangement.
Keeping tobacco but kicking combustion could reduce health risks associated with smoking and nicotine use.
Credit: Shutterstock

Smoking by the numbers

6 million: Number of annual deaths caused by tobacco use

600,000: Number of nonsmokers who die annually from secondhand smoke

$113 billion: Amount paid by tobacco companies to 46 states, the District of Columbia, and five U.S. territories through April 2016 since the 1998 settlement of a civil lawsuit over health care costs

$300 billion: Estimated annual cost to the U.S. economy of smoking, including direct health care expenses and work time lost

Sources: WHO, National Association of Attorneys General, CDC

One thing becomes clear when talking to public health experts about smoking: It’s hard to imagine a product that’s more dangerous than cigarettes.

Cigarette smoking and other tobacco use kills roughly six million people per year. Of those, more than half a million are nonsmokers exposed to secondhand smoke, according to the World Health Organization (WHO). Lung cancer is a leading cause of death, and cigarettes cause a number of preventable cancers and other potentially fatal illnesses.

The flip side of these data is that it should be possible, if not simple, to design a safer way to provide smokers with the nicotine they crave from cigarettes. Addiction is the major health concern for nicotine use by adults who aren’t pregnant. The more deadly and debilitating consequences of smoking can be blamed on other compounds found in smoke, of which there are thousands.

Reducing the level of the more harmful chemicals would therefore provide a safer way to deliver nicotine to more than 1 billion smokers worldwide, so the argument goes.

Tobacco companies are now chasing this goal by investing billions in noncombusting products, including emerging devices that heat tobacco instead of burning it, improved versions of old-fashioned Swedish smokeless tobacco, and electronic cigarettes. Although the chemistry of these products appears safer than that of cigarettes, regulators and researchers disagree on whether these alternatives are ready to be trusted as benefits to public health. While this debate plays out, these products are already testing policy and, to some extent, shaping it.

In December, tobacco giant Philip Morris International (PMI) presented a new device it calls iQOS to the U.S. Food & Drug Administration. FDA has the authority to regulate if and how the device is marketed in the U.S. thanks to the Tobacco Control Act of 2009.

PMI’s iQOS (top left), Swedish Match’s General Snus, and BAT’s Vype products deliver nicotine and other chemicals without smoke.
Credit: PMI/Swedish Match/BAT
A photo shows three new nicotine delivery systems.
PMI’s iQOS (top left), Swedish Match’s General Snus, and BAT’s Vype products deliver nicotine and other chemicals without smoke.
Credit: PMI/Swedish Match/BAT

Although FDA has not yet announced a decision on iQOS, the product is already available in nearly 20 countries worldwide. PMI started selling the product in Japan last April, and it has already claimed more than 5% of the country’s cigarette market, Bloomberg reported in February.

Wells Fargo stock analysts are “increasingly bullish” on the product and its parent company after PMI submitted its application with FDA, according to a recent report for clients. The same report predicts profits for the iQOS system could exceed $1 billion by 2020, with the company supplying up to 60 billion of the consumable, tobacco-filled sticks iQOS uses.

The sticks slip into a reusable holder that houses an electronic heater. The heater warms the stick to less than 350 °C, roughly half the temperature of the combustion processes taking place in the toxicant foundry that is a lit cigarette. Users put the holder in their mouth and inhale an aerosol that delivers nicotine.

The action will be familiar to smokers, and the nicotine levels are reduced but comparable to what’s found in cigarettes. Both similarities are important factors if smokers are going to switch, experts say. But it’s the differences that Stéphanie Boué, manager of scientific transparency and verification with PMI, stresses.

Most of the iQOS aerosol is water and glycerin, the latter of which maintains moisture levels in tobacco sticks.

As for the non-nicotine remainder, the heat-not-burn aerosol contains lower levels of more than 50 harmful and potentially harmful chemicals that researchers compared with cigarette smoke, Boué says. PMI researchers selected which analytes to monitor based on lists that health agencies, including WHO, use to set or suggest cigarette emission guidelines.

Based on PMI’s analysis, performed with techniques including gas chromatography/mass spectrometry, most constituents are reduced by more than 90% in the heated product’s aerosol compared with cigarette smoke (Regul. Toxicol. Pharmacol. 2016, DOI: 10.1016/j.yrtph.2016.10.001). PMI researchers have also examined the biochemical impact of the aerosol in a number of studies using cell cultures, mice, rats, and people, Boué says.

