Author: GTNF Trust Staff

Assessing the safety and evaluating the risk of novel tobacco and nicotine products

By Marina Murphy

E-cigarettes are expected to be big news this year. India will host the seventh Conference of the Parties (COP) of the Framework Convention on Tobacco Control, which is the World Health Organization’s (WHO) international treaty on tobacco control.

The COP is the governing body of this treaty. The WHO does not support e-cigarettes. This is despite the fact that many in the public health community¹ do, and despite the prediction that around 1 billion people will die from smoking-related disease in the 21st century compared with “just” 100 million in the past century.² This is because, although the percentage of smokers has decreased, the number of smokers has increased due to population growth.³ By contrast, Public Health England (PHE), an agency of the U.K. Department of Health, and others believe that the popularity of e-cigarettes, as well as the fact that they are safer—95 percent safer compared with cigarettes according to PHE—could be the answer to this public health crisis.

E-cigarettes therefore hold great potential for reducing smoking-related disease. But this needs to be scientifically proven. To this end, British American Tobacco (BAT) and others are developing tests to help them understand their products and their biological impact. Such tests will also help better define and further reduce any residual risks to as low a level as possible; help establish appropriate quality control and standards; and further reassure consumers, regulators and public health as to the reduced risk potential of these and other products.

ASSESSING NEXT-GENERATION PRODUCTS

Recent years have seen the emergence of some very high-tech gadgetry and technology in the area of nicotine products. Fresh eyes and new tests are required to ensure that products based on these technologies are as safe as can be. BAT has proposed a new scientific framework⁴ to do just that.

This framework has four basic stages. The first step is understanding how consumers use the products and then using this information to understand the products. Laboratory and clinical testing is then used to determine whether these products emit and deliver fewer toxicants than conventional cigarettes. Testing then moves into the real world to determine what impact, if any, a reduction in toxicants will have on a person’s individual risk, as well as the collective risk of a population using the products.

UNDERSTANDING CONSUMER BEHAVIOR

Understanding how consumers use their products is an essential first step. This helps to ensure that machine testing of e-cigarettes mimics real-life use and therefore gives realistic results. BAT has developed a test, based on a technology called a Smoking Analyzer (SA7), to help it do that. The SA7 was developed initially to measure smokers’ puffing behavior. This is a portable device capable of measuring pressure and flow, and it provides information such as the size and length of a puff and the time between puffs.

The company has observed many different types of vaping behaviors, and by using an average it can program lab-based “vaping robots” to make measurements in the laboratory more accurate and true to life.

CHARACTERIZING VAPOR PRODUCTS

Vaping robots produce vapor in the lab in a similar manner to a consumer, and a series of chemical tests are used to identify and measure the constituents in e-cigarette emissions. For example, a “GC-GC-MS” technology combines gas chromatography, which is used to separate out the component parts of the aerosol, and mass spectroscopy, which then identifies each component part.

The separation technique uses a very long, very narrow column through which the aerosol passes. Different molecules travel through the column at different rates and exit the column at different stages, at which time a mass spectrometer is used to identify each of them. This involves breaking the molecules into smaller fragments and then identifying each fragment according to its mass-to-charge ratio. The results of this and other tests demonstrate that the e-cigarette aerosol is much less complex than cigarette smoke (see Figure 1). BAT has observed reductions of 90 percent and more in the levels of certain toxicants present in e-cigarette vapor compared with cigarettes.

E-CIG VAPOR COMPARISON TO CIGARETTE SMOKE

The biological impact of e-cigarette vapor compared with cigarette smoke can be tested in the lab using cell-based tests. One test uses a 3-D model of human lung tissue to examine the impact of e-cigarette vapor versus smoke on cell health. Also, there is a “scratch test” that examines a tissue’s ability to repair itself (when scratched) after exposure to e-cigarette vapor or cigarette smoke (see Figure 2).

The first test uses a dye to observe the impact of aerosol exposure on the cells. Healthy cells have an enzyme that breaks down the dye so that it changes from purple to yellow. Healthy cells will therefore appear more yellow in color than unhealthy or dead cells. This test reveals that exposure to cigarette smoke for six hours causes near complete death of human airway cells in this test. But even after hours of continuous exposure, the impact of the e-cigarette vapor on the airway tissue was found to be similar to that of air.⁶

In the “scratch test,” a layer of cells is scratched and the cells’ ability to close the scratch/wound is observed. The scratch mimics natural wear and tear in the cardiovascular system. This test can be used to compare the effect of e-cigarette vapor on wound healing compared with cigarette smoke. When the cells were exposed to smoke, they seemed to lose their sense of direction and position relevant to other cells; they appeared “confused” and could not find their way across the gap—the wound did not close. By contrast, when the cells were exposed to e-cigarette vapor, the cells quickly closed the gap in much the same way as they do when just exposed to air.

