UNITED STATES OF AMERICA DEPARTMENT OF HEALTH AND … · 319 Professional Video Associates, Inc. 2515 Saint George Way Brookeville, MD 20833

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Professional Video Associates, Inc. 2515 Saint George Way Brookeville, MD 20833

301-924-1556

UNITED STATES OF AMERICA

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

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CENTER FOR TOBACCO PRODUCTS

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ELECTRONIC CIGARETTES AND THE PUBLIC HEALTH: A PUBLIC WORKSHOP

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June 2, 2015 8:00 a.m.

The Marriott Inn and Conference Center

Chesapeake Ballroom Salons A&B University of Maryland University College (UMUC)

3501 University Blvd. East Hyattsville, MD 20783

FDA:

CAROLYN DRESLER, M.D., M.P.A. Associate Director for Medical and Health Sciences Workshop Moderator Center for Tobacco Products JEANNIE LIMPERT, M.D. Medical Officer Office of Science Center for Tobacco Products

This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.

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PUBLIC COMMENT SPEAKERS KEVIN ALTMAN CITMA BILL GODSHALL Smokefree Pennsylvania ALI A. ROSTAMI, Ph.D., ASME Fellow ALCS Research Development & Engineering Altria Client Services SCOTT BALLIN Health Policy Consultant ANDREW COLLINS Imperial Tobacco SVEN-ERIC JORDT Duke University School of Medicine CHRISTOPHER WEBBER Free to Vape GREGORY CONLEY American Vaping Association ERICA HALLER-STEVENSON National Association of County and City Health Officials MARK GREENWOLD Campaign for Tobacco-Free Kids JAMES XU Avail Vapor

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EXHALED E-CIGARETTE AEROSOLS: EVALUATION OF CONSTITUENTS AND EXPOSURE ANDREW PERSILY, M.A., Ph.D. National Institute of Standards and Technology JONATHAN THORNBURG, Ph.D. Research Triangle Institute MOHAMADI SARKAR, M.Pharm., Ph.D. Altria Client Services JOHN D. PRITCHARD Imperial Tobacco Limited, UK FRANCIS (BUD) J. OFFERMANN, PE, CIH Indoor Environmental Engineering MACIEJ GONIEWICZ, Ph.D., Pharm.D. Roswell Park Cancer Institute HEALTH EFFECTS OF SECONDARY AND TERTIARY E-CIGARETTE EXPOSURES NEAL L. BENOWITZ, M.D. University of California, San Francisco DONALD GRAFF, Pharm.D. Celerion J. MICHAEL COLLACO, M.D., M.B.A., M.P.H. Johns Hopkins Medicine JEANNIE LIMPERT, M.D. FDA Center for Tobacco Products KEVIN CHATHAM-STEPHENS, M.D. Centers for Disease Control and Prevention DIANE M. ASHTON, M.D., M.P.H. March of Dimes Foundation National Office CARL PHILLIPS, Ph.D. Consumer Advocates for Smoke-free Alternatives Association

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M E E T I N G

(8:01 a.m.)

DR. LIMPERT: Welcome back to Day 2 of our third workshop

on e-cigarettes.

I am Dr. Jeannie Limpert from the Center for Tobacco

Products, Office of Science.

Yesterday we addressed population health issues associated

with the use of these products. This morning we will first

hold a public comment session. Each presenter will be limited

to a 3-minute presentation. As mentioned yesterday, if the

public comment session ends early, we will move on to the rest

of the agenda. This may mean that we will run ahead of

schedule today.

After the public comment session, we will have two

sessions consisting of a series of presentations followed by

clarifying questions and panel discussions. The first session

will focus on the evaluation and constituents of exhaled

e-cigarette aerosols, and the afternoon session will focus on

the health effects of e-cigarettes in nonusers. Dr. Carolyn

Dresler from CTP Office of Science will again be our moderator.

Similar to yesterday, our presenters have been asked to keep

their presentations within the time period allotted, and a

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timer will be used in order to stay on schedule.

We will have two 15-minute breaks, an hour for lunch, and

end the day at approximately 3:30.

Similar to yesterday, if you have a clarifying question or

a question for the panel, if you are here on site, please write

your question on one of the cards provided, using legible

handwriting, and give the card to one of our volunteers. If

you are participating by webcast, you can e-mail your questions

to [email protected]. Please write on the card

whether the question is clarifying and, if so, for which

speaker or whether the question is for the panel. We will try

to get to all the questions but may not be able to do so due to

time limitations. We will try to combine related questions to

avoid duplication.

The workshop is being recorded. The transcript and

webcast recordings will be posted on our website when they

become available.

I would like to remind you of a few things from yesterday.

The purpose of this workshop, and the two previous

workshops, is to gather scientific information about this novel

category of tobacco products. This workshop is not intended to

inform the Agency's proposed deeming rule. We are not looking

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for advice or consensus but are interested in an open exchange

and discussion of scientific information.

We request that all workshop participants be considerate

and respectful of all other participants, the information being

presented, and the opinions expressed by others.

We request that you refrain from use of all tobacco

products, including e-cigarettes and other electronic nicotine

delivery systems, during the meeting.

The restrooms can be found outside this room, in both

directions down the hallway.

For lunch, a deli buffet will be available for purchase in

Patuxent Room 2, and the cost of the buffet is $14.

Please note that for any media inquiries, Michael

Felberbaum is our press contact, and he's standing in the back

of the room.

I would now like to turn the podium over to our moderator

for the workshop, Dr. Carolyn Dresler.

DR. DRESLER: Thank you. And good morning. All right,

let's start.

Everybody see the green, yellow, red? So green you're

okay to go, yellow, be thinking about wrapping it up, and this

is where I stand up, okay? And then if I walk towards you,

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you're done, okay? But you also have a timer here, and it says

the amount of time that you have.

So could we please have the first speaker?

(Off microphone comment.)

DR. DRESLER: Okay.

MR. ALTMAN: That will be Number 2 on your scorecard, but

Number 1 in your heart, okay?

(Laughter.)

MR. ALTMAN: My name's Kevin Altman. I work with a lot of

people at already regulated companies, through tobacco,

smokeless, and roll your own, but I'm also working now with a

lot of e-companies. Our role through CITMA is to help people

understand how FDA involves and works with their company so

they can comply with all the regulations that are coming.

So I'm not a scientist, so excuse me for my ignorance, for

most of you that have much more advanced degrees than I, but I

want to make two points today. If you watched yesterday, you

could see there's a wide array of science on these products, a

wide array. You can also see a lot of bias that creeps into

that science because you're all talking about the same product.

Yet some people say oh, this is awful, and some people say this

is the best thing since sliced bread. That's confusing to a

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non-scientist, and it's certainly confusing to the public.

So what I think is appropriate is that the stakeholders on

all sides, be they antis, the non-antis, the pros, the

industry, the FDA -- these groups need to come together, see if

there's a way to formulate studies where the same questions are

asked to the various groups you want to ask so you get good

science. Not looking for a particular outcome, but what does

the science really tell us, because the FDA's objection and

goal is to see what the health effect is on the population as a

whole.

I looked at something yesterday. If we heard "ever use"

one time, we heard it 100 times. I don't understand how

somebody who uses something once in 30 days is a user. I'll

give you a prime example. I like ice cream. At the hotel last

week, Chunky Monkey was the only thing they had. Ben and

Jerry's. Never had it. Will never have it again. I'm not a

user, but I had it one time. And that's a live example.

So I would just ask that the groups that are going to be

informing this science -- and we have FDA, I think, doing 50

studies, somewhere in the neighborhood, I hear, of 50

studies -- we need to make sure those studies are coordinated,

and the questions and the answers are tailored to the right

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group of people. We don't want to talk to young people, as an

industry. It's not something we think is appropriate, but we

understand that's something that has to be done.

But we have to get away from the way we used to think

about doing scientific studies under cigarettes because these

products are totally different than cigarettes. So if we run

under that same model, we're probably not going to get the

right answers.

So I'd ask that anyone in the room that's going to be

involved in this process going forward, make sure you work

together to come up with a study, survey, whatever you want to

call it, that gets us the right science, because the science is

what has to take us where we go. This is an ever-changing

environment we live in, and it's not like traditional tobacco

products, because they haven't changed in 20 years. These

products change daily. The way people use these products

changes daily. And it's important to keep that in mind and

maybe go back now and look at, okay, what did we ask in the

past? And what I hear from some people is, well, if we do

that, Kevin, and we make these changes, we have no way to

compare it. It's okay that we can't compare something to last

year or 2 years ago, because what's important is what are we

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doing going forward?

Thank you.

(Applause.)

DR. DRESLER: Okay. So the request is -- and I know there

are some empty chairs and there are some travel issues, et

cetera. So as the next speaker comes up, if you could come to

the next speaker chair, because that will make sure that your

correct name is up there. So that will help a lot. So, for

example, Bill is coming up to the front, and the next speaker

would move over to the next speaker chair, over there. That

helps the process. So we'll see. Kindly.

MR. GODSHALL: I'm Bill Godshall, Founder and Executive

Director of Smokefree Pennsylvania. Since 1990 we've

successfully campaigned to ban smoking in work places, stop

cigarette marketing to youth, increase tax rates on cigarettes,

and require the FDA to impose a regulation requiring graphic

warnings on all cigarette packs, something FDA doesn't deem

important.

In 2010 we filed an amicus brief with other public health

advocates opposing the FDA's e-cigarette import ban with the

D.C. Court of Appeals, which upheld Judge Richard Leon's 2010

ruling striking down FDA's ban as unlawful.

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Since 2011 we've opposed the FDA's proposed deeming

regulation because it would ban more than 99.9% of all nicotine

vapor products currently on the market, protect cigarettes,

increase smoking, threaten the lives of several million vapers

and tens of millions of smokers, and create a huge black market

of totally unregulated vapor products.

For disclosure, neither Smokefree Pennsylvania nor I have

ever received any funding from any tobacco, drug, or vapor

product company, nor from any government agency whose policy is

to ban vapor products, which is also a clear conflict of

interest.

The scientific and empirical evidence consistently finds

that nicotine vapor products are 99%, plus or minus 1%, less

hazardous than cigarettes, have never been known to be

associated with any disease, and pose no known risk to

nonusers. Nicotine vapor products have already replaced 3

billion packs of cigarettes, and more than 99% of all nicotine

vapor products are consumed by smokers or by ex-smokers who

switched to vapor products, which are more effective and pose

fewer risks than FDA-approved and hawked smoking cessation

drugs.

Adult and teen surveys consistently find that ex-smokers

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account for more than 90% of past 30-day e-cigarette users. It

appears that more than 99% of daily vapers are smokers or ex-

smokers who have switched to vaping. But the Department of

Health and Human Services has refused to conduct or fund any

surveys that inquire about daily vaping or even if nicotine was

vaped, which has only served to bury the truth.

Two recent surveys found that 3 and 4 million U.S. smokers

respectively are no longer smokers because they switched to

vapor products. Thus, it is mathematically impossible for

vapor products to harm overall public health, even if every

nonsmoker in America began daily vaping. And yet there's no

evidence that vapor products have created daily dependence in

any nonsmoker anywhere in the world, nor is there any evidence

that vaping has served as a gateway to cigarette smoking for

anyone.

But since 2009 the FDA and the CDC have made many false

and misleading fear-mongering claims to confuse, scare, and

lobby to ban these lifesaving products under the deceitful

guise of protecting children and public health.

Dozens of DHHS funding recipients have also misrepresented

evidence on the scientific -- to scare the public on the

scientific evidence, to scare the public and the lobby to ban

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vapor products and/or vaping, including most presenters and

panelists FDA invited to speak at these three so-called public

workshops on e-cigarettes. The FDA should stop protecting

cigarettes and start protecting public health and telling the

truth.

(Applause.)

DR. DRESLER: Next speaker, please.


DR. DRESLER: No, I don't think so. This isn't Greg.


DR. DRESLER: We'll let him go. We'll get his right, but

we'll still get to you in a few minutes. Okay.

DR. ROSTAMI: Good morning. Thank you for the

opportunity. My name is Ali Rostami. I am an associate

principal scientist at Altria Client Services, and I'm speaking

on behalf of Nu Mark, which develops and markets e-vapor

products.

FDA is interested in gathering scientific information on

questions related to health effects of e-cigarettes on

nonusers. Some of these questions are what chemicals are

delivered to nonusers; how aerosol properties impact exposure;

how far aerosol can travel; what is the aerosol level in

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different space settings?

Running multiple experiments in a study to account for all

combinations of these variables is challenging. As a result,

we're using a parallel approach. We're using computational

modeling tools to simulate multiple scenarios. These models

will be validated by the experimental data that my colleague,

Dr. Sarkar, will talk in the next session.

The models are based on physical and thermodynamic

interactions between air, vapor, and particles, as shown in

this diagram. Exhaled aerosol is released into the room. It

mixes with the room and the ventilation air. It dilutes and

some of the volatiles evaporate. Over time, some of the

aerosol is carried out by ventilation air, some inhaled by

occupants, some remains airborne indoor, and some deposits on

the surface. These processes can be represented mathematically

by a set of equations, including conservation of mass,

vapor/liquid partitioning, mixing and dilution, as well as air

flow and species transport.

The model takes in the measure of the aerosol exhaled,

exhaled aerosol properties, space size, air change rate as

inputs and delivers the full components on the right as

outputs. The most relevant to the secondhand and thirdhand

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exposure are also indicated in this diagram.

To summarize, we developed computational models using

principles similar to those referenced by EPA for indoor air

quality analysis.

We are validating models using data from controlled

studies that my colleague Dr. Sarkar will talk about.

We'll apply models to address types of questions listed

earlier, and we will run simulations for multiple scenarios.

We intend to submit the work for publication, and we will

improve the models as additional data become available.

Thank you.

(Applause.)

MR. BALLIN: Good morning, everybody. I'm Scott Ballin,

and I've been involved in tobacco and nicotine policy related

issues for 40 years. Many things have happened over that 40-

year period, and many things will continue to evolve in the

coming months and years. As this is the last workshop before

the deeming regulations are issued, I wanted to make some

general comments.

Much of the discussion with respect to the impact on the

use of ENDS on the population is focused on, and presented

from, the standpoint of concerns about unintended consequences.

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Will such products keep people from quitting? Will they

encourage new users? Will they result in dual use? Will they

entice children and adolescents to use the products? The

answers to those questions depends on how we decide to move

forward.

And while using models and other tools are helpful in

trying to evaluate population effects, I think we all know that

this is a dynamically changing environment. I don't think

anyone, for example, could have predicted that the ENDS

marketplace would have developed as rapidly as it has. And

everyone seems to concur that innovation and technology are

going to continue to impact that marketplace.

It doesn't take an expert to recognize that we are dealing

with a very different environment, one that's going to require

new thinking and new processes in working together, which is

why I have on many occasions commended Director Zeller, as well

as the Agency, for speaking about the need for more rational

and comprehensive tobacco policy that is based on the continuum

of risk.

In addition to the questions I have mentioned, I think

there's an overarching, equally important question that needs

to be asked. What are the unintended consequences of not

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making science-based, lower-risk, regulated alternative

products available to the users of cigarettes?

This year 5.3 million people will die globally from the

use of the deadly cigarette. In this country, over 400,000

will die prematurely from using the combustible cigarette. The

devastating effects on the cigarette -- on the population

should be a paramount consideration in whatever is considered

and discussed, whether it be ENDS or other lower-risk,

noncombustible products such as snus, lozenges, dissolvable

gums, or even NRT.

It really is time to seize the opportunity to establish a

regulatory structure that meets the rapidly changing

environment, and I encourage the Agency to make that the

primary priority.

And, lastly, let me reiterate, because there was a lot of

discussion on children yesterday and adolescents. I think the

majority of people do agree that all stakeholders need to be

involved in ensuring that all tobacco, nicotine, and

alternative products, including ENDS, should not be purchased

or possessed or used by children and adolescents. Dealing with

that issue head-on, on both the individual and the public

population, I have suggested that there should be a national

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summit to discuss those issues and to work cooperatively to

achieve those objectives.

Thank you very much.

(Applause.)

DR. DRESLER: Andrew Collins.

DR. COLLINS: All right. Good morning, everybody. My

name is Andrew Collins, and I currently work for Imperial

Tobacco, within the product science department. I'll be

presenting to you some data we ran from a consumer survey

looking at e-vapor products. What I'll be doing is

specifically looking at how the consumers and the response to

that survey reported that EVP, or e-vapor products, affected

their tobacco use.

So our survey encompassed a little over 2,100 different

adults in seven different markets, shown up here. Top-level

demographics -- there we go. Sorry. It's an online survey of

weekly vapers who were vaping for at least a month. There we

go.

So top-level demographics show that the entire cohort,

about 72% of them, are dualists. So that is to say they smoke

and use EVP products simultaneously. Twenty-four percent are

quitters. So these are people who used to smoke cigarettes but

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have since quit since starting using their EVP products. And

3% are defined as newcomers. So these are people who self-

perceive as coming from a non-smoking background. But in order

to actually qualify for the survey, there had to be some degree

of smoking background there, even if it was just one cigarette.

So this graph illustrates the percentage of people who are

dualists versus those who are exclusive EVP users. Here we can

see that for heavy user classes, over 100 puffs per day, we

have 29% of people who are actually quitters. And if we

compare that to -- if the slide works. It's not working,

sorry, the forward. Oh, there we go. It did, and it's taking

its time, by the looks of it. Let's go back. So there we go.

If we compare that to the medium and light users, we can see

that the contrast is actually quite stark, particularly when we

contrast the heavy users to the light users.

So what about those who still smoke? How does EVP affect

their tobacco consumption? Well, broadly speaking, two-thirds

of people do actually report cutting down on their cigarette

consumption. So, for everybody -- so this is all the dualists

-- we see a mean loss of about five cigarettes per day compared

to levels before they started smoking. So that's a little over

27%.