For example, researchers conducted a five-day clinical study in Poland to compare biomarkers of exposure in smokers who kept smoking cigarettes, smokers who stopped smoking for the trial, and smokers who switched to the iQOS system (Regul. Toxicol. Pharmacol. 2016, DOI: 10.1016/j.yrtph.2016.11.003). All the data point to a product that is safer than cigarettes. And all the data suffer from the same problem.

“The only research done is done mostly by Philip Morris themselves. There’s really a need for independent research,” says Reinskje Talhout, a physical organic chemist at the National Institute for Public Health & the Environment (RIVM) in the Netherlands.

Back in 2011, she and her colleagues developed a list of 98 hazardous components found in smoke based on existing literature. The researchers acknowledged there may be more.

Talhout believes the heat-not-burn product does reduce emissions, but she says the results presented by PMI should be interpreted cautiously. For instance, the chemical study of the aerosol constituents used machines to controllably generate samples from iQOS and cigarettes. But smoking machines cannot completely reproduce the behavior of real smokers.

And despite their outward similarity to cigarettes, the new tobacco sticks conceal polymer inserts. These could potentially contribute compounds to the aerosol that are not found in smoke, Talhout says. “New” compounds have been one of the larger concerns surrounding the safety of e-cigarettes, which heat liquid rather than tobacco to deliver nicotine.

All this is not to say Talhout dismisses the potential benefit of alternative tobacco products for smokers. Remember, 1 billion people worldwide smoke deadly, addictive products. “We can’t just say, ‘You shouldn’t have started smoking in the first place,’ ” she says.

She finds the heat-not-burn alternatives interesting but stresses that more data are needed on these and other reduced-risk products.

Responding to Talhout’s comments, PMI’s Boué says that smoking machines help establish well-controlled experiments that can be considered alongside experiments with human subjects, who are harder to control. PMI researchers also analyzed the aerosol as completely as possible to make sure there were no new compounds that are not in cigarette smoke, she adds.

Still, those are the words of a researcher paid by a tobacco company. Boué acknowledges that fact and understands the distrust of an industry that was nontransparent years ago. That’s part of why PMI is publishing peer-reviewed articles that are publicly available, she says. The company also created an open website where researchers can share data on iQOS and other reduced-risk products, which can be found at systox.sbvimprover.com.

But PMI’s data are meant to do more than build trust with the public. They may also help PMI secure FDA approval for iQOS as a modified risk tobacco product, or MRTP. Should FDA grant this designation, Philip Morris could market iQOS in the U.S. with warning labels that deviate from the standard language used on approved tobacco products.

Of risk and reduction

New and emerging devices aim to deliver nicotine to smokers while reducing their exposure to more harmful chemicals found in cigarette smoke. Here, C&EN presents the levels for a few of those compounds generated by two such products: Phillip Morris International’s iQOS heat-not-burn tobacco device and a British American Tobacco e-cigarette, the Vype ePen. Each company measured concentrations in the aerosol for its product, which C&EN shows as a percentage of the value reported for cigarette smoke.

Constituent iQOS Vype
Acetaldehyde 12.4% 0.1%
Acrolein 6.5 0.4
Formaldehyde 8.6 1.4
N-Nitrosonornicotine 2.2 0.2
Nicotine 61.7 18.5

Note: The compounds listed are included on the U.S. Food & Drug Administration’s list of 93 harmful and potentially harmful chemicals in tobacco products. Percentages reflect a puff-to-puff comparison: That is, C&EN shows a relative level of a compound in the aerosol from one puff of a PMI heated tobacco stick or BAT e-cigarette liquid relative to its level in the smoke from one puff of a reference cigarette. The values shown for each product use data obtained from smoking machines, which allow researchers to control experimental conditions but do not necessarily recreate human smoking behaviors.
Sources: Regul. Toxicol. Pharmacol. 2016, DOI: 10.1016/j.yrtph.2016.10.001 (iQOS); Chem. Res. Toxicol. 2016, DOI: 10.1021/acs.chemrestox.6b00188 (Vype)

For example, the tobacco company Swedish Match submitted a modified-risk application to FDA in 2014 for a smokeless tobacco product and proposed this label: “WARNING: No tobacco product is safe, but this product presents substantially lower risks to health than cigarettes.”