These early-stage results demonstrate that in comparison to cigarettes, these new products have great potential to demonstrate a reduction in disease-relevant risk.

REAL-WORLD TESTING

Lab tests can be used to study the products to determine whether the aerosol from e-cigarettes contains fewer toxicants than cigarette smoke and to examine the biological impact of e-cigarette vapor on human tissue models, compared with the impact of exposure to cigarette smoke.

Clinical testing with consumers is required to determine exposure to toxicants, using biomarkers of exposure, which could be the toxicant itself or its metabolic breakdown product, which is found in blood, saliva and urine. Or it could be a physiological measurement like cholesterol levels. The higher the levels observed, the higher the exposure. This can give an indication of individual risk, but e-cigarette usage and uptake by consumers must be measured in order to assess their impact for reducing risk at a population level.

This assessment framework will help build the required evidence base needed to demonstrate that novel tobacco and nicotine products can deliver a net population health gain in comparison with cigarette smoking. There is now a great opportunity for the industry, regulators and academia to come together and agree on standards and testing protocols for e-cigarettes and other novel products.

Marina Murphy head of scientific media relations, research & development at British American Tobacco.

References

¹ E-cigarettes: an evidence update. A report commissioned by Public Health England, 2015; [www.gov.uk/government/uploads/system/uploads/attachment_data/file/457102/Ecigarettes_an_evidence_update_A_report_commissioned_by_Public_Health_England_FINAL.pdf, accessed 22nd October 2015]

² WHO Report on the Global Tobacco Epidemic 2008. MPOWER report; [www.who.int/tobacco/mpower/mpower_report_full_2008.pdf]

³ Marie Ng, et al. (2014). Smoking Prevalence and Cigarette Consumption in 187 Countries, 1980-2012. JAMA. Vol. 311(2) p183-192; doi:10.1001/jama.2013.284692.

⁴ F. Lowe, I.M. Fearon, O.M. Camarcho, E. Minet and J. Murphy (2015). A framework for the biological assessment of reduced risk tobacco and nicotine products. Recent Advances in Tobacco Science: Vol. 41, p 51-8.

⁵ C. Proctor, et al. (2014). Integrating chemical, toxicological and clinical research to assess the potential of reducing health risks associated with cigarette smoking through toxicant regulation, Recent Advances in Tobacco Science: Vol. 40, p 1-34.

⁶ L. Neilson, et al. (2015). Development of an in-vitro cytotoxicity model for aerosol exposure using 3D reconstructed human airway tissue: application for assessment of e-cigarette aerosol. Toxicol in Vitro, Vol. 29, p 856-86.

While perhaps less ‘scientific’ than the American way, there’s something to say for the British approach to vapor product regulation.

By George Gay

Although it is generally frowned upon to make generalizations about countries and their people, it is common to do so. Generally, each country will have two sets of generalizations appended to it: one, generally positive, scripted by the people of that country; and another, generally negative, written by those of other countries, often neighboring countries.

Great Britain is a good example and, since I live there, I shouldn’t get into too much trouble for using it as such. In 2006, Gordon Brown, the then chancellor of the Exchequer but soon-to-become prime minister, in part described British ideals as a commitment to fairness for all. But elsewhere, many people refer to us collectively as perfidious—“perfidious Albion” being the famous phrase. The contrast couldn’t be more jarring.

To me, a more accurate generalization of Britishness is one that describes us as people who muddle through, and a good example of such muddling was due to unfold in February—possibly as you read this piece—as our latest EU hokey cokey (“You put your left leg in, you take your left leg out …”*) was due to come to a head. And as well as being a more accurate generalization, muddling through is more useful because it can be seen as both positive and negative; it can be used by both British people and others.

I raise this point because it strikes me that the British ability (positive) or tendency (possibly negative) to muddle through is what has in no small part caused the significant—and otherwise rather hard to explain—differences in the approach to e-cigarettes that have been seen in Britain and the U.S. of late.