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The story gets a little more interesting if we compare

that and once again stratifying to heavy, medium, and light

users. So here we can see that the heavy users showed the

biggest loss in tobacco consumption, averaging about eight

cigarettes less per day compared to levels before they started

smoking. So that's about a 38% reduction.

So, in summary, heavy users of EVP were found to be far

more likely to be quitters than those who use EVP less

frequently. For those who still smoked, we see that the

majority actually successfully cut down on their tobacco

consumption, with heavy users showing the biggest reductions.

This clearly demonstrates EVP's potential as a tool to

help users reduce their tobacco consumption. Any future

regulations on this topic should be proportional in order to

realize this opportunity and give people the chance to cut down

on their tobacco consumption with effective devices.

Thank you very much for your time. If you have any

questions, I'll be happy to answer them if you come find me

later on.

(Applause.)

DR. JORDT: Okay, my name is Sven-Eric Jordt. I am an

Associate Professor in the Department of Anesthesiology of Duke

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University School of Medicine. My expertise is in the biology

of chemical irritant receptors. In 2004 we discovered a key

receptor for toxic aldehydes, and we also linked chemical

irritation to asthma, and recently we published on mechanisms

through which menthol facilitates smoking initiation. And we

are funded by NIH.

So I'm here to voice a scientific concern about the

content of highly reactive aldehydes that are flavors in the

e-liquids, specifically unsaturated aldehydes such as

cinnamaldehyde, carvone, or damascenone. So these are

contained in some of the popular flavors, but also at very high

concentrations in some flavors sold by boutique vendors online.

This is just one example. We tested a wide range of different

products.

You can see here that this Atomic Cinnacide flavor, sold

by the company Tasty Vapor, has concentrations of more than 7%

at the 24 mg/mL nicotine solution, 13% of a reactive

unsaturated aldehyde. You can also see that the consistency

among the different flavors offered is very low. So the "no

nicotine" flavor has 7%, and the nicotine has 13%. And this

again changes depending on when this is purchased.

So reactive aldehydes are obviously acute irritants.

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There is a concern about these effects. But what I also wanted

to mention, they are known as allergens. So it's known in

studies in the '90s and from flavor industry workers that these

workers can develop contact allergies against cinnamaldehyde.

Also, in the actual -- in bakeries, this has been found. These

compounds can induce contact stomatitis. This is an allergic

condition of the mouth. Carvone has been showing the same.

So I just wanted to stress that these aldehyde flavors

don't only have acute effects, but they can also cause

allergies.

And I would like to advise FDA to regulate aldehyde-

flavoring contents, especially at these boutique vendors, and

support further research that can study the potential allergic

effects of these compounds.

Thank you very much.

(Applause.)

MR. WEBBER: Good morning. My name is Chris Webber. I

started smoking at age 15 and smoked for 10 years. Two years

ago I discovered vaping and put down cigarettes immediately.

Currently I'm also the assistant director of Free to Vape.

We're a national nonprofit organization representing tens of

thousands of vapers who successfully replaced their tobacco

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with vapor products.

Now, regardless of what side of the debate you're on, we

all share a common goal, which is ending the mortality or

morbidity associated with tobacco use. With close to a half a

million deaths a year attributed to smoking cigarettes and not

a single death ever attributed to vaping, it should be clear

that combustible tobacco is the enemy, not vapor devices.

We heard quite a bit yesterday about youth initiation of

vapor devices. But what we have not heard much about is the

continued rate of youth smoking initiation, which until the

emergence of vapor devices remained stuck at about 20%.

Now, the current generation grew up in a tobacco-control

utopia. They've never been exposed to cigarette ads. Taxes

make it exorbitantly expensive. And youth are routinely and

explicitly told about the health risks. The fact remains,

however, one in five youths still pick up a cigarette and light

it. And this tells us one thing very clearly. The existing

methods of tobacco control simply do not work.

The definition of insanity is to repeat the same action

for 20 years and expect a different result. Unfortunately, it

would seem like many tobacco control professionals in this room

are advocating doing just that. Twenty years of failure and

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millions of lives lost should tell us that we need vapor device

regulation based in reality, not fantasy. Though one could

argue a completely nicotine-free society is the ideal outcome

we should work towards, the magnitude of the tobacco control

movement over the past 2 decades, coupled with its continued

failure to stem or eliminate youth smoking initiation,

demonstrates one thing very clearly: a nicotine-free society is

simply not realistic or achievable. The reality is, in a free

society, youth will rebel, youth will experiment, youth will

make poor choices simply because they're told not to.

Unfortunately 20 years of data indicate that despite all of our

best efforts -- and I know we have all been trying really

hard -- one of those poor decisions is going to be starting

tobacco use.

Now, I'm by no means advocating for youth adoption of

vapor devices, and obviously all the age restrictions that

we're currently employing should continue to be employed. But

I am suggesting that we must accept the simple reality that

there's going to be a percentage of youth that will always

rebel and choose to inhale and exhale substances other than air

to do so.

Therefore, we must also accept that vapor -- we must also

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accept that youth initiation of vapor devices isn't always

necessarily a public health cost, because that has to be

weighed against the probability of that individual youth

rebelling with tobacco instead.

If we really want to create a society free from the death

and destruction of tobacco, we have to accept that youth

rebellion is a fact, and that while inhaling vapor may pose a

slight risk over breathing pure air -- and again we saw, in the

last workshop, it's a pretty small risk, you know, 95%, 99%

less harmful -- we have to agree that it's better than smoking.

And in the past 20 years, you know -- and this is my

generation. We grew up in a system designed to prevent us from

smoking, and I still did. I prefer that the youth don't smoke.

And that's it. Thank you.

(Applause.)

MR. CONLEY: Good morning. My name is Gregory Conley, and

I am the president of the American Vaping Association, a

nonprofit that advocates for small- and medium-sized businesses

in the vapor market. In August I will be celebrating 5 years

as a nonsmoker.

Ever since the first surveys on vapor product usage were

released years back, fair-minded researchers and advocates have

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been trying to communicate that better survey methods are

necessary to truly understand how adults and teens are using

and experimenting with vapor products. I was extremely pleased

to see that our calls have been vindicated, as several of

yesterday's presentations acknowledged the need for more

thorough and detailed data collection, especially on details

like days of the month usage and nicotine versus non-nicotine

usage.

On the other hand, regrettably, many of yesterday's

presenters were clearly guided more by ideology and less by

science and reality than others. For example, first, a

panelist assumed that until regulations are in place, one

cannot assume that vaping is any safer than smoking, as if the

absence of scientific -- as if the absence of regulation

somehow cancels out the clear body of scientific evidence on

the topic.

Second, on the marketing panel, not one speaker could

admit that if restrictions led to less adult smokers using

vapor products, such a regulation could be bad for public

health. That's not balanced.

Third, upon hearing that many doctors were truthfully

informing adult smokers that vaping was a good way to quit or

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substantially reduce their smoking, one panelist gleefully

began plotting ways to reverse that by misinforming doctors of

the relative risk of smoking versus vaping.

Fourth, panelists pushed for flavor bans without even

pausing to consider whether such restrictions could harm public

health by discouraging quitting, while another panelist felt

the need to disclose "I'm not pro harm reduction," as if that

wasn't already clear.

Fifth, panelists endorse campaigns that seek to

unethically scare smokers away from switching to vaping by

highlighting scary-sounding chemicals found in vapor, even if

those levels are far below those allowed in inhalable

medications.

To cap it off, the day ended with a panel where not a

single person was willing to state that it would be a bad

thing, and that it is a bad thing, for smokers to grossly

overestimate the risk of vapor products versus smoking.

I will close by proposing this. Instead of having

speakers declare their financial conflicts of interests, it may

be more useful for future participants at these meetings to

start off by answering the question: Are vapor products less

hazardous than smoking? After all, not knowing the truth about

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relative risk, or being unwilling to tell the truth about

relative risk, is a much bigger conflict than any financial

interest ever could be.

Thank you.

(Applause.)

MS. HALLER-STEVENSON: Good morning. I'm commenting on

behalf of the National Association of County and City Health

Officials, also called NACCHO. Thank you for calling attention

to these important issues.

NACCHO is the voice of over 2,800 local health departments

across the country. During this workshop, we are learning a

lot about research data regarding use of e-cigarettes, products

that are used by adults and youth, the related health effects,

and consumer protections about the products. I'm going to tell

you how local communities are grappling with the surge in use

of e-cigarette products and their availability and what that

means for the public's health.

In the absence of overarching laws and product regulation,

local health departments are establishing policies regarding

e-cigarettes in their own communities to create environments

that make it easier for people to be healthy and safe. Over

350 communities and three states have established e-cigarette

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use restrictions to align with their existing smoke-free air

laws. Communities are also beginning to create minimum-age-of-

sale laws for e-cigarettes to reduce youth access to the

products. There is a demand from communities to minimize the

risk to the public.

The availability of scientific information regarding the

safety and potential risks to users and bystanders related to

e-cigarettes is increasing. The area of concern for the

public's health is that there is a risk involved with the use

of e-cigarettes and that the risks should be -- there is a risk

that should be mitigated.

Generally speaking, the position of the public health

sector is not to outlaw e-cigarettes. It is to protect the

public's health. E-cigarette users should know what the

products contain, and the associated risks, through consistent

and accurate product and warning labels.

Nonusers should not be exposed to e-cigarette aerosols in

public venues, in order to limit harm. Youth access to

e-cigarettes, as many of us have already agreed to, should be

restricted to the remarkable -- due to the remarkable increased

use of the products. And child-resistant packaging should be

in place for the e-liquids to prevent the escalating child

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poisonings, as reported to poison control centers across the

country.

We cannot leave local communities to manage this emerging

public health issue alone. We need to create an environment

that supports informed e-cigarette users and protects youth and

nonusers. We have an opportunity to reduce the potential for

harm much earlier than we did related to the increase and

popular use of combustible tobacco products. Don't make this a

50-year path.

Thank you for your attention and for the opportunity to

comment on this important issue.

(Applause.)

MR. GREENWOLD: I'm Mark Greenwold, senior consultant with

the Campaign for Tobacco-Free Kids.

In order for e-cigarettes to play a constructive role in

reducing tobacco-related disease, FDA must act promptly to

subject them to regulation. The unregulated market for

e-cigarettes has permitted e-cigarette manufacturers to target

adolescents in their advertising and marketing, and led

millions of young people to experiment with this addictive

product. Regardless of the potential e-cigarettes may have to

help adults quit smoking, exposing our kids to addictive

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products is too high a price to pay. FDA's first and

overriding priority should be the protection of our youth.

Nicotine is not a harmless substance, especially to kids.

Besides being highly addictive, it interferes with brain

development in adolescents. Kids who use e-cigarettes not only

risk addiction, they also jeopardize their mental development.

Increased e-cigarette usage among kids is no accident. It

is the inevitable result of federal regulatory paralysis that's

done nothing to prevent or even discourage e-cigarette

companies from marketing to kids.

FDA should take the following steps:

First, it should promulgate the deeming rule as soon as

possible. When it sets a target date, it should actually meet

it.

Second, it should immediately apply to e-cigarettes all

the provisions of the 2010 rule on marketing to youth.

Third, it should prohibit the sale of e-cigarettes in

remote transactions, including Internet sales.

Fourth, it should prohibit kid-friendly flavors in

e-cigarettes. To the extent there may be tradeoffs between

maximizing the range of conceivable flavors in order to appeal

to adult smokers and potentially addicting kids to nicotine,

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those tradeoffs should be resolved in favor of preventing kids

from becoming addicted.

Fifth, FDA should adopt rules requiring e-cigarettes to

meet high standards of purity and strict product

specifications, and prohibit the sale of e-cigarettes unless

they're manufactured according to good manufacturing practices.

Sixth, FDA should immediately require child-resistant

packaging of e-cigarettes.

None of these steps would prevent e-cigarettes from

playing a constructive role in promoting adult cessation. The

current unregulated market does nothing to facilitate this

goal. Instead, it rewards the most irresponsible companies who

focus their marketing on young people.

Establishment of a strong regulatory framework is the most

effective way to enable e-cigarettes to help smokers quit while

minimizing the risk of adverse population-wide effects.

(Applause.)

MR. XU: Good morning, everyone. My name is James Xu,

President of Avail Vapor.

In response to FDA's questionnaire, Avail Vapor conducted

a survey last month with 45 retail stores. With the help of

other online websites, we were able to receive 8,500 responses

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within 2 weeks. The complete report is available online at

availvapor.com. And here are some of the key findings.

If you look at the male-to-female ratio, that's about 2:1.

Our largest age group is 30 to 39, closely followed by 20 to 29

and 40 to 49; 85.2% of our respondents have reported that

vaping has helped them to quit smoking. An additional 13.06%

were able to reduce their tobacco use; 69.05% of all

respondents have reported that they're able to quit tobacco use

within 1 month or less. And 96% consider e-cig a much

healthier choice than a tobacco product.

It's not a required field for people to fill out other

comments, but 20% of our surveyors decided to leave their

comments and tell us their personal experience.

Just like we see every day in our stores, most of the

beginners, when they're coming to start vaping, they start with

traditional tobacco and the menthol flavor. Very quickly they

move on to other different flavors.

When we asked them to pick two top choices of the

e-liquid, the number one, by far, is fruity followed by dessert

and savory. And if you look at the traditional tobacco and the

menthol, they are among the least favorite by adult vapers.

And combined, it is about 86% of the users, that they switch

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their flavor at least once every week.

Safe manufacturing is extremely important to all users,

and purchasing habit, mostly online and the specialty stores;

convenience store is only less than 2%. For the e-liquid it's

only 1.4%. And very few of them started vaping without being a

traditional tobacco user.

Thank you. You can find the entire survey result on our

website, availvapor.com. Thank you.

(Applause.)

DR. DRESLER: Do we have anyone else who's -- no? No.

Okay. Then we will move on to our first session.

So the first session after the public comment session is

on Exhaled E-Cigarette Aerosols: Evaluation of Constituents and

Exposure. And our first speaker is Dr. Andrew Persily from the

National Institute of Standards and Technology, speaking on

Relating Airborne Contaminant Emissions to Occupant Exposure.

DR. PERSILY: Good morning. Thanks very much. A pleasure

to be here.

As you can see from the title, you won't see the term

e-cigarettes in there, and I'm not here to talk about that

technology or product specifically. I'm really here to talk

more about indoor air quality in general.

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I am a mechanical engineer at the National Institute of

Standards and Technology, which is an agency of the federal

government up the road a bit, where I've been doing research on

indoor air pollution for a number of years, where we try to

understand if you have a contaminant source, what aspects of

the building and the building systems impact contaminant

concentrations and subsequently human exposure, and how we can

reduce that exposure by different strategies and ideally, you

know, strategies that are effective and don't consume a lot of

energy.

As part of this work, I've also been involved in the

development of voluntary industry consensus standards for

ventilating buildings, and those ventilation rates are based on

contaminant sources that may be a factor.

So, in terms of disclosure and conflict of interest, I

have received a salary from this for 33 years, and I'm still

interested. And some days I'm conflicted, but we aren't doing

any research related to this, again, to e-cigarettes, in

particular.

Okay. So I'm really talking about, you know, if you have

a contaminant source in a building or outside, what concepts

and approaches are used to predict indoor contaminant levels

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and then subsequent human exposure. So, in some ways, this is

less about the user of the e-cigarette than the other building

occupants.

And so when we -- you know, first we think about the

source. What's emitting the contaminant that we care about?

What is the emission rate?

The transport mechanisms. Where does this contaminant go?

How is it removed? Does it stick to surfaces and so on? I

didn't mean to do that, but that's okay.

So, you know, you start with a building and that building

has air coming in. And for many contaminants, you know, that

you have -- that exist in the outdoor air, right? So if you're

trying to understand the indoor contaminant, you better make

sure you understand what's going on outside because you're

bringing air into the building. So that's an important

concept.

Yeah, okay. There you go. And then you have a

contaminant source in the building. There are lots of them.

Very different properties. Some emit one contaminant only, but

that's rare. Most of them can emit a lot of contaminants or a

variety of contaminants at different rates. So that's the next

step in the process.

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And there you go. And then you get the concentration in

the space, which will vary in time and location. And there are

a lot of important details, you know, that we could get into.

And then, finally, you have the people. And while they

all look the same in this sketch, they're all very different in

terms of age and breathing rate. And preexisting health

conditions are an important factor. Do they have asthma or

some other issue which, you know, relates the exposure they

experience to the health risk or comfort situation that they

may realize?

So those are kind of some of the fundamental concepts.

And I'm just going to kind of go through contaminant sources to

emissions, the concentration to exposure, in very general

terms, hopefully providing some useful context for some of the

discussions you're having.

Oh, there we go. So, first, airborne contaminant sources.

There's a whole host of materials and activities in buildings

that emit contaminants. And that's just a fact of life. You

know, if you're going to be inside, which we do -- 90% of our

time is spent indoors unfortunately, and there are things

inside that you need to do. You know, you need chairs, right?

You know, you do want to sit occasionally. So there are

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building materials. And I don't know if these were purchased

from Lumber Liquidators or not --

(Laughter.)

DR. PERSILY: -- but building materials emit chemicals.

The outdoor air can be a pretty important source of indoor

contaminants. And I will note that outdoor air is regulated in

this country by the EPA, and that's a big issue. EPA doesn't

have the regulatory authority for indoor air, but there are

certain agencies that have regulatory authority for specific

types of products.

And then combustion or other activities. This is a very

safe candle because it's not lit. Okay, light it, and it will

produce particulates and all sorts of other chemicals that

might not be as safe.

So, you know, you need to understand the contaminant

sources and the contaminants that might be emitted by those

sources and whether it's a constant source or it's impacted by

temperature or it's impacted by what the occupants do.

And then you're interested in the contaminant emission

rates, and people measure those in environmental chambers.

Here's just kind of a diagram. I'm having trouble with this.

There it is. You know, where you put a source. It might be a

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floor covering or something. It could be just about anything.

Here's a picture of some actual chambers, and you put the

source in there. You put some -- it better be clean air,

right? And then you measure the concentration coming out and

you can back out the emission rate.

