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E-Cigarette Summit - Dr. Konstantinos Farsalinos

Dr Farsalinos: Thank you very much, ladies and gentleman, thank you very much for the invitation. My disclosures I don’t have a slide. I have been the main researcher in some studies in which the institution has received funds from EC delegate companies, but no compensation was provided to the researchers. I have never been funded by the tobacco industry or the pharmaceutical industry.

Slide02

We know that e-cigarettes are new in the market. They have been developed because of the inefficiency of currently approved medications in supporting cessation with very low success rates, as we know. They are currently used by millions of people around the way usually of a young age around 40 years old. They provide nicotine but, at the same time, they are dealing with the behavioural addiction. They have no tobacco, no combustion, as also Lynne said, and they should be regulated in my opinion but based on scientific evidence.

Slide03

 

Slide05

The studies concerning the safety of use can be divided into laboratory and clinical. We are starting with laboratory with chemical studies which are the most commonly performed and most easily to be performed. For example, in Greece, in two university laboratories there have been more than 300 analyses for the presence of TSNAs, Tobacco Specific Nitrosamines. They provide, however, indirect evidence on safety because the findings depend on what you are searching for. You can’t search for everything that is present there. We have the issue of flavourings which are generally regarded as safe but for food use, and we don’t know of their implications when inhaled and we have an example of diacetyl which is perfectly safe when ingested but when inhaled it can, in rare cases, lead to the development of bronchiolitis obliterans.

Slide06

Chemical studies, one of the first reviews by Cahn and Siegel published in 2011 saw that concerning tobacco specific nitrosamines electronic cigarettes were similar to currently approved nicotine replacement therapies, both the Nicorette gum and patch. You can see that tobacco products have much higher levels of nitrosamines.

Slide07

Another study by a Korean group in South Korea which evaluated 105 samples of e-liquids. They found on average the total number was around 13 nanograms per millilitre or micrograms per litre which is in fact 76 to 142 times lower in daily exposure compared to just one tobacco cigarette, according to the literature.

Slide08

The study by Goniewicz, which I think was also shown by Jacques before, he tested twelve different e-cigarette samples in 150 puffs. He found several toxic chemicals like formaldehyde, acrolein, some tobacco specific nitrosamines were found although not in all samples, and some heavy metals.

Slide09

The problem with such studies is, as you can see, and as Lynne said, there is a huge variety of variability and variety of devices available in the market, and, as you can see, different batteries, different atomisers, different cartomisers, which means that they have different abilities, the amount of liquid inside is different.

Slide10

However, in this study, every device was handled by the same way. In every case, two second puffs every ten seconds which is, in fact, quite unrealistic. And this is important because you can very easily overheat the device and leads to the production of toxic chemicals. Despite all these limitations, you can see, as Jacques also showed, that there is a huge difference between cigarette smoke and e-cigarette vapour in their release of toxic chemicals.

Slide11

Another study by the group of the University of California found some heavy metals in electronic cigarettes. We are expecting to see heavy metals because it’s a metallic structure, in fact. The levels were not so high. In some cases, they were higher than the cigarette; the tobacco cigarette is not a metal structure so you expect that. The levels were not that dangerous but it shows that we need more studies on e–cigarette materials which is, in fact, an area in which almost no research has been performed.

Slide12

Concerning passive vaping from chemical studies, there was a study by a German group published this year, they found that for most of the emissions they tested they did not find anything. The levels emitted from the e-cigarette were below the levels of detection.

Slide13

They found a very small amount of formaldehyde which they said – that was interesting. They found the formaldehyde was increasing even before the e-cigarette was used. So this is where the time when the participants, the volunteers, entered the room, it was an eight cubic metre room, so formaldehyde levels started to elevate even at that point. And even when the e-cigarette was used, there was no further elevation, so the authors concluded that the formaldehyde that was measured was probably from the exhaled breath that was coming from the metabolism of the volunteer, not from the e-cigarette use. And this is the peak after smoking one conventional cigarette.

Slide14

We have done a study in Italy in a realistic setting. It was in a hotel room. We asked five vapers to vape freely for five hours. On another day, we asked five smokers to smoke ad lib for five hours. We measured several components, total organic carbon, huge differences between e-cigarette use and tobacco cigarette use.

Slide15

For most samples we didn’t find anything, zero means below the level of detection. Meant that while for traditional cigarette several toxic chemicals were emitted.