In my view, the British approach has been better in that it is providing for a quicker, more positive response to these products than is the case in the U.S. And in my view, the reason why this is so is that muddling through provides an opportunity for the development of a strategy that sits between the scientific and the spiritual—between proof and faith. It relies on neither one, but each one can be conjured up when needed. The U.S., on the other hand, has been wedded to the idea of science, or a particular form of science, even though most of the science is unclear and will be for some time.

The British approach was nowhere more apparent than during a question time exchange in the U.K. Parliament on Dec. 16. According to a Hansard report, the Conservative MP Mark Pawsey said that by the time the House of Commons next met for question time, many people would have started on their New Year’s resolutions, and, for many, one of those resolutions would be to give up smoking. “Given that Public Health England recently stated that e-cigarettes are 95 percent safer than tobacco and half the population is unaware of that fact, will the prime minister join me in highlighting the role that e-cigarettes can play in helping people give up tobacco for good?” he asked.

In replying, Prime Minister David Cameron initially made the point that he was speaking as someone “who has been through this battle a number of times, eventually relatively successfully.” He said that lots of people found different ways of giving up smoking and that clearly for some people e-cigarettes were successful. “We need to be guided by the experts, and we should look at the report from Public Health England, but it is promising that over 1 million people are estimated to have used e-cigarettes to help them quit or have replaced smoking with e-cigarettes completely. We should be making it clear that this [is] a very legitimate path for many people to improve their health and therefore the health of the nation.”

It seems to me that the timing of Pawsey’s question was spot on. As he said, it was in the runup to the time when people would be making New Year resolutions, and, though he didn’t spell it out, there was still time for smokers’ friends and families to go looking for e-cigarettes to give as Christmas gifts. And I think that Cameron pitched his reply perfectly in respect of a technology that suggests it is a near-safe alternative to smoking but that still needs to stand the test of time.

What I liked also about this exchange was that the prime minister was not afraid to lay out his credentials as the head of a nation of people dedicated to muddling through—dedicated to doing things “eventually relatively successfully.” We do our international relations that way, we play sport that way, and we learn foreign languages that way.

THE SCIENTIFIC ROUTE

As I understand it, the president of the U.S., Barack Obama, has also had a battle with smoking, but I’m not sure whether he has been completely successful or is holding out to be relatively successful eventually. But what is clear is that the U.S. Food and Drug Administration (FDA) has not been muddling through in respect of e-cigarettes. It, we are told, has been taking the scientific route, which ordinarily would probably be all well and good, but which in the case of the new and emerging technology of e-cigarettes seems to be leading to a dead end. On Dec. 18 I read a piece by Robert King in The Washington Examiner in which he says that a major lobbying effort to save e-cigarettes from falling victim to U.S. federal regulation has failed. King said that a $1.1 trillion spending bill released on Dec. 16 did not include a rider to change the “grandfather” date in upcoming federal regulations governing e-cigarettes.

The grandfather date, Feb. 15, 2007, which was originally established by the U.S. Tobacco Control Act of 2009, signaled that any tobacco cigarette or smokeless tobacco product (those products that were initially put under the authority of the FDA) on the market up to that date would not have to be the subject of burdensome applications for approval by the FDA, whereas those firstly marketed after that date would be subjected to such applications. Now, as part of its so-called deeming regulations, the FDA has proposed that e-cigarettes should be subject to the same grandfather date.

Given that the “deeming regulations” deem that e-cigarettes are tobacco products, this approach seems to deliver a consistency, at least until you think about it for a few seconds. The first problem here is that e-cigarettes are not tobacco products, unless you are prepared for an argument about whether all of those breakfast cereals fortified with niacin are also tobacco products.

But, even if you accept that e-cigarettes are tobacco products, there is a gulf between how tobacco cigarettes have been treated and how it is proposed that e-cigarettes should be treated. The difference: Whereas the tobacco cigarette market was well-established with products by 2007, the e-cigarette market was only just taking off. So the decision means that a majority of the e-cigarettes on U.S. shelves will need to undergo burdensome applications that their suppliers, which are generally small- to medium-sized companies, are unlikely to be able to afford.

Some observers believe that the FDA requirements will kill off that part of the industry not supplied by the major tobacco manufacturers. And these people are not only those with a financial vested interest. Writing at the beginning of December, at a time when some still hoped that the grandfather date might be changed in respect of e-cigarettes, two respected U.S. health experts asked why it should be that the most toxic consumer products on the market—combustible cigarettes—have to do absolutely nothing to stay on the market, while a burdensome and prohibitively expensive applications system is being proposed for much safer, tobacco-free e-cigarettes.