But for some contaminants, you know, they will stick to

the surfaces, and it really complicates the calculations. You

need to understand the contaminant and its properties. You can

estimate emission rates from buildings, you know, put the

source in the building and measure the concentration. But

that's tough. I mean, the advantage is it's reality. The

disadvantage is, is that real buildings are complicated and

there are all sorts of things happening.

In general, you know, there's a lot of variability in the

contaminants released, the temporal patterns in those releases,

temperature effects, and a whole host of other issues.

But, you know, these emission rates then get you to the

concentrations, and the concentrations you can get from indoor

air quality modeling. We heard some discussions and that's

kind of what this is. Take a real building and turn it into a

computer model. There are a lot of building features that

impact the concentrations that exist in the buildings: the

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size, the ventilation rate, surface properties, a whole host of

other things, and then the emission rates I've talked about.

And then, finally, you have the concentration and then you

start to talk about exposure. You know, how many people are in

the space? You know, when are they in the space? What is

their age or activity level? And then I mentioned preexisting

health conditions already. And this is the input to the risk

assessment. So, you know, we're talking about the people in

the space exposed to contaminants emitted from various sources.

And we saw an earlier version of this in the comment

session before. But this is just a contaminant -- a very

simplified contaminant mass balance equation that we use to

understand the relationship between contaminant sources,

building ventilation rate, loss mechanisms in the space, and

then generation. I'm not going to go into this in much detail,

but I figured I should show one equation to be true to my

engineering roots.

I will make one point here. Under contaminant

concentration, you know, for different sources, there are lots

of contaminants you might be interested in, and in general,

each contaminant is a different measurement approach, and you

really need to understand the measurement technique you're

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using to get reliable data.

So whenever, for example, I see the concentrations were

not detectable, my first question is, well, what is your

detection limit? You know, because if you have sensitive-

enough equipment, you will detect it -- you know you will

detect it. It may be at a level that you don't care about from

a health or comfort perspective, but you know, keep that in

mind when you read papers and you see "not detectable." Go see

if they said what the detection limit is. And if they didn't

tell you, there's kind of a gap there to keep in mind.

So, you know, I'm talking about indoor exposure to a wide

range of contaminants, but indoor exposure takes place in

buildings, and there are no typical buildings.

You can oversimplify and say there are two types,

residential and commercial. There are about 100 million

dwellings in the United States, you know, and I wouldn't say

every one is different, but there's a lot of variation in age

and size and height and number of occupants and how it's built

and how it's heated and cooled.

And the Department of Energy has this great database where

you can learn all about the residential building stock in the

U.S. I have a link on a later slide.

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What's important to understand is that most residential

buildings are ventilated by leakage. You know, there are leaks

in the walls, and the wind blows and the air comes in. They

are not intentionally ventilated. There's a tiny, tiny

fraction in this country, and it's becoming more common, that

are ventilated intentionally. So most of them are ventilated

by accident.

There are about 5.5 million commercial buildings in the

U.S. that include offices, schools, retail spaces, healthcare,

restaurants, and so on. Again, a lot of variation. DOE has a

database on commercial buildings if you want to look at the

types, because if you're going to relate a source to exposure,

you've got to look at the building. You know, you've got to

understand the building features as well. And in most

commercial buildings, there is a mechanical system that's

designed and installed to bring outdoor air. It might not

function very well and it might not be maintained very well,

but it's there, at least on the plans.

I don't know what I did. There we go. So I talked about

buildings. The other key factor is ventilation. It's not the

most important thing, but it's pretty darn important, and

that's kind of where I've done my research all these years, is

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how much outdoor air is brought into the building? And there

are a lot of factors that influence the ventilation rate of the

building: how it's laid out, how it's built, the air tightness

of the walls, what systems you have in there to heat and cool

and move the air, how it's operated. And that's not just the

operation of the system, but are there operable windows, you

know, because that's going to have a big impact on the

ventilation rate. And how well the system is maintained.

That's a huge issue because you can have a very good system

design, but if it's not maintained, it's not going to perform

very well. And then, finally, weather conditions impact

leakage rates and how the system operates.

You know, a ventilation rate is not a constant number. In

residences, anyway, it's common to see the ventilation vary by

a factor of five to one, just due to weather alone. And so you

need to keep that in mind. When I see somebody in a paper

report a ventilation rate with no information on the conditions

under which that ventilation rate was measured, I don't know

anything, you know, because was it a windy, cold day? Was it a

calm, mild day? Was the system on or was the system off? So a

single ventilation rate without any associated information

isn't very informative.

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Similarly, and maybe more important, you know, an airborne

contaminant concentration measurement in a building without a

ventilation rate is really hard to interpret. You know, was

the ventilation system on? Was it moving five air changes an

hour? Was it moving, you know, 0.25 air changes an hour?

Without that ventilation rate, you really can't interpret the

concentration, and you can't compare it to contaminant

concentrations in other buildings. So that's an important

point to appreciate. You know, you need to understand what's

going on in the building, what's going on with ventilation to

interpret indoor contaminant concentrations.

These are just some -- I mean, these slides would be

available, right? So this is a link to that residential

building survey database, the commercial. The census folks do

an interesting housing survey periodically.

And the EPA Exposure Factors Handbook, if you're not

familiar with it and you're getting into risk assessment, you

need to take a look at it. Well, it used to be a great big

book. Now it's a great big webpage, and it's all sorts of

information that is used to relate exposure to risk. You know,

it has ventilation rate data, and it has building data. You

can look up how many pounds of carrots a 7-year-old girl eats a

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year and things like that, you know, if you're talking about

ingestion exposure.

Some other resources. ASHRAE is the engineering society

that writes ventilation standards in this country. I was

involved in that organization for a long time. Those are

voluntary standards. If they're adopted by a local

jurisdiction, they have the force of law. But these are

standards on how much ventilation air is required in a

building.

There's ASTM standards for measuring contaminant

concentrations and ventilation rates, and a few papers that

we've published on ventilation and infiltration in buildings

that may be of interest if you're pursuing that angle, and an

indoor air quality model, called CONTAM, that we've developed,

that is in the public domain.

So closing thoughts. The bottom line: You know, in order

to understand airborne contaminant sources, you need to look at

the contaminants. You know, not just the one that you happen

to have a device on your shelf that you can measure, but all

the contaminants that may be relevant; you know, the

contaminant measurement accuracy and the limits of detection

that I mentioned; how the source emission rates vary over time;

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the effects of the environment. A good example is temperature.

And I guess I mentioned measurement already. Hopefully the

point got across that the building in which the contaminant

exists and the systems in that building are really important to

understand exposure.

The good news is we have a lot of knowledge and tools and

data, you know, to support estimating human exposure to

airborne contaminant sources. And I mean, that's the good

news. So if you're going to do that kind of work, you need to

take advantage of this knowledge, these tools, and this data to

do it right.

And I believe that's it. It should end with the bottom

line, right? So we did. Thanks very much.

(Applause.)

DR. DRESLER: Okay, our next speaker is Dr. Jonathan

Thornburg from the Research Triangle Institute, speaking on

Methods of Personal Level Measurements of Secondhand Exposure

to Electronic Cigarette Emissions.

Jonathan.

DR. THORNBURG: Thank you. And thank you, Andy; your

excellent presentation made it much easier for me to give mine,

by providing all of that background information.

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So I'm the Director of Exposure and Aerosol Technology at

RTI International. As disclosures, I do not have any financial

interests. I do not receive, and my research program does not

receive, any funding from the government or from industry on

electronic -- related to electronic cigarettes. I did have

some disclosures up there on the slide.

Essentially, if you're going to do your own secondhand

exposure research, it's up to you to pick the types of devices

and measurement methods you want to use, no matter whether

you're in government, industry, academia, or a citizen

scientist. My goal today is to just present the facts.

Before jumping into the background, it occurred to me this

morning that I should probably give some background of why we

might -- you should be collecting secondhand exposure data at

the personal level or at the stationary level, and I think

there are two important reasons.

One, we know there's a lot of research going on, and we're

looking at the health effects. And I think there will be some

talks this afternoon about the health effects from electronic

cigarette emissions and secondhand exposure. Well, if you're

looking at the health effects, you know, a big part of that is

looking at the biomarkers that are produced when you're exposed

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to these chemical contaminants. Well, to do those types of

studies, you need -- you typically do that in an exposure

chamber, and you need to understand what the person is actually

breathing to make that relationship between what's in the air

that they're breathing and what happens inside their body.

Second, there was a lot of discussion yesterday about

longitudinal observational studies, you know, about usage

behaviors and such, or randomized controlled trials. Well, the

same types of studies are conducted when you're looking at

secondhand exposures. But to do that right, you need to

understand what the people are breathing.

As Dr. Persily said, there is the -- the air in our

environment is very complex, and there are lot of the same

contaminants in the outdoor air that might be contained in the

electronic cigarette emissions that lead to secondhand

exposure.

So that means you have to be able to apportion, you have

to do the source apportionment. Where did that exposure to

that contaminant originate? Was it from an electronic

cigarette, or was it from another source, like a candle burning

or a combustion byproduct from your automobile?

So moving on, so some background information here. I

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presented this slide in my first talk I gave in the December

workshop, just to clarify that the electronic cigarette

emissions generate a mixture of vapor and aerosols, where the

vapors are gas that is formed by the boiling or evaporation of

the liquid. And the vapor can contain a lot of different

contaminants: aldehydes, nicotine, and non-polar organics. The

aerosol is a solid or liquid particle suspended in the gas, and

it's usually reported in sizes such as micrometers.

I also want to point out, during my talk I will frequently

switch the terminology between aerosol and particle, but

they're both synonyms.

I also need to point out that there are several organic

species in electronic cigarettes as well as other sources that

are semi-volatiles, that is, they exist in both the gas phase

and in the particle phase.

So today's presentation will focus on the methods to

measure secondhand exposure to electronic cigarette emissions.

These are all based on scientifically proven approaches used to

investigate exposures to outdoor air pollution, formaldehyde

from building products, combustion sources, you know, many

different sources.

So I'll be talking about the methods for collecting, the

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devices you can actually use, the different approaches, whether

you use stationary measurements or personal-level measurements.

And for all of these approaches, I'll be talking about the pros

and cons.

And I'll talk about cost in some places. And I sort of

arbitrarily picked an $8,000 per device threshold to be defined

as a con.

I will not be talking about using biomarkers of exposure

or toxicology or physiological responses as a means for

assessing secondhand exposure.

So aerosol measurements. There are many different ways

available to collect aerosol measurements. So these are the

measurements of the particles in the air. One common approach

is -- anyways, the single-stage filter. So that's a common

device that's been commercially available for a long time.

Very easy to use, portable, and not very expensive. You

collect the particles on a filter. So it's very easy to take

it back to the laboratory, weigh the filter on a balance, and

then you can also analyze that filter to understand what metals

were in the air or what organic species were in the particles.

Some of the disadvantages. It's a one-shot sample. It

doesn't provide any time-resolved data. If someone wears that

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device for 24 hours, you don't know when their exposure

occurred during that 24 hours.

For electronic cigarette emissions, we know that there are

a lot of semi-volatiles in organic particles emitted,

especially initially upon exhalation by the user. As those

particles collect on the filter, they could evaporate, so you

can actually get some significant evaporative losses and you

would actually underestimate someone's exposure.

No size data. That means that you don't know the sizes

because you don't know how many particles or how much of the

mass is less than 100 nm or greater than 100 nm or greater than

500 nm.

Another big con with this device is the need for a pump.

The picture just shows the device itself, you know, that you'd

wear up here on your chest. There is a whole separate pump

that runs -- that you need to run from the inlet that you have

to wear in a waist pack. So the whole device would be rather

bulky.

You also have a similar device, a cascade system. It

collects on a filter. The big advantage for this one is it

provides size distribution data. Most of these types of

cascade systems are only used for stationary. But there is one

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device that was developed by the University of Southern

California that is commercially available that you can wear --

actually wear as a personal monitor.

Moving on down to the particle counters. We're getting

more into some of the time-resolved data now with the particle

counter and the nephelometer. You know, these are actually

electronic devices that provide real-time data, so you actually

get the time interval so you know when the exposures occurred.

And for the particle counter, you actually get the exposures as

a function of particle size.

The issue with the particle counter is the cost.

Obviously, with more data, the actual cost for the instrument

is a lot more expensive.

Another issue is that these are basically stationary

instruments. You know, these are 8, 10 pounds, and you

wouldn't be able to wear one for an extended period of time.

That being said, the University of Cincinnati is developing a

personal prototype that hopefully should be available in a few

years.

Then there's the nephelometer. It's the same type of

thing, but no size data.

And then you have these new devices called the -- which we

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have as the dual system. It collects with a filter and

provides the nephelometer data. And that's the RTI MicroPEM.

And I just happen to have one in my pocket, measuring my

personal exposure during my talk today.

Moving on to organic gases. Many different methods. You

can select the collection media based on what you're trying to

sample for. So you have the DNPH. That's a type of sorbent

media for aldehydes; activated carbon for PAHs and alkanes;

usually a filter and some sort of XAD or polyurethane foam for

semi-volatile organics; sodium bisulfite, specifically for

nicotine. And there are actually new devices coming out called

auto GC-MS units or VOCs.

All of these devices, except the auto GC-MS, you know --

well, actually the first two -- I'm sorry. The first two can

be run in passive mode or active mode. So passive mode means

it's just the little badges you see there in the pictures that

you actually clip onto your shirt. Or you can run in active

mode, which means you actually have to put it in a pump,

connect it to a pump. But those pumps are usually very large,

so they're only useful in a stationary mode.

The sodium bisulfite system for nicotine. It has been

used quite frequently historically, but there's a lot of recent

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data becoming available that is questioning its suitability for

measuring secondhand exposure to nicotine due to sampling

artifacts.

So for stationary measurements, basically you're taking

these instruments and you're putting them in a room and leaving

it at one place for an extended period of time. It can be an

exposure chamber or an occupied building.

I want to point out, one of the big cons with stationary

measurements is the exposure misclassification. That means,

just because it's stationary, it doesn't mean it's actually

measuring what someone is breathing. So if we had a stationary

system on the other side of the room, but I'm up here and

there's a strong -- and someone was vaping right next to me,

that system would not be detecting what I was actually

breathing.

Personal exposure assessment obviously is a more accurate

way to measure what someone is breathing. You know, that's

where you actually have to go out and recruit participants to

wear the aerosol and gas samplers for both either an exposure

study -- exposure chamber study or an observational study. As

I said, it's the most accurate assessment. You're actually

getting -- reducing exposure misclassification due to they are

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actually wearing devices.

But also if you design the system to be low burden,

especially like this middle system, where it's very lightweight

and very easy to wear, you can actually get people to wear the

devices for like up to 90% of the time they're awake.

But, again, these types of studies are rather expensive,

and also they require human studies research approval.

You can also do a combination of both, which is probably

the most representative exposure assessment. It actually

allows you to do some source apportionment, so identifying

where the exposures occurred, whether it's inside your home or

outside your home or in your car or at work or whatever. But,

again, these types of devices -- because you're doing both the

personal and the stationary type of monitoring, cost becomes an

issue.

So I did a quick survey -- not quick. I did a survey of

the literature looking for electronic cigarette exposure

studies, secondhand exposure studies, and I found two that have

been published in the literature.

One was Schripp et al. from 2013, very anecdotal, kind of

more of a proof of concept, you know, trying to see if there

was any exposure by putting one volunteer in a chamber where

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they just sequentially smoked -- used three types of e-liquids

in an electronic cigarette and one cigarette, conventional

cigarette.

As Andy said, it gets into the types of -- they did not

select the most appropriate experimental design, whether it's

the amount of e-cigarette emissions they generated or the

devices they used to measure the exposure. They only used six

puffs in a very large chamber, and they sampled for 15 minutes.

Their real-time formaldehyde detector, this AL4021, was not

meant for low levels of exposure assessment, so a lot of their

data was with a low detection limit. The good news about their

data is that their aerosol size distribution that they measured

does agree with several other studies that have been published

since.

The second study was Schober et al. from 2014. Here's a

summary of kind of what they did. This is a German study.

They did it in an office building with volunteers who had 2

hours of exposure over 5 different days. Their goal was, I

think, to determine if a potential exposure exists. Yes, it

does, in my opinion, based on their results. However, the

study was very underpowered and did not control for potential

exposure to other sources. That really limited their ability

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to attribute the air concentrations and the biomarkers they

found on their participants to the electronic cigarette

emissions.

Finally, one of our own studies at RTI that has not been

published, kind of looking at the spatial temporal distribution

of the secondhand exposures to electronic cigarette emissions.

This is a very anecdotal study, sort of a very low-budget, one-

shot deal just showing that secondhand exposures are very

transient, usually lasting less than 10 seconds, and that there

are also large spatial gradient concentrations within the room.

So basically, in conclusion, when you're designing a

secondhand exposure study, you know, what you want to do and

the type of instrumentation you use depends on what you want to

prove. Is it proof of concept? Does an exposure occur? Are

you looking at method development studies maybe looking at

biomarkers, for example? Fate and transport types of studies.

Exposure characterization looking at the different levels. Or

you go all the way and do a population-representative exposure

assessment.

A very important point is the last bullet -- and I'll

finish on that -- is that when you're designing and then trying

to propose an exposure assessment study, it's very important to

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consider the cost per data point. You can design a study and

propose something for $100,000, but you have to convince the

funding agency that if you can double that budget to $200,000,

you could probably get 10 times as much data.

Thank you.

(Applause.)

DR. DRESLER: Thank you. Good luck with that persuasion.

(Laughter.)

DR. DRESLER: Our next speaker is Dr. Mohamadi Sarkar from

Altria Client Services. So this is looking at ALCS Controlled

Clinical Study to Evaluate Constituents Released When E-vapor

Products are Used.

DR. SARKAR: Well, I'm happy to be here. I want to thank

the organizing committee and CTP for inviting me to participate

in this workshop.