Slide18

Concerning toxicology studies which, in my opinion, are much more important because they give you the end result of use, the first study that was published was by the University of California in a great sample of e-liquids. However, the main problem of the study was that they tested the liquids in their original liquid form. You know that with e-cigarettes we don’t drink the liquid, we don’t use it in liquid form, and the evaporation process is quite a complex process, it’s not that simple.

Slide19

Our study that was published this year in 21 samples and also compared with the same methodology and protocol of cigarette smoke, you can see that even in this protocol which is a protocol that is used to get approval for medicinal devices or products, it is a relevant protocol.

Slide20

If the viability rate is lower than 70% this is considered according to the ISO protocol as toxic. So, for cigarette smoke, we could see cytotoxicity even when the original extract was diluted to four times, and only at 1 to 8 dilution it was not considered toxic. For the electronic cigarette samples, we could find only coffee that was slightly cytotoxic toxic only in the undiluted extract, and all the other samples were in fact above the level considered cytotoxic. The relative difference was up to eight times in survival between the difference between tobacco smoke and cigarette smoke.

Slide21

And, in our latest study, for the first time we used what Lynne said called mods, the mod device, modified devices, variable voltage device, we used – we compared the second generation device with a variable voltage device at higher levels of energy delivered to the atomiser at approximately nine watts using the same protocol, the same standardised protocol.

Slide22

And, of course, once again we found that cigarette smoke was quite cytotoxic in cardiomyoblasts. We found three e-cigarette liquids that were cytotoxic even when the extracts were diluted to 50%, and I have to say that these liquids are made by using tobacco leaves in a stepping process leaving them into a mixture of propylene glycol and glycerol for several days, so these are – only four of the samples were produced using this process. Three of them were cytotoxic. And we found marginally cytotoxic the cinnamon flavour from another e-liquid.

Slide23

These are some examples of the cells under the microscope. The cells untreated which means that they were cultivated with clear cell medium, the cells treated with e-cigarette vapour, one of the previous samples, and you can see the difference of the cells treated with cigarette smoke extract.

Slide24

Lately, one week ago, a study was published, online first, it is currently available but it is uncorrected proof, about cinnamon toxicity in liquids. Once again, it’s the same group from the University of California that did the previous study I showed. Once again, they tested the liquids in liquid sample. This is more relevant to food use rather than to electronic cigarette use and there are many reasons for that, but unfortunately I don’t have the time to explain to you. Another problem is that – yes, I have a lot of slides! Another interesting point is that they found that the main component of cinnamon flavour was cinnamaldehyde which is a well-known substance and is approved for use in food, and they found in the cells they tested that it was toxic at a level of 10 to minus 4 moles per kilogram or per litre, which is strange because the currently approved and tested cinnamaldehyde dose is up to 4 times 10 to minus 2 moles per litre, which means that the currently approved dose of cinnamaldehyde for use in food is 400 times higher than the amount found toxic in their study. Interesting results. I think they deserve a letter to the editor.

Slide27

Now, clinical studies. The main issue, the main problem, the most important thing which unfortunately we cannot do. We cannot perform any long term studies yet. First of all, we cannot randomise a group of non-smokers into smoking or electronic cigarette use, so this is in fact – this cannot be done. But, in general, we cannot have long term data from use because it’s a relatively new product because the electronic cigarette users are young, so they have a low prevalence of disease at this age, so we need a huge number of participants, follow them up for several years in order to have any valid clinical data concerning health related issues from long term use.

Slide28

So we must rely on studies concerning the pathophysiology of smoking disease, the immediate effects of use, and some short-term follow-up surveys or population studies. As Jacques said previously, nicotine levels will unlikely cause harm unless someone wants to commit suicide and will drink it. He cannot get any kind of overdose of using the liquid in electronic cigarette.

Slide29

The levels of nicotine absorption are lower compared to smoking. I think we should make the products more efficient, I mean deliver more nicotine and faster, the nicotine to the user. As Jacques previously showed, there is a trend for electronic cigarette users to gradually reduce their nicotine intake, but still they initiate use with other high levels.

Slide30

Clinical studies, acute effects of lung function, a study from a Greek research group, found that some parameters of airway resistance were elevated after use of electronic cigarette, and nitric oxide was also elevated after electronic cigarette use. They did not do any similar study with cigarette smoke to show us what’s going on and make the comparison. We know, and a lot of lung physicians will tell you, that short-term mechanical irritation may be the cause for some short-term elevation in pulmonary resistance, and we are not sure if this means that there may be any health-related issues in the long-term. We know from data from surveys that at the initiation of the e-cigarette use, users report some cough as an initial symptom, but in general they feel much better afterwards.