In a blog published in The Hill, Michael Siegel, a professor in the Department of Community Health Sciences at the Boston University School of Public Health, and Scott Ballin, a health policy consultant and former vice president and legislative counsel for the American Heart Association, went to some pains to point up how irrational such proposals were. “This means that every cigarette brand on the market is allowed to continue being sold, without any changes in nicotine content, without eliminating menthol—which is known to appeal to youth—and without lowering the levels of any of the more than 60 known carcinogens in these products,” they wrote.

“Therefore, it may come as a surprise to many to find out that despite the lack of any safety regulations for deadly cigarettes, the FDA has sent for executive branch approval a set of regulations for e-cigarettes—devices that contain no tobacco, involve no combustion and have been shown to be orders of magnitude safer than cigarettes—that require every e-cigarette product to submit burdensome, expensive and technically near-impossible applications just to stay on the market.

“The FDA has apparently decided that e-cigarettes pose a much greater threat to the health of the public than the extremely toxic tobacco cigarettes that are killing more than 400,000 Americans each year.”

ON NODDING TERMS

So why is it that, in my view at least, science has failed where muddling through has succeeded? This is an interesting question that led me to ask another: Could all issues be better solved by applying the principles of muddling through rather than science? It seems unlikely. Sending a man to the moon, building a nuclear power station and designing a new vaccine are probably all examples where you really need science, along with other, possibly linked, disciplines.

So could it be that the science wasn’t given enough time? Hardly. Concern had been expressed about what the FDA was up to from at least early in 2013, and the FDA announced its new e-cigarette rules—described by some as “long-awaited”—in April 2014.

No, I think the answer is more straightforward than that. I think the problem is that, despite the hype, what the FDA gets up to in respect of tobacco and nicotine often is only on nodding terms with science. At the end of their piece, Siegel and Ballin said they believed that the federal government needed “a more rational approach” to the regulation of tobacco and nicotine products that regulated all products based on their risks and relative risks. Protecting the cigarette industry while stifling innovation of new and much safer products did not achieve that goal and would damage public health efforts, they added. Of course, rationality and science are not one and the same thing, but they are closely related, and it seems to me that the only way that the scientists at the FDA could have followed the science and, as seems to be the case, come up with an irrational proposal would be if the task they had been set was irrational. That is a possibility.

But it is also a possibility that minds get made up early on and it is difficult to change direction. Early in 2013, Elaine Keller, president of the Consumer Advocates for Smoke-free Alternatives Association, a nonprofit, volunteer organization formed in 2009 by e-cigarette consumers to promote tobacco harm reduction policies, made the point that the FDA had firstly tried to remove all e-cigarettes from the market by calling them “drug delivery devices.” “Having failed in their attempt to ban e-cigarettes, the FDA has announced its intent to propose a ‘deeming’ regulation to apply Chapter IX of the Family Smoking Prevention and Tobacco Control Act to e-cigarettes,” she said. “However, portions of Chapter IX would essentially ban all e-cigarettes from being sold, and other provisions would decimate the e-cigarette industry, protect cigarette markets and otherwise threaten public health.”

Muddling through is quicker, cheaper and, at least in some cases, more likely to come up with a sensible, satisfactory result. And, to my mind at least, it has the advantage that tens of thousands of laboratory animals don’t have to be sacrificed on the altar of an esoteric science.

*If you’re unfamiliar with this dance form, you should watch this video of Bill Bailey and Kraftwerk.

With the passage of the Child Nicotine Poisoning Prevention Act by both houses of Congress, the U.S. Consumer Product Safety Commission (CPSC) will likely soon get new authority to require child-resistant packaging over certain packages of nicotine-containing e-liquid, according to the law firm Keller and Heckman.

If the President signs the bill, covered products will be subject to the same requirements that CPSC already enforces on packaging of prescription drugs, some over-the-counter drugs, and other potentially hazardous products found in the home.

Bottles of refillable nicotine-containing e-liquid sold directly to consumers for use in “open-system” electronic vaping devices are covered, but packaging for zero-nicotine e-liquid—a growing segment of the e-liquid market—is not covered by the definition, according to Keller and Heckman.

Keller and Heckman’s full article is available here.

Evolv has named Lou Ritter of the American E-Liquid Manufacturing Standards Association as the chair for the new Vape and Vapor products U.S. Technical Advisory Group (TAG).

A designer and manufacturer of electronics used in e-cigarette devices, Evolv was the only applicant for the TAG administrator role, according to the company.