As Dr. Dresler pointed out, my name is Mohamadi Sarkar.

I'm from Altria Client Services, speaking on behalf of Nu Mark,

which is an Altria company that develops and markets innovative

tobacco products, including e-vapor products for adult tobacco

consumers.

What I'm going to do today is share with you results of

studies that we have conducted to address many of the questions

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that FDA has posed for this specific session.

In a recent review, Dr. Chang, one of the FDA scientists,

did a nice job of summarizing the state of the science on

passive vaping and acknowledged that there's a paucity of data

on this topic. Dr. Chang also stated that a study addressing

and measuring levels of constituents during e-cigarette use

under different conditions would be highly informative,

particularly if the study was done with a range of e-vapor

products that are currently available. And we agree with that.

So what we have done is we have identified three main

questions that need to be answered. They are, what are the

levels of the constituents in a room where such products are

used? The second question is, what is exposure to nonusers?

And the third one, and probably the most important one, is that

if there is indeed measurable exposure, what is the potential

for harm to nonusers?

We've gone about trying to address this using a very

systematic approach. We started by constantly reviewing and

monitoring the published literature, but we've also generated

our own data. We've done three studies: two pilot studies and

one controlled study. Today I'm going to give you an overview

of the pilot studies and describe the controlled clinical study

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in greater detail.

As you heard from Dr. Rostami, my colleague at Altria, we

are also in the process of developing a computational model to

predict air levels under different use conditions. And then

ultimately what needs to be done, as the previous speaker

pointed out, that one needs to do a risk assessment by

integrating all the available evidence to determine the

potential for harm to nonusers. Today I'm going to just talk

about the studies that we have conducted and share the results

of the studies.

So the pilot studies that we ran were done with the

objective to evaluate the major chemical constituents in a room

where e-cigarettes were used. The second study was done to

replicate the first study. These studies were conducted in a

room which was compliant with the applicable U.S. building

codes and were conducted by our industrial hygienist in the

environmental safety group of the company, primarily to

determine the potential workplace exposure to the staff.

So we measured a number of these constituents using

sampling and analytical methodologies that have been

established by NIOSH for workplace air contaminants.

In this study, adult consumer participants were in the

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room evaluating various prototype e-cigarettes. The study was

set up in such a way that the participants were asked to take

six puffs. There were six 1-hour rating sessions over a

duration of 12 hours, and we conducted the air sampling over

the 12-hour duration for 4 consecutive days. The participants

were asked to take the six puffs, fill in a ballot, and then

move to the next sample. And depending on the number of

participants and the number of products tested, there was a

range of puffs from 200 to about 1,300 puffs per day. We also

conducted background measurements before and after the 4-day

period.

The total sample size for the first study was 183

panelists, and the second study, 165 panelists. The

participants were seated in the perimeter of the room, as you

can see in the schematic.

So what did we find? The results showed that the levels

of the constituents that we measured using the NIOSH analytical

method -- and as the previous speaker pointed out, it's

important to remember the analytical detection limits. So at

the detection limits of the NIOSH methods, these levels were

below the detection limit.

We also measured formaldehyde and that was found -- the

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levels of formaldehyde, which was measured under a similar

method, were within the background range.

So the overall conclusions from these two pilot studies

were that these measured chemical constituents were several-

fold below the current limits. Arguably, although the levels

were below the detection limit, even if we used the detection

limit as the maximum limit, these levels were several-fold

below the threshold.

And we have presented the results at many scientific

conferences, and the details are available at our science

website. We've also written this up as a manuscript and

submitted it to the Journal of Occupational and Environmental

Hygiene for publication.

So now let me talk to you in greater detail about this

third study, which I'm describing as the controlled clinical

study. This study had two objectives. The first objective was

to evaluate the exhaled breath, room air, and surface levels of

selected constituents following the use of various types of

e-vapor products as well as conventional cigarettes under

controlled and ad-lib conditions. The second objective, as my

colleague pointed out, was to generate input parameters for the

computational model.

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This was an open-label, single-center, observational

study. We targeted to recruit 40 participants that were

healthy adult males and females who were either e-vapor users,

tank users, or conventional cigarette smokers.

In this study, we tested four products. The first product

was a MarkTen Classic e-cigarette. The second was a prototype

GreenSmoke e-cigarette. The third were tanks where the

subjects were asked to bring their own e-liquids. And the

fourth group was of conventional cigarette smokers where they

smoked their own cigarettes.

And as I mentioned, we conducted three investigations:

exhaled breath, room air levels, and surface samples. Due to

the time limits, I'm just going to focus on the last two

endpoints.

So let me just describe a little bit about the background

of the study. This study was done in collaboration with a CRO,

Inflamax Research, which specializes in respiratory research.

And the reason we partnered with this CRO was that they have

this unique chamber, as you can see in the schematic, that is

being designed to do allergen research where they actually

release allergens in the room and the therapeutic agents for

the allergens are tested in this room. And these have been

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submitted and approved for FDA -- in clinical studies.

Now, this chamber is unique in the sense that it allows

you to constantly monitor the temperature, the humidity, and

the airflow in the chamber. Also, it has its own dedicated

HVAC system, as you can see from the lines leading into the

room, and this dedicated HVAC allows for accurate control and

precise control of the inflow and the outflow of the air from

the room.

Now, Inflamax set up this room at a site in North

Carolina, and they validated this chamber, as well as the

sampling of the room air was done through Enthalpy, which

specializes in air emission measurements. I don't know whether

you can see this, but there are some airflow monitors that were

set in the room. They were custom designed by the scientists

at Enthalpy.

This slide shows you kind of a bird's eye view of the

room. And the point I want to make from this slide is that we

set up four sampling manifolds for the air measurements, and

four surface sample measurements were taken at different

locations within the room. We also took one inflow air

measurement.

Now, remember I told you that we had four groups in the

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study, the MarkTen, GreenSmoke, tanks, and conventional

cigarettes. I'm going to use the MarkTen just as an

illustrative example to walk you through the sequence of events

that were taking place during the study.

So, on Day 1, after an air purge and taking background

measurements, we brought the participants in and took baseline

measurements without them using any product. These were

baseline measurements of the subjects in the room.

On Day 2, after additional background measurements, we

brought the participants in and asked them to use the product,

which was MarkTen in this case, under controlled use

conditions, which was they took 10 puffs, each a 5-second

duration every 30 minutes for a period of 4 hours. So a total

of 80 puffs were generated per participant. Now, the 5-second

duration was based on a topography study that we had published

previously, and that kind of represents the maximum use

condition.

After background measurements, we actually allowed the

participants to use the products under ad-lib conditions for a

period of 4 hours and to the same kind of -- the same

measurements.

On Days 3 and 4, we carried out similar measurements for

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the GreenSmoke prototype. On Day 5, we took the tank

measurements. Now, for the tank measurements, we only did the

ad-lib measurements and not the controlled use. And on Day 6,

we did the conventional cigarettes, once again under only ad-

lib conditions.

We collected several measurements of different

constituents, including nicotine, propylene glycol, and

glycerin, as well as about 15 carbonyls, including formaldehyde

and acrolein, and 12 volatile organics as well as trace metals.

Now, due to the time limits, I'm going to only be focusing

on the selected constituents of interest for today's

presentation.

So let me just show you the results. I want to first

orient you to the slide. On the y-axis you're looking at the

room air levels of nicotine -- this first slide is on

nicotine -- and on the x-axis the four different groups.

And I want to highlight one point that was made by the

previous speaker. The detection limit that you see on this

slide is set at 0.26. Now, this is much lower than the

detection limit of the previous study. Remember I told you

that in the two previous studies we didn't see any detectable

levels of nicotine in the room. Because that method was based

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on the NIOSH method, the detection limit for that was 15 µg/m3.

And because we wanted to generate data for the computational

model, we really pushed the sensitivity of the method, and if

you really stretch it and if you look hard enough, you will

find it, as was pointed out by Dr. Persily.

And you can see, from the results of the study, which is

showing the baseline controlled use and ad-lib use, that there

were no baseline measurements of nicotine because people are

not exhaling nicotine when they don't use the product. And

with the MarkTen, the levels were slightly above detection

limit, and low levels of nicotine were observed for the other

e-vapor products. On the contrary, the levels of nicotine with

cigarettes were about tenfold higher in the room.

So what do these levels mean? Just as a point of

reference and putting some context around these levels, if you

compare the nicotine levels in the room for the e-vapor

products against the permissible limit set by OSHA, these

levels were several-fold below that threshold.

This next slide is for propylene glycol, once again set up

the same way. The y-axis is the room air levels, and the

various groups are shown on the x-axis. Now, in this case we

measured -- we were able to detect baseline levels of propylene

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glycol, and you see a lot of variability between the groups.

Now, this is interesting because this suggests that we exhale

propylene glycol even without using any product. That's not

surprising because propylene glycol is a common food additive,

and it's found in many household products.

Interestingly, the levels of propylene glycol from the

e-vapor products were reflective of the proportion of propylene

glycol in the different products, with the tanks having the

highest level.

Once again trying to contextualize the results, now OSHA

does not have a permissible exposure limit for propylene

glycol, but there is a consensus limit based on the American

Industrial Hygiene Association set at about 10 mg/m3. And you

can see that these levels are several-fold below that threshold

limit.

This next slide is on glycerol. Once again we are set up

the same way. The y-axis is the room air levels, and the

different groups are shown in the x-axis. And if you try to

compare the baseline controlled use and ad-lib use for the

e-vapor products, similar to what we saw with propylene glycol,

the levels are proportionate with the levels that you would see

in the products, and the tanks having the highest levels.

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There were no measurements in the cigarettes, probably because

it gets combusted, and if you compare with the OSHA limits,

several-fold below for the e-vapor products.

The next series of slides I'm going to show you are

formaldehyde. And, once again, referring back to Dr. Persily,

that formaldehyde is omnipresent, if you look at the levels or

the 6-day duration of the study, you see a lot of variability.

But, nevertheless, measurable formaldehyde levels were

found in the room without any people present in the room. And

note the variability then on some data points on Day 2 are

higher than the others.

Now, if you superimpose the results for the different

usage period, whether it was under controlled use or ad-lib

use, they were all within the background levels. And just to

compare it against the cigarette, you see that it was

significantly above the background. And that was one of the

main reasons we had used the cigarette group, was to include it

as a reference to demonstrate the sensitivity of our detection

methods.

And if you then contextualize the levels of the e-vapor

products against OSHA limits, they were several-fold below the

threshold set by OSHA.

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Now, the last set of results that I want to show you are

for the surface sample. Just a reminder that we had four

different stations where we measured the surface levels of the

constituents.

And this is the result for nicotine. We were able to see

slightly above detection limits on two of the surface samples.

Now, I can't sit here and tell you whether these are real or

whether they are artifacts of experimental collection

techniques. But, nevertheless, 22 of the 24 samples were below

detection limit over the duration of the study, including the

ones for cigarettes.

So, in conclusion, what we can say based on the three

studies that we have conducted under the study conditions and

with the products tested, the room air levels of the

constituents were several-fold below the threshold set for the

exposure limit.

And based on the results of the surface sample analysis,

the evidence suggests that the thirdhand exposure of non-

exposures [sic] to nicotine is unlikely.

Now, you know, we saw that we were able to see measurable

levels for the different constituents if you truly stretch the

analytical limits. Now, how does that translate into actual

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exposure to nonusers? Well, I think that based on the

biological variability and the other sources of exposure, I

don't know whether we would be able to differentiate that.

But, nevertheless, further research would be needed to

definitively determine the exposure of these constituents in

nonusers under different conditions. And then, of course, the

risk assessment needs to be done to evaluate the potential for

harm with this level of exposure.

And that's about where I end. Thank you very much for

your attention, and I'll be ready and happy to answer any

questions.

(Applause.)

DR. DRESLER: Okay, we will take some clarifying questions

from your cards. If you can write on your cards and pass those

to the sides, we'll spend a few minutes with clarifying

questions and then a break, and then we'll continue with this

session with further speakers. Thank you.

Dr. Persily -- Dr. Sarkar. I'm sorry, this is for

Dr. Sarkar. Dr. Persily stated that it is important to

understand building ventilation when studying airborne

emissions. Did you measure ventilation in the pilot studies

and the controlled clinical study?

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DR. SARKAR: Yes. So, in the pilot study, as I said, it

was conducted in a commercial building, and we did measure the

airflow exchange rates. And in the controlled clinical study,

of course, since we were able to measure this in a very precise

way -- because remember I told you that there was a dedicated

HVAC in it where the inflow and outflow could be measured. So

yes, we did measure that.

DR. DRESLER: Okay. You must have explained it so well,

guys.


DR. DRESLER: Oh, they're writing. Okay.

UNIDENTIFIED SPEAKER: Yeah, we're still writing legibly.

DR. DRESLER: Oh, legibly. Yes, please, that will be very

kind.


DR. DRESLER: Okay.

Considering the recent concern about nanoparticle

generation in e-cigs -- I'm going to guess that that's e-cigs

-- how do we measure and assess this risk? So considering the

recent concern about nanoparticle generation in e-cigs, how do

we measure and assess this risk? So nanoparticles.

UNIDENTIFIED SPEAKER: Is that directed to someone?

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DR. DRESLER: I'm sorry?

UNIDENTIFIED SPEAKER: Is that directed to someone?

DR. DRESLER: No.

UNIDENTIFIED SPEAKER: It's a panel question. Save it for

a panel.

DR. DRESLER: Oh, save it for a panel. Okay. You guys

are off, so you have a few minutes to think about that one,

okay?

Dr. Persily, how does formaldehyde release from furniture

compare to e-cigarettes? So formaldehyde measured that's in

the room at baseline anyway. So how does the release from

furniture compare to e-cigarettes?

DR. PERSILY: For me?

DR. DRESLER: Yeah. I'm sorry, I was looking at him.

Sorry about that.

DR. PERSILY: I mean, that's a really good question, but

you know, I don't really have an answer. You know, the amount

of formaldehyde emitted by the piece of furniture depends on

what it's made of and its history and the temperature and the

environment. And whether that's higher, lower, or the same as

an e-cigarette is just -- you know, there are too many

variables to just give a simple answer to that. So I'll give a

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short but not simple answer.

DR. DRESLER: Okay. Maybe it will come out more in the

panel, too.

Dr. Sarkar, this one is for you. Can you please provide

details about your study participants? Were they e-cig users?

If so, what type? Conventional product users?

DR. SARKAR: So, you know, we're going to present these

results at an upcoming TSRC meeting, and we're going to publish

this. So the details of the study --

DR. DRESLER: What's a TSRC meeting?

DR. SARKAR: The Tobacco Science Research Conference

meeting.

But, generally, if you remember the slide that I showed,

we targeted 40 participants. Twenty of them were regular

e-cigarette users. They had used e-cigarettes in the past 30

days. Ten of them were tank users, and 10 of them were

conventional cigarette users.

DR. DRESLER: Thank you. You used a 30-minute interval.

Did you mean 30-second interval? Again, Dr. Sarkar, this is

for you. Thirty-minute interval or a 30-second interval?


DR. DRESLER: Yeah, I don't know either.

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DR. SARKAR: So the controlled puffing conditions were set

where the participants were asked to take 10 puffs, each a 5-

second duration, and these 10 puffs were repeated every 30

minutes over a period of 4 hours.

DR. DRESLER: Oh, the next one is for you too.

Formaldehyde data from aerosol from electronic cigarettes was

interesting, but were there any chemicals of concern that you

saw above background levels? So you presented data, I think,

you had at the top, right? That's the information that you

presented. It was nicotine and formaldehyde and --

DR. SARKAR: Propylene glycol.

DR. DRESLER: Thank you. So did you find anything else

interesting?

DR. SARKAR: So there were lots of constituents that we

measured, and I don't have the data with me in front of me.

But, generally, most of these constituents were below detection

limit when the e-vapor products were used, and of course a lot

of them were above detection limit when cigarettes were used,

which was the purpose of including the cigarette as a reference

group. There were occasional sporadic measurements for acetone

at slightly above levels. That's what I remember. But, once

again, I think it's worthwhile to wait for the publication.

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Once we write this up and publish it, you can get all the

details in the publication.

DR. DRESLER: Okay. I'm sorry, don't sit down.

(Laughter.)

DR. DRESLER: Are you ready for this longer one? Okay.

And -- okay. Do you really think -- so that's always something

when it starts out that way. Do you really think occupational

exposure guidelines are appropriate for assessing the exposure

to nonusers in an office space? IAQ -- do you know what IAQ is

as an initial?

DR. SARKAR: Indoor air quality.

DR. DRESLER: Oh, thank you. That's very good. All

right, indoor air quality researchers typically use 190 of --

1% of occupational exposure guidelines. Your ACGIH guideline

for propylene glycol exceeded 300 µg/m2, which is three times

1% of what is in the guideline.

DR. SARKAR: I was going to say, maybe we should save that

for the panel.

DR. DRESLER: Do you want to? That sounds good.


DR. DRESLER: Okay, that sounds good.

All right. Yeah. And this one I'm going to save for the

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panel too. I think that's a good one for the panel.

So break time. Okay, so 15 minutes. So let's make it 17

minutes and come back at 10 o'clock, okay?

Thank you.

(Off the record at 9:44 a.m.)

(On the record at 10:02 a.m.)

DR. DRESLER: Shall we gather back together, please?

Okay, welcome back.

We're going to continue on with this first session that is

on Exhaled E-Cigarette Aerosols: Evaluation of Constituents and

Exposure. And our next speaker is John Pritchard from Imperial

Tobacco from the UK, speaking on the Assessment of Indoor Air

after E-cigarette Use: Modelled and Experimental Findings.

MR. PRITCHARD: Thank you very much. Okay, good morning.

I'm John Pritchard from Imperial Tobacco Limited, UK, and I

thank the FDA for this opportunity to talk here today. My

presentation is entitled Assessment of Indoor Air after E-

cigarette Use: Modelled and Experimental Findings.