Slide31

Here is another study by another Greek research group in which there was a comparison between tobacco and e-cigarette use, both active use and passive use, and they found that only after tobacco use there was an elevation in airway resistance, while no statistically significant difference was observed after electronic cigarette use in a group of smokers.

Slide32

Slide33

Slide34

Our study, presented last year in the European Society of Cardiology Annual Meeting in Munich, Germany, 42 participants, half were smokers, half were electronic cigarette users, we use the medium level of nicotine concentration, 11mg per millilitre, that’s why we found some lower elevation in blood pressure with electronic cigarette use compared to smokers, and also lower difference in heart rate compared to baseline.

Slide35

Anyway, I will proceed first. We found that four parameters of the systolic function were adversely affected by electronic cigarette use, sorry, by tobacco cigarette use, but were not affected by electronic cigarette use.

Slide36

Our latest study which was presented two months ago in this year’s Annual Congress of the European Society of Cardiology, we measured, this is the left anterior descending coronary artery as you can see it from ultrasound, and we measured the coronary flow velocity reserve, it is the maximal ability of the coronary artery to deliver blood to the myocardial, and the resistance index which is the resistance to the blood flow.

Slide37

Here is what happened to smokers after they smoked tobacco cigarette. Their flow velocity reserve decreased by 16% and their resistance to flow was increased by 19%.

Slide38

The same group of smokers after using the electronic cigarette on another day there was no difference both in the flow velocity reserve and resistance index. While the e-cigarette users who tested only the e-cigarettes, it was unethical to give them a tobacco cigarette, all of them were former smokers, they had quit smoking with the user of the e-cigarette, there was no difference between baseline, baseline was eight hours at least without smoking or without electronic cigarette use, and post e-cigarette use. We also measured blood carboxyhemoglobin level for in venous blood and we saw that even at baseline smokers although they were eight hours without smoking they had quite high levels of carbon monoxide in blood. We know that they need at least 48 hours for carbon monoxide to go to low levels.

Slide39

On the contrary e-cigarette users had almost normal levels, almost what you find in non-smokers, and there was no difference after use of the electronic cigarette.

Slide40

In smokers there was an elevation after using the tobacco cigarette but no elevation after using the electronic cigarette.

Slide41

We have more to come from our group, we are going to present a study in EuroEcho next month about the effects of the e-cigarette compared to tobacco cigarette on aortic elasticity. For next year we have the results of the pulse wave velocity which is a measurement of the stiffness of the big arteries, and we feel that we should always compare with tobacco cigarettes because e-cigarette is a product for smokers and only for smokers, as a method to either reduce or completely substitute smoking or quit smoking as Professor West said. We’re not going to play with words. They should be used for people to quit smoking. So what we need to know.

Slide42

Slide43

Of course, as we said, long-term studies are very difficult to perform right now but we can make some shorter-term studies or as I said, measure the pathophysiological mechanisms of disease, for example measure inflammatory markers, but we know that even in these cases smoking cessation does not lead to any improvement in these parameters in the short-term. For example C-reactive protein, which is a measure of inflammatory stress of the organism, takes more than five or six years to be reduced in smokers after they quit smoking.

Slide44

So in conclusion, that was quite fast, although there are several chemical studies, few of them are performed in vapour which is the most important but of course chemical studies of liquid are the easiest to perform. There is a need for more toxicology studies because I think they give more information compared to chemical studies. We have to perform studies on materials of the device and mostly I’m talking about the atomiser, we know about batteries, they are just lithium batteries, but for atomiser materials the atomiser is the place where the liquid is stored and where the operation process takes place. A very important factor, especially in laboratory studies, is that the design of the protocol and the handling of the device, the puff duration, the inter puff interval, whether you have overheating or not, are extremely crucial factors in getting results that are applicable to real use, because you must know that electronic cigarette users can understand from the taste when the device is overheated. In the laboratory setting you cannot understand that, there is no way to measure that.

Slide45

Clinical studies as I said are scarce and we need some more but long-term studies are impossible. However I can say that based on currently available data it is quite reasonable although not proven to expect that there will be a significant benefit for the health of smokers who switch from tobacco to e-cigarette use even in long-term e-cigarette use, and research will help us define the best possible materials in e-liquids and devices, but we should be careful not to kill the variability and the innovation of this product. Thank you very much. (Applause)

Chair: Wow, thank you very much, Konstantinos. That was a massive amount of material you covered there, and it’s possible that in the questions we might want you to just go over one or two of those slides in a bit more detail. We could take any direct questions now for Konstantinos, we’ve got five minutes before we open up the floor to all the speakers, so one over here.