The product, called Swedish snus (pronounced snoose), is similar to chewing tobacco, but it comes in a pouch that users tuck under their upper lip, and there’s no spitting involved.

In December, FDA announced it would not approve the Swedish Match application as it currently stands for the product General Snus.

So far, FDA has not approved any of about two dozen modified-risk applications, including seven others from Swedish Match for various sizes and flavors of General Snus. But General Snus still became the first product to complete the MRTP process.

“We are the only experience FDA has with this. We’re sort of like the trial balloon,” says Jim Solyst, Swedish Match’s vice president for federal regulatory affairs.

One of the ways Swedish Match says it reduced the risk of its snus was by decreasing the levels of carcinogenic, tobacco-specific nitrosamines in the product. Two of these are particularly potent: N-nitrosonornicotine (NNN) and nicotine-derived nitrosamine ketone (NNK).

Humans metabolize these products into electrophiles that react with DNA to form addition products, or DNA adducts. Adducts hanging onto nucleic acids can generate errors in genetic coding. When these errors occur in certain critical genes, they can lead to cancer, explains Stephen S. Hecht of the University of Minnesota.

Hecht began identifying and studying these compounds in the 1970s—he gave NNK its name—and his team remains a leader in the chemistry and biology of tobacco’s nitrosamines.

NNN, NNK, and other tobacco-specific nitrosamines are absent from the green tobacco leaf, Hecht says. They form from tobacco’s natural alkaloids during the curing process, when leaves are dried. Conventional smokeless tobacco products, also called dip, snuff, and chew, usually contain much higher levels of tobacco-specific nitrosamines than cigarette smoke does. Conversely, the products possess minuscule levels of many of smoke’s harmful chemicals, such as polycyclic aromatic hydrocarbons, which billow out during combustion.

“These products are, in general, safer than smoking cigarettes,” but that doesn’t mean they are safe, Hecht says. They lead to oral cancer, and researchers have also linked their use to pancreatic cancer. Yet reducing the levels of harmful chemicals in these products could reduce their health risks.

Swedish Match achieved reductions in snus by careful selection of its tobacco and curing process, Solyst says. FDA largely agreed, stating that General Snus contains less NNN and NNK than more than 97% of the similar smokeless products available in the U.S.

That assessment came as part of FDA’s evaluation of Swedish Match’s premarket tobacco application, which is separate from a modified-risk application. FDA approved the premarket tobacco application in 2015, making Swedish Match’s snus the first product to earn one. Any tobacco product that was not sold in the U.S. before Feb. 15, 2007, will need this approval to appear or remain on U.S. shelves.

With this approval, Swedish Match can market its snus in the U.S. with standard warning labels found on tobacco products. Still, the company would like approval for the modified-risk labels it applied for and FDA has not yet granted.

Based on the data in the application, FDA denied the company’s request to drop warnings that its product can cause tooth loss and gum disease. However, the agency deferred decisions on Swedish Match’s request to remove a mouth cancer warning label and a request to add a label that indicates the product is a lower-risk alternative to cigarettes.

FDA noted that although General Snus had lower levels of carcinogens, they were still present. The agency stated that removing the label about mouth cancer would imply the product was incapable of causing the disease.

Solyst says epidemiological data from Sweden and Norway, where snus has been used for centuries, show snus is safe. The company also submitted clinical, toxicological, and pharmacokinetic data to support this claim. “No matter how much evidence you collect, you can’t disprove the negative,” Solyst says.

Swedish Match plans to revise its labeling requests, at which point FDA will reassess the MRTP applications.

Although some people find the regulatory environment restrictive, others applaud FDA’s rigor. “This standard is appropriate and necessary given the tobacco companies’ long history of making deceptive claims about supposedly safer products,” writes Becky Wexler. Wexler is the director of media relations for the Campaign for Tobacco-Free Kids, a nonprofit group working to curb tobacco use in the U.S.