Okay. So let me begin by stating that the work we

conducted was supported by Imperial Tobacco Limited, UK. By

way of reference, Imperial Tobacco Limited, through its wholly

owned subsidiary Fontem Ventures, manufactures and sells a

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range of e-vapor products, that is, e-cigarettes, in the UK and

elsewhere in Europe.

And I'll use the term e-vapor products, or EVPs, through

the talk, since the product category is broader than simply

e-cigarettes. And today I'll cover some of our work in this

area.

We acknowledge and are extremely grateful for the input

provided by the independent external laboratories who helped

design and conduct the experimental work that we undertook, as

well as the contribution of our coworkers at Imperial Tobacco.

Okay. So today I'll provide a brief context for this

talk, give an overview of our mathematical model, which was

developed to evaluate constituents in ambient air following

e-vapor product use. With regards to the experimental data,

we've conducted studies which directly assess the source of

e-vapor product emissions into ambient air, that is, the

exhaled air immediately after EVP use. I will also present an

indoor air quality assessment made in a small office space

before, during, and after EVP use. And nicotine has been the

focus of some discussion on the topic of potential secondhand

exposure. And I'll report early findings from a study in this

area and relate this to potentially thirdhand or tertiary

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exposures following EVP use. And, finally, I'll give a

summary.

So context for the talk today. It's been reported by

Action on Smoking Health UK last year that as many as 2.1

million British adults currently use e-cigarettes and e-vapor

products. In a report last week, this has increased to 2.6

million consumers. Two-fifths are ex-smokers; three-fifths

report using both EVP and cigarettes.

With increasing prevalence of e-cigarettes, there's a

growing discussion amongst public health organizations and the

scientific community as to whether the aerosol exhaled from

such products has implications for the air breathed by

bystanders through so-called passive vaping, akin to that which

has been reported for environmental tobacco smoke from

combusted tobacco products. Given the recent emergence of

EVPs, the scientific research in this area is burgeoning. And,

to date, a range of approaches have been applied to assess

different products using different methodologies and under

different study designs and conditions, and as a result, it can

be difficult to compare results of the studies that have been

undertaken.

It has been reported that the common components of

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e-liquids -- so nicotine, propylene glycol, glycerol -- may be

released into the air during the use of e-cigarettes, as well

as compounds including carbonyls, polycyclic aromatic

hydrocarbons, and trace metals. And to investigate the topic

we've taken two approaches, mathematical modeling and

experimental studies.

So mathematical models have been widely used to

investigate a range of potential exposures in the workplace or

public spaces. And, furthermore, it's a flexible approach

allowing investigation of the effect of different parameters,

different scenarios, or environmental conditions. We developed

and published a mathematical model to explore the potential

levels of nicotine from a bystander perspective in an office

environment. The full details, such as the formula applied,

are available through the QR code or at this reference given

here. And I'm going to give an overview of the key points of

interest.

So model output: single puff profile. The model may be

used to predict indoor air concentrations of chemical

constituents based on successive steps or puff phases. So

following exhalation of a single puff, a profile of nicotine

concentration in ambient air at the bystander position can be

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derived from the model shown here.

So, in Phase 1, the e-cigarette user takes a single puff

and inhales the nicotine-containing aerosol, and then the user

exhales this into the indoor air, and this is dispersed in all

directions. And here the bystander is not yet exposed to the

aerosol.

In Phase 2, the bystander's peak exposure to exhaled

nicotine in the air is observed, corresponding to the time the

exhaled aerosol reaches the position of the bystander and

dispersion of the exhaled vapor in the indoor air is not yet

complete.

In Phase 3, there is a reduction in the concentration of

nicotine at the position of the bystander due to dispersion,

dilution of aerosol in the air, and any potential surface

deposition. And it is assumed that air extraction starts when

80% of the room volume is filled with the exhaled aerosol.

In Phase 4, mixing of the exhaled aerosol in the ambient

air is complete, and the concentration of nicotine is reduced

by the air extraction and any further surface deposition. And

there is a further reduction in the concentration of nicotine

at the bystander position.

That's a single puff profile. Let's consider repeat

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product use.

So here we can illustrate the flexibility of the model

approach in the scenario described. Two employees are working

in the same office. One is an e-cigarette user and makes one

puff every 5 minutes, inhaling 60 µg of nicotine per puff and

exhaling 30 µg of nicotine per puff. So a 50% retention rate

there.

The room size: 50 m3. The air exchange is 1.33 air

changes an hour. And that generates movement to convection,

which makes an exhaled puff fill the room in around 5 minutes.

The other employee is not an e-cigarette user. They're

seated 2 m from their colleague and spend 8 hours at work

together. And here's a 1-hour lunch break as well. As you can

see, in the computer simulation that's running in the

background here, there's an increase in the ambient

concentration following successive exhalations over the morning

period, and the maximum concentration is reached when the

exhaled aerosol emission rate and the air extraction rate are

equal.

And what we see then is a rapid decrease in the room

during the lunch break and an increase with recommencement of

vaping in the afternoon. And in this scenario, the maximum

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concentration of nicotine in the ambient air over the working

day is 1.8 µg/m3. And by way of context, the UK 8-hour

workplace exposure limit, as well, is at 500 µg/m3.

Okay. Great. I'd like to show an additional capability

within the model. So what you can also do is to consider the

contribution of each of the parameters on the level of nicotine

in indoor ambient air, and therefore potential bystander

exposure.

So here we examined the collective effect of varying --

all of the five parameters concurrently over an 8-hour working

day in the scenario we gave in the previous slide. And the

dataset was generated by assigning each parameter a value of

low, medium, and high, which resulted in 243 unique modeled

scenarios at 3 to the 5, which collectively predicts the range

of average nicotine concentrations in ambient air over 8 hours

in the workplace.

And in reviewing the data, perhaps unsurprisingly, the

most important model parameter identified here was found to be

the quantity of nicotine exhaled. Therefore, it is essential

that precise measurements are made regarding the quantity of

nicotine exhaled or retained by the e-cigarette user, when

determining potential bystander exposure in exhaled e-cigarette

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aerosol.

The second approach we took was an experimental one, and I

will now present some of our work in this area.

Okay. We have conducted studies that consider EVP at

source, that is, the exhaled air, and also the potential impact

of e-vapor products on indoor air quality. The details of the

indoor air quality study are published in an open-access

journal and are available through the reference given here, or

for those with technology at hand, the QR code.

Okay. So I'd just like to show this here. Let's look at

the exhalation at source. And this row was presented at the

SRNT meeting here in the U.S. earlier this year. And here we

investigated, in real time, directly exhaled air following a

single puff on an e-vapor product, and we also considered

conventional products by way of comparisons.

The technique here, proton-transfer-reaction mass spec,

has been previously used for exhaled air analysis in other

industries and other settings. It has the advantage that no

sample preparation is required, and measurements can be made on

a per-puff basis. And this gives a clear snapshot and reviews

the technique published elsewhere.

What we see here are mass spectra comparing exhaled air

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analysis following a single puff from a conventional cigarette

and an e-cigarette. And it's clear that the aerosols are not

equivalent, with the data showing how complex the combustion

aerosol for a cigarette is when compared with the aerosol

generated from heating a simple liquid phase.

And this study considers the initial exhalation without

dilution. Well, then, the ambient air impact from successive

puffs were indeed the effects from multiple users in a typical

indoor space.

So, as noted earlier, there are several studies that

report different findings within EVP aerosols, and using these

publications, we looked at the chemicals highlighted in these

reports and conducted a comprehensive screening under a

realistic scenario in a small office space. Findings are

reported against relevant exposure values and were published,

including UK workplace exposure limits. And to replicate a

real-life scenario, we conducted an assessment of indoor air

quality before, during, and after e-vapor product use.

The study was conducted in an independent, accredited

laboratory in the UK, with expertise in indoor air quality

assessment. A small unoccupied office was available at the

laboratory for this study, which was furnished for a typical

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business meeting and fitted with a range of sampling and

monitoring equipment, with samples collected in an adjacent

room.

The schematic illustrates the office space and sampling

arrangement where five individuals were seated in the office

space, arranged around the table. Three participants were

experienced e-vapor product users and two were nonusers.

The volume of the room was 38 m3 with a measured air

exchange of 0.8 air changes per hour. For context, the UK

Chartered Institution of Building Services Engineers state that

such a space should have at least one air change per hour. So

the findings from this study were likely to represent an

overestimate.

Doors and windows remained closed for the duration of the

study, and there was no entry or egress from the room by

participants. And there was no mechanical ventilation or

recourse to cooling, and the sampling schedule was as follows.

Okay. In conducting such a study, it's essential to

establish adequate baseline data. To that end, measurements

were taken of the unoccupied office and also once the office

was occupied by the participants, but before product use. The

product used in this study was a closed-system disposable

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product containing 16 mg of nicotine in a propylene glycol and

glycerol base, which is a common product confirmation in the

UK.

And I'll present the key findings from the chemical

analyses. Further details are given in the publication.

So the first two chemicals that we'll go through are

propylene glycol and glycerol, principal components of

e-liquid. And as expected, PG, or propylene glycol, increased

with vaping and dropped at the end of the vaping period. For

glycerol, which was also expected to show similar changes over

the study phases, the method was not as sensitive as

anticipated. Nonetheless, in both cases, measured levels were

substantially lower than the UK workplace exposure limit.

So carbonyls. Carbonyls have been reported in the ambient

air following e-vapor product use, and it's been reported that

a potential source of these compounds is the heating process of

propylene glycol. Formaldehyde changes across the different

measuring periods remained substantially lower than the indoor

air quality guidelines established by the World Health

Organization in all measurements. And this is consistent with

other data in the literature shown on the right.

Similarly, for acetaldehyde, we saw changes across the

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different measuring periods. And as with formaldehyde, these

remained substantially lower than the European Union indoor air

quality guidelines. And, again, this is consistent with other

data in the literature.

Okay, so other chemicals. A further part of the screen

loss considered other chemicals. We saw no measurable increase

of any of the U.S. EPA Priority 16 polycyclic aromatic

hydrocarbons. By way of context, the LOD there is of less than

1.25 µg/m3 compared to the U.S. OSHA PEL of 200 µg/m3.

So, for metals, air samples were taken on filter

assemblies and analyzed for the U.S. EPA Method 29 metals plus

aluminum and phosphorus. We did not identify any increase in

metals or metal particles in any of the air samples taken, and

all samples were below the respective UK workplace exposure

limits, where established.

Acrolein has been reported as a substantial breakdown

product from the heating of glycerol, and in our work there was

no measurable increase of acrolein, which corroborates other

findings in the literature.

With regard to tobacco-specific nitrosamines, there was no

measurable increase in any of the samples.

Okay. So nicotine is present in most e-liquids, and in

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our study there's no measurable increase in the airborne

concentrations of nicotine with vaping.

Several studies have looked for the presence in ambient

air using different experimental approaches, and where

detected, this has been at levels below the UK workplace

exposure limit. The low level measured in this study and

elsewhere is of interest and may be attributable to the high

retention rate of nicotine by the user, which has previously

been reported following inhalation for tobacco smoke. And

further e-vapor product research in this area will be

informative for us in seeking to explore this further. And

we've also conducted nicotine retention investigations.

So here we show a novel approach to determine nicotine

retention, and this recent work is in preparation. By

determining the quantity of nicotine inhaled and the quantity

of nicotine exhaled, retention rate can be determined. And

it's well known, as I said, that nicotine is retained with high

efficiency with conventional combusted tobacco products and

other nicotine-containing aerosols, up to 99% in cigarettes.

And here we found the nicotine retention used in a closed-

system product to be around 98%. And this high retention may

account for the low measured levels in our air quality study

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and other studies and shows the importance of not relying on

smoking machines when looking at potential bystander exposure.

And with this mind, let's now consider potential tertiary

exposure from exhaled e-vapor aerosol. Okay. So I think we're

going to hear a little bit more on this later on, so just very

briefly here.

So the main point here is the impact that different

methodologies and experimental designs could have in the

evaluation of potential thirdhand exposure. So we can see

here, on the one hand, machine-generated aerosol, a chamber

study where necessarily, as a machine, there won't be

retention. There's 100% emission.

And then we have -- in our evaluation of thirdhand

exposure in a study on the different materials, we can see the

presence of nicotine. Compare this with the real-world study

using vapors in their own homes, high nicotine retention. And

then a really good question of thirdhand exposure. There's no

significant difference between the homes of those that do not

smoke and do not vape compared with those that use electronic

cigarettes.

Okay. So, in summary, our model offers -- it went ahead

again. Okay. This is very sensitive. Okay, I think we're

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there. Our model offers a flexible approach to explore

potential bystander exposure under different conditions and

scenarios. Model outputs are comparable with the published

experimental data.

And inside the model, the quantity of nicotine exhaled is

an important factor, and therefore precise measurements need to

be made when looking at this area. And the experimental data

indicates high retention.

And inside our study, any additional chemicals in the

ambient air from exhaled EVP aerosol are unlikely to present an

air quality issue when compared with regulatory standards, and

a clear need for further research in this area to support the

development of appropriate product standards and other science-

based regulatory measures.

And from the currently available literature, thirdhand

exposures in real life are unlikely to be an issue for

bystanders, and more research in this area will be informative.

Thank you all for your attention this morning. Thank you.

(Applause.)

DR. DRESLER: Okay, our next speaker is Francis (Bud)

Offermann, who is from Indoor Environmental Engineering, and he

will be speaking on Chemical Emissions from E-cigarettes:

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Direct and Indirect Passive Exposures.

MR. OFFERMANN: Thank you. Well, I want to thank you for

granting my request to come and share our research here. I

thank Dr. Persily for letting me sleep in his basement last

night.

(Laughter.)

MR. OFFERMANN: I'm going to talk a little bit about a

study I did. Or, actually, used Maciej Goniewicz's data, but I

have some new data to share with you.

Indoor Air is a conference that happens every 3 years. It

was in Hong Kong last summer, and I was amazed that there

wasn't a single paper on e-cigarettes there. So I told the

conference coordinator, I said, I know it's only a month away,

but I'm going to put together a paper on a hazard assessment,

both direct exposure and indirect exposure to chemicals emitted

by e-cigarettes. So the right one is the front one.

Okay. So we're looking at the chemical emission rates

through the literature for direct exposure for the e-cigarette

user and the indirect passive exposure.

All right. So I used Maciej Goniewicz's data at the time

that I did this. And, boy, the field is really evolving fast,

right? So back last summer, this was deemed the best, largest

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study of chemical emissions from e-cigarettes. Eleven

chemicals were measured. He used 150 puffs. They were 1.8-

second 70 mL puffs. He did carbonyl compounds. We, at least,

analyzed the data from his carbonyl emissions, volatile

organics, tobacco-specific nitrosamines, and heavy metals.

So let's look at what we've got here. And I am going to

share a little extra data here. As you can see, the big guys

on this are the propylene glycol, right? And that is a big

issue. And I think we need to talk more about not carcinogens

all the time, but the immense amount of oil of nano-sized

droplets filled with flavorings and stuff that go deep into the

lungs. That's the big one. Nicotine, not surprisingly, is the

next biggest item. And then there are these aldehydes, and

there's been a lot of talk about the carbonyl formations,

formaldehyde and aldehydes from thermal oxidation in the

e-cigarette.

For formaldehyde, the Goniewicz study had a maximum of

56.1 µg in this 150-puff sample. We kind of know now,

recently, that most of the formaldehyde, more than two-thirds

of the formaldehyde, is not in the particle phase, which the

sampler that was used in this study was designed to catch

mostly the vapor phase. So two-thirds is in the particle

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phase.

We developed a sampler and did QA/QC on recovery and

stuff, using DNPH on silica gel, but with a very fine mesh

size. And we were worried about if you put so much oil into

that DNPH sampler, could we get good analytical recovery? And

we did. We got 99%. And in our study, just for comparison,

our median was 200 µg for 150 puffs, and our maximum was 2,233.

Oh, I'm sorry. I'm sorry, 555 µg for formaldehyde and 1122

maximum.

For acetaldehyde, the maximum in the Goniewicz study was

13.6, and we had a median of 200 and a maximum of 2,223.

So one of my conclusions is that a lot of people are

measuring the formaldehyde emissions with techniques that

under-measure it. And I also think the same thing applies to

nicotine, and we'll get on to that.

So these are the players, these are some of the big

contaminants. Of course, I think we need more research on what

the real usage per day is. I used Etter's data, self-reported.

I think we can do better than self-reported. Dr. Goniewicz has

an excellent study that's going to come out. I will use that.

But for now I'm using 175 puffs per day. Dr. Farsalinos says

600 puffs per day is average. I don't know. But I used 175

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for direct.

Indirect exposure. We had -- this is worst case -- a

small space, 0.3 air changes an hour, one user and one nonuser.

For the cancer health effects, we're using the OEHHA

CRELs. Non-cancer effects -- I mean, for the cancer effects,

we're using the OEHHA NSRLs. So, for formaldehyde, it's 40 µg

a day. For the non-cancer effects, we're using the OEHHA

chronic reference exposure levels, the CRELs.

For the nicotine and propylene glycol -- and we talked

about detection limits and occupational standards. We

certainly think there's no place for occupational standards

really in assessing exposure to nonusers, like in an office

space. That's just not right. We used 1% of the PELs when we

didn't have a CREL.

And I will note that if you take compounds, 13 compounds

that have CRELs and have OEHHA and have PELs of exposure

guidelines, it's about 1% of the exposure guideline is the

CREL. So, indeed, you know, when we have children and

sensitive people, we need to have lower exposure guidelines

than occupational guidelines.

Now, what I'm going to show you in the next thing is

hazard quotients. It's easier because you don't have to look

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at the number and then look at the guideline for exposure. It

boils it into one thing. A hazard quotient is the exposure in

micrograms per cubic meter divided by the exposure guideline.

So here we are for the direct. This is the person that's

smoking or vaping. Or, really, it's not vapor, right?