Claus: Hi, I’m Claus Hecking from Capital Business Magazine in Germany. You were so quick, just a very practical question, could you just provide us your slides, please, also?

Konstantinos: Yeah, sure.

Klaus: Okay, thanks.

Liam: Konstantinos. Liam Humberstone from Totally Wicked Eliquid. Hi. Has any work been done on the irritant effects of propylene glycol used as a diluent within the eliquids?

Konstantinos: Yes. This is a main issue that has been discussed over the news media or between the researchers, but we have data back to 1947. There were some studies by Professor Robertson from the United States because at that time they wanted to test whether propylene glycol vapour can be used as a disinfectant of the air of the hospitals. So in fact they performed a long-term study in experimental animals, in monkeys, for 16 months, they exposed the animals to an atmosphere fully saturated with propylene glycol in vapour form for 24 hours per day, and they found absolutely no change in any organ or body system after sacrificing the animals and doing histological analysis of all the organs. This is the greatest evidence we know concerning propylene glycol, they are dated back to 1947, and it showed that at least in the animals in primates there was no problem after 16 months of use. In humans we have evidence from the theatrical fog which is propylene glycol which in fact is even worse than electronic cigarette because it’s heated at much higher boiling temperature and it’s not pharma grade propylene glycol, and there is some irritation but no long-term damage in people like actors who are exposed long-term in theatrical fog.

Liam: Yeah, it does appear to me that people using electronic cigarettes will occasionally get a reaction when they first start using them, but then that settles down in time.

Konstantinos: Yes. Dry mouth and some throat irritation is the most common side effect that is reported by the electronic cigarette users, and this is mainly due to propylene glycol. Liam: Thank you.

Riccardo: Riccardo Polosa from Italy again. Konstantinos, very nice talk, very quick as usual. I just want to open a little debate about the cell toxicity studies. I don’t really understand what they mean because in my long experience in the lab I understand the scientists they just pick the cell lines that provide the best answers. In simple terms, if you use immortalised cell lines these are commonly more resistant to any injuries whereas the primary human cell lines are more likely to respond. The simple question would be, in relation to the toxicity study with cinnamon which has been recently published do you know what cell lines they’ve used?

Konstantinos: Yes. They used the human embryonic stem cells, I don’t know the relevance of that concerning electronic cigarette use, and they used human pulmonary fibroblast which is quite relevant. In fact they found that human pulmonary fibroblast were less sensitive to the effects of cinnamon compared to the embryonic stem cells, but in any case, none of these cells come in contact with the liquid in liquid form. The main issue of this study was that they used the liquid in liquid form. I’ll tell you an example why this is quite different from using vapour. What is commonly used as a mixture in e-liquid is 90% glycerol, 10% distilled water solution. This has an evaporation temperature of 138 degrees Celsius. Cinnamaldehyde, which is the main component of the cinnamon flavour, has an evaporation temperature of 250 degrees. So when you have a mixture that supplies the wick and you apply then the energy to the resistance, the most volatile substances will be the propylene glycol and less cinnamaldehyde because it has a higher temperature. So the contents of the vapour will be quite different from the liquid. We expect much more glycerol, propylene glycol and water to be in the vapour and much less flavouring. That is why if you ask every vaper he will tell you that there is a significant discolouration of the wick material when he is using flavours, because most of them are oily substances or substances which have a high evaporation temperature, and they are not evaporated from e-cigarette use at the same level at which they are present in the liquid. Another problem for which I don't know if authors were either misinformed or are uninformed. I found out they reported in their study that between samples they tested eight cinnamon flavoured liquid samples. They said that between samples the levels of cinnamaldehyde differed by up to 100 times the amount of cinnamaldehyde in liquid. So I did the research on the internet and the websites and I found that four of the eight samples were not refill liquids, they were concentrated flavours. And I even contacted the companies themselves and they informed that they have never produced any refill liquids with this name, and these are concentrated flavours. You have to understand that there are in the market a lot of companies who are provided concentrated flavours that must be diluted to 3 - 5% in a mixture of glycerol or propylene glycol and nicotine before being used. But the authors, surprisingly they refer to all their samples as refill liquids which is not the case. So even in that case you expect it’s even less relevant to e-cigarette use because you don't use this liquid as it is, you have to dilute it and then produce vapour from that.

Chair: Thank you very much, Konstantinos, for that very fully explanation of that and clarifying it for us.

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