Jean-François Etter, a professor of public health at the University of Geneva, has a different view. Regulations that make it harder for products that are demonstrably safer than cigarettes to reach smokers are a disservice to public health, he says. A rule that FDA finalized last summer allowing it to oversee e-cigarettes as tobacco products seems particularly harsh to him.

E-cigarettes don’t use tobacco directly, but they use nicotine derived from the plant. Like iQOS, e-cigarettes use a heater rather than a flame, but they vaporize a liquid laced with nicotine instead of solid tobacco.

Small e-cigarette companies lack the resources of big tobacco firms and will likely choose to bow out of the U.S. rather than invest in regulatory compliance, Etter says. That diminishes competition and alternative products for smokers.

“Everything that’s done against e-cigarettes just protects cigarettes. That’s a mistake,” he says. “It’s disappointing to see regulators protect combustion.”

Rules and attitudes vary outside the U.S. The U.K., for instance, has a more lenient stance on e-cigarettes. Cancer Research UK, a cancer charity in the United Kingdom, advocates for “light touch” regulations on the products.

British American Tobacco (BAT), based in London, became the first international tobacco company to launch an e-cigarette in the U.K. with its Vype product in 2013. Although BAT has not submitted the product to FDA, researchers and collaborators of the company are publishing the sort of data PMI presented for iQOS in the run-up to its modified-risk application (Chem. Res. Toxicol. 2016, DOI: 10.1021/acs.chemrestox.6b00188). BAT also launched a heat-not-burn tobacco product called glo in Japan in November.

Meanwhile, snus is banned in Britain and the rest of the European Union except Sweden, which just announced that its smoking rate among men is at 8%, according to . That figure is 25% for the EU.

But many smokers outside Sweden and Norway find snus an unattractive alternative to cigarettes. Furthermore, many e-cigarette users still smoke cigarettes, destroying any health benefit of using e-cigarettes—and many researchers do believe there are benefits to switching completely.

Chemistry is ill equipped to address some of the most important concerns associated with these products. Looming largest among these: How do you ensure any new product is used only by those currently smoking and not attracting new users, especially children, to become nicotine addicts? Or do people have the right to choose to become addicts? The decisions regulators and health officials make to address those concerns are literally all over the map.

“It’s not just about science,” says Talhout of RIVM. “It’s about society.”

CORRECTION: On March 29, 2017, the "Smoking by the numbers" box in this story was updated to indicate that a civil lawsuit over health care costs was settled in 1998 rather than occurring that year.

Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Åsmund Kaupang (Wed Mar 29 17:44:22 EDT 2017)
Hello there,

Another example of news regarding tobacco substitutes that fails to mention the presence of harmala alkaloids in tobacco smoke. See Poindexter et al. (1962), who interestingly find that harmane and norharmane are not present in large quantities in the tobacco itself, but rather in tobacco smoke. There is also an apparent correlation between tobacco tryptophane levels and the measured harmane and norharmane in tobacco smoke:


Now what are these alkaloids? Well, among other things they are MAOIs (in the paper below they were extracted from coffee):


So what does all this have to do with a tobacco addiction? General knowledge about the increased efficacy of neurotransmitters in the presence of MAOIs, may explain why studies in rats find an increased tendency towards self-administration of nicotine when the rats have been treated with MAOIs:


On the other hand, whether nicotine alone is addictive is somewhat debated. See e.g. the article below:


In several of the above papers a genetic disposition towards reward-seeking behaviour is discussed, and this is likely an important aspect in humans as well.

Lastly, this line of argument is not presented to contest the health problems caused by tobacco smoking - it is simply a loud sigh from a young chemical biologist who is tired of reading about nicotine as the culprit of an addiction to smoking tobacco - especially from an apparently well-informed source, such as C&EN.

Be well,

Å. Kaupang (Ph.D.)
S.Sutcliffe (Wed Mar 29 18:46:05 EDT 2017)
Personally Id rather someone used something like dip than smoke so I dont have to breathe in all that foul second hand smoke. But the sight of them spitting the brown slimy goop on the floor or into a soda bottle is enough to make me want to vomit. So the snus sound like the best option as far as Im concerned. I think many smokers arent going to quit, so switch to this.... If the v-cigarette has less nicotine then smokers may end up just smoking more to get enough in their system.
A (Wed Mar 29 19:03:40 EDT 2017)
What a mess.

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