Aerosolizing. The big one, of course, is -- the biggies are

propylene glycol, hazard quotient 967; nicotine 222; diacetyl

butter flavorant -- so we heard talk earlier today about the

flavorants -- 2,720. I mean, these hazard quotients are off

the charts. Formaldehyde, 1.6. But, of course, if you take

the formaldehyde measurements that we're measuring, 32.2. This

is for the user.

Now, if we go to the passive exposure, the primary things

are propylene glycol, hazard quotient 23; nicotine 5.4. And if

you look at the last speakers, the gentleman from Imperial and

the gentleman from Altria, if you use 1% of the OSHA

guidelines, their measurements show there's an issue for the

passive exposures for propylene glycol. And then diacetyl, of

course, the butter flavorant, at 63. So those are the -- and

there's no -- these were all that we saw over here. The blues

are cancer. The CRELs or hazard quotients exceed the cancer

guideline. And the red ones are the non-cancer.

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For the nonuser in the office space -- worst case -- we're

not really seeing hazard quotients for the cancer-causing

compounds so much. It's the propylene glycol.

I think the aldehyde emissions from Goniewicz -- but not

just Goniewicz, but other people that are using DNPH on silica

gel -- you can see the aerosol go right through the sampler,

and we know that most of the formaldehyde is dissolved in the

liquid aerosol droplets.

Also, I think we're all using a smaller number of puffs.

I used Maciej's data. He was using 150 puffs. I believe he's

using less puffs now. But we wonder about how much oil, if you

put in that much oil into a sampler, how effective it can be.

The aldehyde emissions are believed to be, of course,

primarily from the result of oxidation of glycols and -- let's

see if I can get to here -- we think that the formaldehyde

emissions reported by others are about a factor of three low.

We were wondering why our samples had so much higher emissions,

and I think I know now.

The DNPH for the tobacco industry that's using CORESTA

methods within impingers, the aerosol goes right through these

impingers. It's going to underreport. And measurements by

Giese collected the particles first and then the vapor onto

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DNPH, and his measurements were very, very, very low. Again,

most of the formaldehyde -- and I didn't think myself,

formaldehyde is extremely volatile. Who would think it would

be in the particle phase? But it is.

All right, nitrosamines. I won't talk too much about

that. When they do find themselves in e-cigarettes, of course

the nicotine is extracted from tobacco, and there's some

carryover.

Regulation. FDA, we need some regulation. I mean,

literally, there are people mixing stuff up in their bathtubs.

This industry needs to be regulated.

Flavorants. Again, I speak to the FDA. You're being

abused or misused when they cite "generally recognized as safe

by the FDA." That's for ingestion, right? So inhaling these

things and then for the companies to say the FDA approved it, I

think that's not right.

The propylene glycol. This would be the amount of

propylene glycol. And, remember, these are nano-sized drops,

right? So this liquid propylene glycol, nano-sized drops with

nicotine flavorants and formaldehyde that goes deep into your

lungs for the average user in 1 year.

So I know there's a lot of attention to the carcinogens,

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but the immense amount of oil, all for the purpose of just

emulating that tobacco-smoking experience, if you really want

to make a true-sensation nicotine delivery device, I don't

think trying to emulate the tobacco experience is the way to

go, and I think this is a big issue.

Conclusions. E-cigarettes, they do emit many harmful

chemicals. The industry, I think, has backed down a little

bit, but not long ago it was it's just harmless water vapor.

Some of these are carcinogenic, such as formaldehyde, the

metals, and the nitrosamines that are carried over from the

nicotine extraction.

In addition to posing health risks to the users, the

emissions of glycol and nicotine from e-cigarettes pose a

significant health risk to nonusers. So I think we need to

think about those things. And the emissions of formaldehyde

and nicotine need to be examined for both the particulate phase

and the gas phase.

If you really want to know this and you go back to what we

did as researchers on tobacco, on combustion cigarettes, we

used denuders to determine precisely what the phase

distribution is of these chemicals, and that's what I've

suggested to CDC and FDA is that this research get under way.

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E-cigarettes need to be regulated in the same manner as

tobacco smoking. Dr. Persily talked about ASHRAE, the American

Society of Heating, Refrigerating, and Air-Conditioning

Engineers, and they have now adopted into their ventilation

standards, which are the model for the country, no e-cigarette

usage. The ventilation rates are not adequate to protect

people in offices when you have e-cigarette use. So that's

good.

Consumers should be warned, right, that while the health

risks associated with e-cigarettes are probably less harm

reduction -- probably, maybe, we hope -- this is an epi study,

I guess, going on. We'll see. That's a lot of oil. I'm not

sure, but I'm sure it's less. There remain, of course,

substantial health risks associated with the use of

e-cigarettes. It probably is less than combustion cigarettes.

So that's all I have to say. Thank you very much.

(Applause.)

DR. DRESLER: Yeah, we can get those afterwards.

MR. OFFERMANN: Yeah.

DR. DRESLER: Thank you. Unless you want to drink them,

Maciej.

(Laughter.)

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DR. DRESLER: Okay, our next speaker is Dr. Goniewicz from

Roswell Park Cancer Institute, and he will be speaking on

Nicotine Residues in Houses of Electronic Cigarette Users,

Tobacco Smokers and Non-Smokers.

Maciej.

DR. GONIEWICZ: Thank you so much. Thank you for the

invitation.

This is my disclosure. And I want to add that I'm not an

employee of FDA, even though I'm speaking third time on the

third workshop on electronic cigarettes. But thank you so much

for the invitation. It's a glad pleasure and honor to be here.

So we heard yesterday that some of the marketing

strategies for the electronic cigarettes -- from the electronic

cigarette industry -- are actually targeting of the use of the

electronic cigarettes in indoor spaces, whether it's a bar,

it's a home. But you can find some of the advertising

materials showing the message that this product is safe to be

used indoor and can be used indoor. And actually some of the

owners of the bars and clubs encourage using electronic

cigarettes.

And just a little story. I was offered the electronic

cigarettes in one of the bars in Washington, D.C., to try. I

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didn't do it, but I was approached by one of the companies.

So there are some controversies whether we should allow

using electronic cigarettes in indoor air. However, there is a

risk associated with being passively exposed to vapors from --

to aerosols emitted from electronic cigarettes or not. And I

think we try to contribute to this research and try to answer

some of the urgent questions.

When you look at the users, when you look at the smokers,

whether they support the indoor ban on electronic cigarettes, I

only found one study published in the literature, and this is

the study of the almost 300 current or former smokers, and it

was a survey, cross-sectional survey. And what they found is

that the support for indoor bans varied by product type. So

even though the majority of the samples were smokers, they

strongly supported a restriction on cigarette smoking in homes

and workplaces.

But, in contrast, participants were significantly less

supportive of complete or even partial restriction of

electronic cigarette use in either home or workplace settings.

Minority of smokers and former smokers endorse at least

partial indoor ban on electronic cigarette use. And there was

some predictors for being supportive for the ban. So being

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younger, single, and with the lower income, participants were

less supportive of complete bans of both products, electronic

and tobacco cigarettes.

So just a simple model of the secondhand smoke and the

secondhand aerosol, why they are different, what you might

expect that the differences in exposure.

So the secondhand smoke emitted from tobacco cigarettes is

a byproduct of active smoking. So there is the sidestream

smoke, which is a very significant contributor to the

environmental tobacco smoke, and this is the smoke that's

emitted between puffs. So when the smoker is not puffing on

tobacco cigarette, the cigarette is still burning, and there is

smoke emitted from the tobacco cigarettes. We call this

sidestream smoke. There are some compounds. There is some

smoke diffused through the cigarette wrapper, and there is

exhaled mainstream smoke and the smoke escaping through the

cigarette mouthpiece.

And when we compare this with the electronic cigarettes,

we actually eliminated the first two components of the

sidestream vapor, sidestream aerosols. So there was no

sidestream smoke because, when the user is not operating the

electronic cigarette, nothing is emitted from the device, or

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maybe negligible fraction. We should not see compounds

diffused through the cigarette's wrapper.

But when we look closely at the user of the electronic

cigarette, we can see that some of the aerosol is exhaled. And

depending on the product, depending on the user, depending on

the product characteristic composition, we see some variations

in the amount of the aerosol that is exhaled by the user. So I

think the users and the product will be the first very

important variables that will affect the secondhand exposure to

any chemicals from electronic cigarettes.

And when we look at the very simple model, you know, of

what's going on with any chemical that is present in the

electronic cigarette -- and let's take nicotine. What's going

on with the nicotine? So if we have nicotine in the vapor and

part of the vapor is exhaling, if the nicotine is not

effectively absorbed in the lungs, is retained in the lungs --

we saw some data showing that it is. It can be absorbed. And

the nicotine that e-vapers puffed showed that at least some of

the devices are very effective in delivering nicotine. But,

again, if we have the device that does not really provide the

nicotine doses to the users, then part of the nicotine will be

exhaled with the aerosol.

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So we will have the nicotine in indoor air where we will

be able to detect the chemical in the indoor air. And then we

will have a lot of dynamics going on in the air. So we might

observe the deposition of the chemicals on the surfaces.

And the first study that we conducted was to find out

whether the nicotine can be released from electronic cigarettes

and can be found in indoor air. So we recruited the dual

users. We were looking for the people who are using electronic

cigarettes but also continue to smoke tobacco cigarettes. And

we asked them to come to our lab and sit in an exposure

chamber.

First, we took background measurements, and we wanted to

make sure that nothing is there because the exposure chambers

are used for many experiments, so we want to make sure that we

don't have any background levels. And then we asked them to

use electronic cigarettes, twice in the first hour, ad-lib as

they want, but we ask them to use it twice and then smoke two

regular cigarettes. We did not control for the product. We

asked them to bring their own brands and use it as they want.

We used the standard methods.

This study is published. You can look at all the

specifications of the method and validation and the limit of

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quantitations.

So this is what we found looking at the particulates and

the droplets. So there was some emission from electronic

cigarettes. The instruments that we used in the study, that

you heard in the previous presentation, were able to detect

some droplets of the aerosol emitted from the electronic

cigarettes. It was much higher, the really high concentration

of the particulates emitted from tobacco cigarettes.

When we look at the nicotine levels in the air in this

study, we concluded that the electronic cigarettes can be a

source of emission of the nicotine in indoor air, and we found

that the emission is approximately 10 times lower. But, again,

it will depend on the user and the product.

There was a concern about the thirdhand exposure. So

what's going on with the aerosol that is emitted from the

electronic cigarette, is exhaled by the user? What's going on,

whether it's ventilated and is evacuated from the room or it

can be deposited on the surfaces? And then the concept of the

thirdhand exposure. The study with the tobacco cigarette came

out, so we decided to look at what's going on with the vapor

released from the electronic cigarettes.

And why we should bother about nicotine exposure, the

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thirdhand exposure from nicotine? And I think there's really

-- the nicotine per se has the effect, and we know that there

is some dermal absorption and this may happen. And there is

also some evidence suggesting that nicotine, when deposited on

the surfaces, can undergo further chemical reactions, and then

potentially harmful substances can be formed from this

deposited nicotine.

This is the study found in laboratory conditions. We

don't really understand right now what is the health risk

associated with being exposed to the thirdhand nicotine or the

chemicals formed from the nicotine. I think the diffusion

study will answer this question.

So the first study that you already seen, we just released

the vapor in the exposure chamber. We wanted to make sure that

the vapor can stick, or it was the question that explored in

the study whether the vapor can stick to the surfaces and we

can find and detect the nicotine on the surfaces. And we

simply released the vapor in an exposure chamber. We wait a

little bit and we wipe the surfaces, different surfaces, in

exposure chamber, and we were able to see some increase of the

nicotine levels deposited on the surfaces.

So with this very simple experiment, we concluded that

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there might be the danger of the thirdhand exposure to nicotine

with electronic cigarettes, and especially with the floor. The

products that we used in the study, we think that there was

some kind of the droplets of aerosols were actually deposited

on the floor, and that's why we found significantly higher

levels of the nicotine deposited on the floor.

But then we decided to confirm the study with real-life

conditions. And it was a very small study, the pilot study,

but I think this is the first of this kind. We went to the

houses of the electronic cigarette users. We were looking for

long-term user, so the people who are using the product for a

long time. And we also went to smoker houses, and we went to

the nonsmokers and nonusers of electronic cigarettes because we

want to have this control, the negative and the positive

control, in our study.

I want to mention, this is the first study, the pilot

study, but here are the results. We found that nicotine levels

deposited on the surfaces in the houses of electronic cigarette

users are actually the same as what we found in the nonsmokers

and nonusers of electronic cigarettes, and they were

significantly lower than found in the smokers' houses.

So is there any potential that the nicotine either

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deposited on the surfaces or present in the indoor air can be

absorbed by the nonusers? So the people who are living with

the users of electronic cigarettes or the children of the users

at home. And I found one study that is already published,

showing the levels of the biomarker of exposure to nicotine,

which is cotinine, and this study suggested that the nicotine

from electronic cigarettes can be absorbed by nonusers.

So just the conclusions from our studies and the other

studies that I presented.

Electronic cigarettes are not a source of many volatile

toxicants in indoor air. This is the comparator with tobacco

cigarettes. I didn't mention the formaldehyde and other

carbonyls in my presentation, as it was discussed previously.

I think that we need to continue research and look for the

other chemicals.

We have these other ingredients added to electronic

cigarettes, like flavorings, and we don't really know whether

these flavorings are exhaled and in what amount and what's

going on with the aromatic aldehydes and the other chemicals.

Electronic cigarettes are a secondhand exposure to

nicotine, but to much lower extent than tobacco cigarettes. I

think all the studies that were presented today showed similar

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findings. So you see some increase in the nicotine from the

background is low, but it is, and it's much lower than from

tobacco cigarettes. So using electronic cigarettes indoors

significantly reduced secondhand and thirdhand exposure to

nicotine compared to smoking tobacco cigarettes.

And we need research to evaluate long-term effects of

passive exposure to vapor from electronic cigarettes, including

using the products to reduce harmful tobacco smoke exposure to

others or to get around a smoke-free policy.

And I want to thank you for your attention.

(Applause.)

DR. DRESLER: Could I ask the panelists to come up,

please? Okay.

And for our transcriber, first sitting is Dr. Goniewicz,

followed by Dr. Offermann, Persily, Pritchard, Sarkar, and

Thornburg, okay?

All right. So everybody's writing their questions down

and passing them to the inside, please.

Clarifying question. The study on formaldehyde published

in the New England Journal said that no formaldehyde was

detected when used as intended, as designed. Did you consider

this? Wouldn't this show your testing machines are not

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calibrated to mimic human use, as shown by your outlier results

similarly suggest? And that's for Bud Offermann.

MR. OFFERMANN: No. We did 28 brands now, flavors of

e-cigarettes. Only a couple of them were variable to each.

All of them, every single one of them produced aldehydes,

including formaldehyde. Our techniques are robust, sound.

Unlike some of the other studies I've seen, we did a lot of

quality assurance/quality control on the sampler. I believe

the higher emissions that we're seeing in formaldehyde are as a

result of -- most of the formaldehyde is actually in the

particulate phase. So I think that's it.

When we did the variable voltage tests, there were

criticisms in the New England Journal article about that it was

run at too high a voltage and it gave a burned taste; a dry

puff was the criticism. I think that's a good criticism.

Fortunately, that criticism was raised before we did our

variable voltage test. So we had taste tests done to determine

at what voltage we started getting dry puff, and we conducted

our tests below that voltage.

So I believe in our measurements, and I believe we have

found that most of the formaldehyde is in the particle phase

and that research going forward needs to collect both the

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particle phase and the gas phase. And that's also true for

nicotine.

DR. DRESLER: Okay, anybody else? Would you like to?

DR. SARKAR: I just want to add a clarifying comment. And

Dr. Offermann made this comment a couple of times about the

robustness of the methods in other publications. I'm sure

you're not referring to ours because, as far as our methods, we

considered that methods that they had employed were all

validated.

So the data that I showed from the first two studies were

NIOSH methods that were validated and had the appropriate

standards and controls, as well as the analytical methods that

we used for the controlled clinical study were also validated.

DR. DRESLER: So how does someone correctly and most

accurately explain to the average person -- and I'm going to

say, to the average person and then to the scientists -- the

difference between vapor or aerosol? So we keep hearing the

words "vapor," but they're aerosols. So which is

scientifically the correct terms to use publicly and then when

talking to scientists? That's for everyone.

MR. OFFERMANN: Okay. They had a nice definition, one of

the speakers earlier today. Vapor is a gas. And primarily

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what we're dealing here with is aerosol, which is a combination

of gas and suspended particles, and these particles are liquid

droplets.

So I think it has a lot of appeal to say vaping, but in

truth, what people are doing are aerosolizing. So the correct

terminology is aerosol, but I think the public has adopted

vaping. So I don't know if we're going to get away from that.

MR. PRITCHARD: Okay. Yeah, I was pleased to see earlier

that one of the presenters has started to explore definitions

and criteria, because as we heard yesterday afternoon, there

was even the term "smoke" being invoked, and we've seen "fog"

appearing elsewhere, you know, a clear reference to theatrical

smoke, similar terminology. So, again, I would agree, there is

a popular or general term, but I think for us, as we would sit

here today, it would be an aerosol at the technical level.

DR. DRESLER: Anyone else?

DR. SARKAR: I'll just put my two cents. I think that I'd

agreed that scientifically aerosol is the right terminology,

but vaping seems to have the right kind of ring to it, and that

has stuck. But if you're talking in a scientific context,

probably aerosol is the appropriate term.

DR. DRESLER: Okay. I think, you know, this goes to how

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do we educate the public about what they're doing? Since we're

interested in good education to the public, how do we explain

that to them too, that it's actually an aerosol that they're

vaping?

Dr. Offermann, how did you come up with the 1% of OSHA?

MR. OFFERMANN: A good question. Let me just preface that

the 1% -- I think I mentioned that doing something less than

the occupational guideline when you're talking about young

children, women, whatever, the general public, it should be

something less. So what we did is we took the 15 or so

compounds that have both OSHA PELs and have OEHHA CRELs, which

are nonindustrial levels, and we looked at those, and the

average is 1%. It hovers around that. So that's how we

arrived at using 1%.

DR. DRESLER: Okay. And if you think this follows on, can

you please explain in detail the various governmental and other

standards or baselines for chemical exposure for us nonexperts?

So maybe that's for everyone. So whose standard are we going

to use? You picked 1%. NIOSH? How will we decide what we use

as standards or baselines for chemical exposure?

MR. OFFERMANN: I'll just kick it off and then pass it on

down, because I've been critical of studies that invoke the

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occupational exposure guidelines.

First of all, occupational exposure guidelines are not

protective OSHA guidelines. At those levels we're anticipating

having injury and stuff, so we would want to use something not

even approaching that. And when we're working with people that

are going to be exposed for more than 8 hours a day, perhaps in

a home or whatever, or have sensitive people like infants and

pregnant women, we want to use something less. The OEHHA

guidelines from California are designed with that protection

factor in place. If you don't have an OEHHA guideline, you

might look at the ratio of OEHHA to PELs, which is about 1%.

DR. DRESLER: What's PEL?

MR. OFFERMANN: Permissible exposure guideline, the OSHA.

And so we would use 1%, which is what I used and other

researchers in the indoor air quality field use.

DR. DRESLER: Dr. Persily.

DR. PERSILY: Let me just add to that a little bit. It's

really important to distinguish between standards and

guidelines. I mean, standards are formal declarations of what

is or isn't acceptable. We have standards for occupational

exposures out of OSHA, which, as Bud noted, has been -- you

know, is clear. If you look at the indoor air quality field,

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those are not appropriate for nonindustrial environments,

schools, homes, nonindustrial workplaces.

We mentioned the ASHRAE Standard 62.1, the ventilation and

indoor air quality standard. It is a very good explanation of

what those occupational standards are good for and that they

really don't apply to indoor environments. So that's an

accepted -- I hate to use the word "fact," but it's an accepted

principle in the indoor air quality field.

So we have occupational standards. We have outdoor air

quality standards issued by EPA. And then everything else is

kind of a guideline. And that's fine. You know, it's

important, when you look at a guideline, is it an indoor air

quality guideline for nonindustrial environments? And if it

is, then it's relevant. And so you need to keep that in mind

because of the differences in the population and the goals of

those guidelines and standards.


MR. PRITCHARD: Okay, if I could just kind of separate

some of this slightly. When we were presenting the data for

formaldehyde and acetaldehyde, that was not a workplace

exposure. That wasn't the UK WEL, because for those there are

general guidances available, and the guidance set for WHO, at

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their level. There's more detail in the paper. But

essentially the level set by WHO, they state that this value is

sufficient to prevent long-term health effects, including

cancer. And this is based on two distinct risk assessment

models.

So I think, you know, when we're having this debate, we

need to be clear. As you say, there are the workplaces, the

industrial, and there are guidelines which apply differently in

different ways. Okay, so that's just a point there.

And as we were presenting, for us, it was for context

because so often in making communications -- you know, there's

a graph for what does that level mean? What does it mean? How

does that relate to something else which has been established?

So there's a point there as well.

On the ASHRAE standard, I note that being referenced as

sort of -- as a matter of fact. But in there it also calls --

you know, default minimum ventilation is 0.78, and yet we see,

in the data presented, a value of 0.3 was used for air changes

per hour. So I think, you know, there needs to be care

exercised there.

DR. DRESLER: And you're saying it's complicated?

MR. PRITCHARD: I'm saying it's complicated, indeed.

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Certainly for some of the workplace exposure limits, there are,

I think -- from my recollection, there are about eight or nine

different regulations, for example, around PG standards for

that. And they're all coming from the same source data. I

believe it's Schober et al., which is the sort of lead paper in

that area. And yet there are different risk assessment tools

used by different regulatory authorities, all ostensibly trying

to achieve the same endpoints. There's a question there. Why

the big difference? And there are different models applied.

DR. DRESLER: Okay.

MR. PRITCHARD: And just one final point. I believe that

in making a conversion, I would, from a toxicological

perspective, question dividing something by 100 just as a

matter of course. I recall that was common practice over 10,

over 10, you know, division conversions. But I believe that

what is standard practice for risk assessment is more

sophisticated than divide by 100 using such things as DNELs and

so on and so forth. And this is common inside the European

discussion on chemical risk assessment.

DR. DRESLER: Dr. Goniewicz.

DR. GONIEWICZ: Yeah, I want to add one thing. I'm not

using the occupational standards in my research to understand

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the risk of the electronic cigarettes. And the reason is, you

know, if you are taking the chemicals from tobacco smoke --

from tobacco smoke -- and you do the same modeling and the same

prediction, what would be the level in the indoor air, most of

the chemicals will be below limits of occupational exposure.

But we all know how dangerous is secondhand tobacco smoke, and

the people are getting sick from being exposed to secondhand

tobacco smoke.

The second point is that the exposure is the function of

the concentration and the time you are exposed. And when we

are considering the electronic cigarette, the passive exposure

to electronic cigarettes, we need to consider the scenario that

there was a person, for example, living with the users in the

same home and being exposed for 10 years to certain chemicals.

And, finally, we need to remember the effect of being

exposed to either tobacco smoke or secondhand vapor is a

cumulative function of being exposed to all the chemicals,

propylene glycol, glycerin, nicotine, and the other chemicals.

When we are taking just one standard, we are just talking about

one chemical, that you are exposed to one chemical. Tobacco

smoke is like thousands of chemicals. With electronic

cigarette vapor, maybe 100 maximum. But it will be the

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cumulative effect, and I think it's too early to make any

conclusion about the health effects and health consequences

just based on the comparing of the concentration with the work

standards.

DR. DRESLER: Dr. Sarkar.

DR. SARKAR: I just wanted to remind everybody that -- and

as you said, Dr. Dresler, it's not simple; it's complicated.

But also it's not something that we can sit here and answer. I

think it goes back to the point that I made in my presentation,

that what you need is to look at all the available evidence and

integrate it all into a risk assessment and the likelihood of

harm to the nonusers. It's not only just comparing the levels

in the air to some exposure limits set by OSHA. I used that

just as a point of reference to contextualize, but I think what

we need to do is do a full assessment of the potential for

harm.

As Maciej pointed out, you know, what is the cumulative

exposure and what is the likelihood of harm to the nonuser in

making this determination? It should be based on science and

evidence, and the appropriate regulatory body should be

involved in making that determination.

DR. DRESLER: A quick question for Bud. It says, on your

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y-axis of your graphs, I didn't see any units. Was it

micrograms per day or micrograms per meter cubed?

MR. OFFERMANN: That's good. Okay. Well, there were two

graphs. They were the hazard quotients you might remember I

spoke of, which is it's dimensionless. There's no dimension to

it. It's a hazard quotient. So it's just like the ratio of

the exposure.

Let's say the exposure is 100 µg/m3, and let's say the

guideline for exposure is 50 µg/m3. One hundred divided by 50

is 2. The hazard quotient is 2. Hazard quotients over 1

indicate a health risk.

And as Dr. Goniewicz stated, you really need to

cumulatively do what they call the hazard index, and you add up

the hazard quotients for those chemicals that target the same

organ, like the lungs. So I didn't do that in mine, but we

would actually add them up, and that gives you a higher risk

assessment.

DR. DRESLER: Okay, for the panel. Given that there are

hundreds of different e-cigarettes, including the great variety

of nicotine concentrations, voltage, design, device design, et

cetera, is it really appropriate to generalize any study to the

e-cig category? What do we do with all of this being done on

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one, two, three products and there's, what, 450 in the U.S.?

MR. OFFERMANN: Well, I think that's a good question.

We've done 28 brand flavors. They all make formaldehyde but

some make 500 times more, and even within brands. And if you

look at the researchers' data from all of us around this table,

even within the same brand, the same e-cigarette, there's a lot

of variation. The vaporization process, the mass transfer is a

chaotic process. So they don't precisely deliver the same

thing every time. So the point is well taken. You wouldn't

want to generalize from one. I'm generalizing from 28 brands,

but that's a good point.

DR. GONIEWICZ: I agree. We always try to use as many

brands as we can in our research and make a conclusion based on

the variability of the products. I don't know what would be

the optimum approach here. I think we need to decide, for the

product testing, on some kind of standard method that we will

use for all products for the regulatory purposes. I don't know

if this is the best approach for the risk assessment. Maybe

not. But I cannot imagine that we will have standards for the

Product A and standards for the Product B just to evaluate what

is the risk, what is the nicotine delivery, what is the

performance of the products? It will be very challenging for

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you or FDA to test each product with a different standard

method. I cannot foresee it.

DR. THORNBURG: In respect to secondhand exposures, you

know, to get to the question, you know, you're asking for sort

of a representative observational exposure study where you're

not really -- with a sufficient sample size where you don't

have to control for the type of e-cig being used. So that

actually could turn into a very large study.

But I think an advantage of that type of study -- and this

gets into the representativeness of exposures and some of the

earlier discussion. You know, we live in a complex

environment, and there are a lot of chemicals in the e-cig

emissions, but there are also a lot of other chemicals in the

air, and it's trying to apportion, you know, where is someone's

exposure and dose coming from? Is it actually coming from the

e-cig, secondhand exposure to the e-cig emissions, or is it

coming from some other source?

DR. DRESLER: So Dr. Sarkar and then --

DR. SARKAR: Go ahead.

DR. DRESLER: No, it's all right, Dr. Sarkar. Go ahead.

DR. SARKAR: Yeah. You know, I just want to bring us back

to the discussion that we were having on modeling. Perhaps one

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of the approaches could be that if we had a model that was good

enough to simulate the different types of conditions in the

products -- and that would be one way of addressing. Clearly,

it would be very difficult to test all 3,000 or so different

e-vapor products that are on the market, but maybe modeling

will be an approach.

MR. PRITCHARD: Just to follow on from that. I see some

value in that, but it would need to be some kind of a tiered

approaches that are essentially through product standards or by

the development of an appropriate model that you could screen

for different products essentially. And just from a practical

level, testing all 3,000 different iterations of all different

products out there would be a significant challenge for any

regulator and indeed the manufacturers.

So I see, while there is a role in modeling, as we've

seen, there are different approaches you can take just within

the models, you know, like compare ours with that taken by Bud

here.

So, yeah, I think probably a tiered approach screening and

then moving forward with those products. And, you know, you've

got to have some analytical thing. There are clear differences

between some of the experimental techniques, using machine

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based, than we actually see in the real world.

DR. PERSILY: I just wanted to -- oh, excuse me -- point

out that, you know, variability in sources and product types is

a fact of life in the risk assessment field, and people have

been doing risk assessments for years and decades, a

combination of modeling, field studies. And there's probably

no perfect risk assessment, but there are sound techniques and

approaches that are well established, that whoever does this

for this particular class of products or any class of products

you just have to deal with. But you're not making it up from

the beginning.

DR. DRESLER: I have one ton of questions. Okay, so based

on the scientific evidence, what is the most important factors

that raise health concerns relative to the secondary and

tertiary exposures? Okay, so what are those most important

factors? For example, is it the toxicity of the chemicals or

is it the size concentration of the aerosol particles? Which

is it? How do you weigh them?

MR. OFFERMANN: Well, there's a saying, that it's dose

that makes the poison. So every chemical has a certain

toxicity to it, but the e-cigarettes put off a lot of

chemicals. Some of them are more toxic than others. But it

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also puts out different amounts of them. For instance,

propylene glycol, generally recognized as safe for ingestion by

FDA. In my mind, not particularly good to breathe in, but not

exceptionally toxic. But there's just so much of it that is

produced. So you have to weigh both the amount that you're

exposed to and then what the specific toxicity is.

DR. THORNBURG: Yeah, it's a combination of all of the

factors. It's how toxic the chemical is, whether the chemicals

in the particle are gas phase. If it's a particle, how big is

that particle? And then you get into the user characteristics,

you know, like what's your total exposure? You know, not just

the time of exposure, but how much do you actually breathe in

during that time you're being exposed? There are a lot of

different factors that determine whether or not something is

dangerous or not to the public.

DR. DRESLER: Well, would you list out the top four? What

are the top four? Or top two or top one? How do you start

ranking them? How do you start saying what to look at? You're

writing a guideline. How do you make recommendations?

MR. OFFERMANN: Well, the hazard quotient is considered to

be, from a toxicological standpoint, the thing that rolls

everything in, the concentration, the toxicity. And so from a

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hazard quotient for the passive exposed person, it's the

propylene glycol and the nicotine. Those are the top two,

propylene glycol by the far the biggest and then nicotine

second.

DR. DRESLER: Okay.

MR. PRITCHARD: I think there's actually a step before all

of that, and it's the product or device level. We've heard

reports of different compounds, for example, or elements.

There are reports of some metals in the literature, and that

then raises a concern. Yet, in our own work or elsewhere, that

hasn't been seen. And, indeed, on the product level there are

things that can be engineered out such that those wouldn't be

seen, as well as just measuring the end of the product, so to

speak, on the emission side. I don't think it's just about

that. I think there's a role for device quality standards

there also. But, again, I would agree with the gentleman on

the end. You know, it's really integration of all of those

different issues.

DR. DRESLER: Okay. Some of the studies on flavorings

have shown that they can be harmful when inhaled. What are the

best approaches to evaluating the exposure to and potential

toxicity of flavorings in aerosol by exposed bystanders?

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DR. GONIEWICZ: I think there are some standard methods to

evaluate the toxicity of inhalation of substances. We can

start with the cell line experiments, so when we take cell

lines and expose to the vapor or smoke or aerosol. Then animal

studies. They are not perfect, but they provide some

information on the toxicity of the aerosol. And I think this

is the good beginning. We need the data on some of the

compounds that are used as the flavorings.

Right now, even if something is approved as the GRAS

compound for food, when we eat it, when we ingest it, it does

not necessarily mean that this compound will be safe for

inhaling. The acetaldehyde is one of the best examples. It is

GRAS approved, but it is very dangerously retained for the

inhalation. Some of the flavorings, like benzaldehyde, have

been shown to be toxic when inhaled, but they are completely

safe when we eat them.

So I think this step-by-step approach -- I don't think

there's one good method to test this, but there are well-

established methods to test for the toxicity, inhalation

toxicity.

DR. DRESLER: Okay. And this was for bystanders. So the

second- or thirdhand exposure, the same thing?

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DR. GONIEWICZ: It's the same.

DR. DRESLER: Okay, okay.

MR. PRITCHARD: I would agree with that. There are a

number of different approaches that can be taken. So there are

some cell line studies.

But, again, to my earlier point. I think there's a role

around the sort of feedstock for the devices. I was discussing

with one of the panelists earlier. They had some data which

showed the wide variation between flavors being used, and by

that I mean the absolute purity of them and the consistency of

that. So there's a role there in making an assessment on the

emission. If you've got wide-ranging product variability, then

you assess on one level, and it's fine. The product is

entirely inconsistent, unreliable, low-quality control, and

then, you know, that level doesn't achieve the aim there. So

there's a role there.

On the theme of the FEMA GRAS point that's been made a

number of times, now, when I hear that, I have to reflect that

from my own experience, with my own organization, we have a

team of experienced professional toxicologists with probably

combined experience running into the decades, and they're

making their assessment for our products, their product

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stewardship. It isn't simply a case of, well, does it have

FEMA GRAS? Well, that's fine. Any level goes. That is not

how any responsible manufacturer conducts their business.


DR. SARKAR: I just want to add to some of the stuff that

Dr. Goniewicz was saying. Let's not forget that these are not

new chemical entities, so there is probably a lot of published

information on these products already existing. It may not be

for the inhalation route, but maybe for other routes. And if

there are no data available for an inhalation route, then maybe

some preliminary studies where you can assess the breakdown of

the product and what are the levels of the products even before

you start testing them in cell lines or animal studies. Put

some context around what's the actual emission and what the

levels that you test in the test system would be important to

consider.

DR. DRESLER: So this is a do-you-agree question. When

companies are measuring impacts on nonsmokers, shouldn't we use

the alternative as clean air and not cigarettes or from

tobacco? So the comparator is to cigarettes. Are cigarettes

the correct comparator when you use clean air?

DR. GONIEWICZ: I think we should use both. This is my

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answer.

MR. OFFERMANN: Yeah. When you're going into the harm

reduction argument, I guess you certainly would want to look at

them compared to cigarettes. But if you want to look for

passive exposure to a non-cigarette smoker, we would be looking

to the clean air, I think.

DR. THORNBURG: I agree with everyone. Just a good study

would measure the background air concentrations before you

actually did exposures to electronic cigarettes or conventional

tobacco. So when you do those background measurements, your

goal is to make the air as clean as possible.

MR. PRITCHARD: I would go back to the point made by the

last gentleman. In making our study, you know, we were very

minded to the background control, and we're incredibly glad

that we did because what we found was the significant

contribution from personal care products. So things like

cyclohexenes coming up from that. So I think that the

background, the framing of it is absolutely essential. So I

was a surprised. I didn't think I put many hair care products

on that morning, but obviously I had.

(Laughter.)

DR. PERSILY: I just wanted to point out that the

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background level is a not a fixed constant. It's going to vary

from day to day and environment. And if it's a contaminant

from outside, you know, those outdoor contaminant levels can

vary quite a bit. So, you know, it's important to compare it

to the background, but you need to really establish your

background level as relevant to your measurements.

DR. SARKAR: I just want to set the record straight. In

our study, we used a cigarette as a reference, but not as a

reference to compare against but mainly to test the sensitivity

of our method. And as far as, you know, what's the right

comparator, I guess, you know, the background and the

likelihood of exposure from other sources should definitely be

considered. You know, if you really want clean air, you need

to live in the mountains.

DR. GONIEWICZ: If I can just --

DR. DRESLER: I do, I do.

DR. GONIEWICZ: -- add one thing. I think for us, the

scientists, it's more easy because it depends on what's the

question we ask. So if we ask the question of whether

electronic cigarettes can contribute to the secondhand

pollution of the indoor, so then our comparator will be the

indoor air. If we are asking, you know, what's the reduction

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in risk comparing to smoking or being passively exposed to

tobacco smoke, then the comparator will be tobacco smoke. But

I think let's go complex and let's use both comparators in our

studies. It will provide us with the complex answers.

DR. DRESLER: Okay. So what should the public perceive

when one study shows that no formaldehyde is created when the

product is used as intended, and other researchers claim the

polar opposite? So we did have presentations today that showed

that some results showed one direction and some showed the

other.

MR. OFFERMANN: Well, I think we're right.

(Laughter.)

MR. OFFERMANN: Well, we did spend a lot of effort on -- I

realize the other gentleman used NIOSH-approved techniques and

stuff. But I think when you apply these techniques to, like,

e-cigarettes, it's almost incumbent to do some recovery tests

and blank tests and these types of things. We did so much of

that that I'm very confident that although our measurements are

much higher than others, I think there's a good explanation for

it.

In fact, in studies now where we collected formaldehyde

both from the particulate fraction and separately from the gas

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fraction, we're seeing most of it -- two-thirds of it is in the

particulate phase. And most of the other researchers, to date,

are using samplers that primarily collect just the gas phase.

So I think there's a logical explanation for it, and so I trust

my measurements.

DR. SARKAR: Well -- go ahead.

MR. PRITCHARD: To Bud's point, then. He's very confident

in his data, and what I note in his publication, the NSRLs --

so the cancer reference and then the CREL levels that are

coming out for formaldehyde -- you know, notwithstanding

questions I have on some parts of the model, the hazard

quotient is coming up 0.04. And then on the indirect exposure,

they're 0.009, which is clear water below the level of 1. So,

you know, if that's right, read that.

MR. OFFERMANN: I want to agree here, that even with --

well, even with the very much higher emissions of formaldehyde

that we're seeing from e-cigarettes, I think that that

particular chemical, formaldehyde, is not likely to exceed the

hazard quotient. I agree. I think it approaches the hazard

quotient, but it doesn't. So I guess I agree with you. On the

other hand, the direct exposure to the user to these aldehydes

is very high.

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MR. PRITCHARD: Just on that last point -- and I note in

the model that, for the direct exposure, there's 100% retention

assumption, and for the bystander it's 100% inhalation of that.

So I think, you know, in looking at those levels of the hazard

quotient, direct, of 1.64, I think that's with 100% retention

assumed, and is that established?

MR. OFFERMANN: Yeah, a good question. I don't know why I

wrote that in the paper, 100% absorption for the direct user,

because it doesn't come into it. We're talking about exposure,

not dose. And so the exposure has nothing to do with

retention, how much. Although I would say that formaldehyde,

at least in the vapor phases, it's got a high retention factor,

but it doesn't play into the picture of the exposure hazard

assessment because we're talking exposure, not dose.


DR. SARKAR: I don't want to get into a debate about who's

right or who's wrong, but I think the important thing to

remember is that formaldehyde and a lot of these other emission

chemicals, it's a complicated story, right? And what we did

was if you look at what's the recommended method by a

regulatory body -- you know, NIOSH has a recommended method,

and we use that method, and we see that even with our sensitive

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methods, you see formaldehyde background levels.

As it was pointed out by one of the other speakers, this

is omnipresent, and you find it everywhere. So formaldehyde is

kind of a touchy subject anyway, to begin with. But it's also

present from a lot of other sources, and you'd find this in

ambient air.

DR. DRESLER: I think that's one of the things, is how

complex it is and controversial. So how do we move forward in

this?

So this is for the panel, but also Dr. Offermann. And

some formaldehyde -- you expressed a concern about formaldehyde

in particulate phase. For e-cigs, the particulates evaporate

rapidly in secondhand aerosols. Given the small mass of

particles in the aerosol, why are you concerned about

collection of aldehydes on DNPH? So why the concern? You're

saying they're in particles, but they evaporate quickly.

MR. OFFERMANN: Well, right. Well, I would debate that

they evaporate "quickly." Certainly we see people exhale the

particulate phase. The propylene glycol has a pretty low vapor

pressure, but the particles are small, so they do evaporate.

But okay, what's the point, though?

The formaldehyde, a lot of it's in the particulate phase.

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The particulate liquid phase, propylene glycol or glycerol,

evaporates along with the flavorants and the formaldehyde. And

so it changes from the particle phase to the gas phase. It

doesn't exist in the atmosphere. So the fact that there's a

phase transfer from particle to gas phase, I don't think is

relevant. It's still in the air.

DR. DRESLER: So let's change a little bit away from

formaldehyde. The particulate distribution for e-cigarettes is

smaller than for conventional cigarettes, and users exhale

ultra-fine particles. Do these ultra-fine particles remain in

the air longer than conventional cigarette particles and

potentially result in increased exposure for the nonuser?

MR. PRITCHARD: As I recall it, the aerosols have very

distinct properties, you know, on the physical side. I mean,

you saw data that we had on the mass spectrum. My

recollection, the longevity, as it were, of the aerosol, I

believe, has been reported in the literature: about 11 seconds

compared to around 20 minutes for cigarettes, cigarette smoke.

So I think, you know, immediately we're talking of very

different entities here, the rapid evaporation essentially of

the droplets, you know, back into the ambient air.


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DR. SARKAR: If you remember, I presented the overview of

the two pilot studies that we conducted in the room. We had

measured total suspended particles in that study, and it was

remarkable that the levels just drop as soon as the product use

was completed. So, you know, the longevity of the aerosol in

the room was very, very brief. And the results of that

particular graph that I'm talking about is in the publication

that we have on our science website.

DR. THORNBURG: Yeah, I disagree with you slightly on

that. It depends on the types of instrumentation you're using

to measure the aerosol size distribution in a room. Some of

the work we've done at RTI -- and Battelle Memorial Institute

has done similar work using a scanning mobility particle sizer,

which is something that can measure particles smaller than 100

nm. You're getting down into the 10 to 20 to 50 nm size

ranges. Those aerosol particles generated by the electronic

cigarettes do stay in the air for an extended period of time,

and they don't evaporate.

DR. DRESLER: Okay. So could these particles be

potentially moved more deeply into the lungs, into the alveoli

of the nonuser, due to the smaller size distribution?

DR. THORNBURG: So those very small particles typically

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would not penetrate to the deepest part of the lungs because

they're so small. Their diffusion rate is so quick, they would

deposit higher up in your respiratory tract.

DR. DRESLER: Okay. Actually, I thought they were

exhaled. When they get small enough, aren't they exhaled

out --

DR. THORNBURG: And they can also be exhaled too.

DR. DRESLER: Yeah. Anybody else?

DR. GONIEWICZ: I have a question, actually. Can they get

bigger in terms of agglomeration with the bigger particles?

DR. THORNBURG: Yes, they can also -- inside the lungs

they will. These particles will also absorb water, and they

will grow in size as well.

DR. DRESLER: Okay. Dr. Goniewicz, if nicotine was

detected in homes of non-cigarette and non-e-cigarette users,

where did it come from?

DR. GONIEWICZ: There are a few studies showing the same

pattern, that in some houses of the nonusers, nonsmokers, the

nicotine can be detected. First of all, this is the function

of the method that we used. So if you go with the very

sensitive method, you are able to detect low levels of the

nicotine. There might be some carryover effects. So if

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someone smoked in the house many years ago, we are still able

to detect the nicotine deposited on the surfaces. There is

some evidence showing that nicotine can actually penetrate in

the walls.

DR. DRESLER: Um-hum.

DR. GONIEWICZ: And there is some evidence suggesting that

even when there is no smoker present in the room, the nicotine

is slowly released from the surfaces. So this is quite a

dynamic process, and it does not stop immediately after smoking

ends.

DR. DRESLER: And I'm wondering too, for the public. So

nicotine is quite a sticky chemical too. You have to be quite

careful in the laboratory when measuring nicotine also.

DR. GONIEWICZ: Yes, there are studies showing that it's

actually really difficult to remove nicotine from the surfaces.

DR. DRESLER: Right. Anybody else?

(No response.)

DR. DRESLER: Dr. Sarkar, what do we know about harm from

PG or VG above a set limit? What do we know about the harm

from a set limit? It doesn't give me what the set limit is.

And the second part is you distinguished e-vapor from tank

systems. Please describe the difference.

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DR. SARKAR: So let me start with the last question first.

What we had done was, in the study that we had conducted, we

had asked the participants to bring their own e-liquids, and in

order to just standardize the conditions, we had used one

commercial version of a tank. And, of course, I think

everybody in the audience probably knows the difference between

the tanks having, you know, e-liquids versus -- the two e-vapor

products that we tested were cartridge-based systems.

Now, as far as your first question about the harm from PG

or glycerin, yeah, what we had done was compared it to the OSHA

limit as just a reference point. I think that in order to

assess the potential for harm from any of these constituents,

you'd have to take into consideration all the available

evidence, including the actual level of exposure in the

nonusers as well as the likelihood of the breakdown and all the

potential literature that's out there on the specific

constituents to make an assessment. So that's, you know, a

more broader, complicated risk assessment question.

DR. DRESLER: Okay. Anybody else want to -- no. Okay, as

e-cigarettes are proposed as substitutes for combusted

cigarettes, isn't it essential to compare e-cigarette emissions

to those from cigarettes, as some of the data presented? So

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this goes back to the question, I think. You said do both.

DR. GONIEWICZ: Yes. I think it depends on the question

that we ask. So if we are talking, for example, about a smoker

and we are proposing this harm reduction approach to

substituting tobacco cigarettes with electronic cigarettes --

and today, at the session, we are discussing secondhand

exposure and all the data we've heard today suggesting that

this harm reduction approach may be also -- may also affect

nonsmokers.

So if we have a smoker at home exposing their family

members to the tobacco smoke, and this smoker will switch to

electronic cigarettes and will not smoke anymore a conventional

cigarette, then the harm reduction will be also -- will also

affect the members of the family.

If we are taking about introducing electronic cigarettes

to indoor air, clean, protected spaces, then again the data

showing that something is released, something is coming out

from the device, from the aerosol exhaled, then the answer

would be electronic cigarettes can contribute to the secondhand

exposure to the contamination in the indoor air. And then the

answer would be different.

DR. DRESLER: So I'm going to follow up on that because

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sometimes these questions are coming from different people. So

this will be interesting after what you just said.

Speaking of background air quality, can the panelists give

a rule-of-thumb estimate for air constituents in the room we're

in now? Would any e-vapor used in this room make any

significant impact otherwise?

MR. OFFERMANN: So one puff or --

DR. DRESLER: No, let's say someone's having an

e-cigarette in the center of the room.

MR. OFFERMANN: One person with an e-cigarette?

DR. DRESLER: Okay, fine. Three. One, three. I'll give

you any of those.

MR. OFFERMANN: Well, I guess my point is it depends on --

you know, I think Andy's presentation about looking at how much

source there is -- so how many people are vaping and then the

size of the room. And then if we assume that this place meets

code on ventilation, I suppose that one e-vaper in the middle

of the room there, probably it wouldn't have a significant

impact on concentrations here, I would probably guess.

DR. DRESLER: Okay.

DR. THORNBURG: Just a caveat. It depends on where you're

sitting. Obviously, if you're sitting in the middle of the

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room --

DR. DRESLER: Yeah, right. So the caveat. So dose, we

have a dose, how close you are.

DR. THORNBURG: Correct.

DR. DRESLER: Is it ventilated? So some depends.

DR. SARKAR: What's the type of the product? Is it a

tank?

DR. DRESLER: What type?

DR. SARKAR: Yeah.

DR. DRESLER: Okay.

DR. GONIEWICZ: Again, maybe a little bit from the public

health perspective. You know, this same debate we might have

had here maybe 50 years ago. It doesn't really matter whether

it's one smoker or half of you are smoking tobacco cigarettes

right now, what would be the risk?

I don't know if this is the right debate. You know, if we

go with these nuances, the question is whether electronic

cigarettes should be allowed in the indoor spaces. And if the

electronic cigarettes become more and more popular, probably

more and more, we will have more and more users here sitting

and vaping. And then the question is whether we want to be

exposed to the secondhand vapor.

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I think all the factors affects. That's true. The amount

of the aerosol exhaled from the devices is a primary factor

here, the ventilation, the density. I think there are too many

variables.

MR. OFFERMANN: I think that's right. So if we have this

kind of unusual thing where one person way over there is

vaping, and is that a significant thing, I say no. But the

reason I did my passive exposure with, you know, 0.3 air

changes an hour, which, you know, if you don't have mechanical

ventilation and you have open windows and it's cold and it's

closed -- and I did a worst case, right?

So I'm kind of checking the fences, and if all the

chemicals that I evaluated came back with very low hazard

quotients, I'd be like, well, maybe there really isn't a

passive exposure issue here. But as you saw from my

presentation, that clearly was not the case. With the worst-

case assessment, hazard quotients were over 20. So that, I

think, frames the debate on should we allow e-cigarette use

indoors. And I think the answer is clearly no.

DR. DRESLER: Dr. Persily.

DR. PERSILY: I just wanted to comment on the 0.3 air

changes an hour is really not a low rate for a home. You know,

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for residences, the building -- the ventilation standards are

in the 0.2 to 0.3 air changes an hour range. For office

buildings, it really depends on the type of space, whether it's

a conference room or an office or, you know, a big office or a

classroom. You know, the air change rates can cover quite a

range.

And there's an important distinction to be made between

what the standards say and what occurs in actual buildings.

You know, just because you write -- put a ventilation

requirement in a standard, in a building code doesn't mean it's

actually going to happen in a real building. If you want to do

these things and think about worst cases or best cases, you

want to look at the standards. But you also want to look at

the ventilation measurements that have actually been made in

homes and commercial buildings and use those numbers. But back

where I was, 0.3 is not low for a house.

DR. DRESLER: You know, sort of following up on this, one

last question, I guess. So when you're talking about those

standards and the commercial standards and the standards in a

home, do those take into account the contamination over the

long term or is that -- you know, we heard before that we're

measuring at a single point. But when you're looking at those

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standards, is that for exposure over the long term?

DR. PERSILY: The standards are based on really all the

science that's available to the committee, which is limited,

okay, and a lot of it is based on practical experience. They

aren't based on, you know, strong episodic sources. You're not

going to control a strong episodic source with ventilation.

You know, you're going to control that with source control or

exhaust or something. So, you know, they don't -- they're not

really -- the ventilation standards don't really use a risk

assessment, you know, public health model to things.

DR. DRESLER: Okay.

DR. GONIEWICZ: One thing. In a risk assessment, if we

are going this road, I think we also need to consider who is

exposed to the potential secondhand vapor, and we should also

include what we called here, I think, in some presentations,

the sensitive population. So we might have the person with

asthma. We might have a pregnant woman. And so we need to

consider all these variables. So my reaction on the secondhand

exposure will be different than the other one, the other

person. And I think this is also the complex problem, and I

think that most of the occupational standards consider the

healthy subject being exposed.

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DR. PERSILY: Most of the occupational standards are based

on very, very old data for healthy white males, you know, which

I guess is not the population at large, and it is intended to

protect them from these -- Bud can probably -- he knows the

language better than I -- but from severe impairment on the

job. They're not intended for the general population of

sensitive individuals and children and people with asthma.

MR. OFFERMANN: Yeah, it's even worse than that. I mean,

it is a compromise between labor, industry, and government.

And these are not at all protective at the occupational level.

The healthy adult worker that is only exposed 40 hours a week,

half of them are expected to be impacted adversely. So we

don't start worrying, in industrial hygiene, when we're

approaching the PEL. We take action well below that. And what

we're suggesting for nonindustrial is like 1%. But even if it

was industrial, if we were at a third or a half of the PEL, we

would be in a respiratory program.


DR. SARKAR: I just want to make a comment. This was in

response to one of the previous questions. I think that

clearly this is a charged issue, and you know, there are a lot

of opinions. But at the end of the day, I think what we need

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to do is just rely on the scientific evidence and get a bunch

of experts together in a room -- no pun intended -- and just

have the regulations that are based on evidence and science.

DR. DRESLER: What a great way to end up the panel. So

thank you. Thank you very much to the speakers and to the

panel. This was a difficult topic. Thank you very much.

(Applause.)

DR. DRESLER: Okay. So we are going to do lunch. So we

are going to come back 1 hour later at a quarter to 1:00.

Okay, thank you very much.

(Whereupon, at 11:56 a.m., a lunch recess was taken.)

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A F T E R N O O N S E S S I O N

(12:46 p.m.)

DR. DRESLER: So welcome back for the afternoon session.

A heads-up. They were thinking they were going to march on

through, and probably not with that break. If anybody

disagrees with that -- I'm not seeing any disagreement with

that. So we'll go with clarifying questions and the panel

discussion.

We'll start out with the first session. The session is on

Health Effects of Secondary and Tertiary E-cigarette Exposures.

Our first speaker is Dr. Neal Benowitz from the University of

California in San Francisco. He will be speaking on Biomarkers

of Exposure to Secondhand Tobacco Smoke and Electronic

Cigarette Emissions: Implications for Predicting Adverse Health

Consequences.

And the other thing too. Because he needs to leave, so if

people will be doing their questions and write those and get

them over to the side so we'll ask them during the clarifying

questions. So clarifying and hard questions for Dr. Benowitz,

okay?

DR. BENOWITZ: Thank you, Carolyn.

So what I've tried to do in this presentation is to

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address the issues of what we know about passive smoke exposure

and disease, and what we know about the extent of exposure to

electronic cigarette emissions, and what we might be concerned

about for disease risk. The bottom line, as I'm sure you all

know, is that we don't know what the disease risks are from

secondhand e-cigarette emissions at this time.

Okay, so my disclosures. I have been a consultant to

pharmaceutical companies that market smoking cessation

medications, and I have in the past been a paid expert in

litigation against tobacco companies.

So if you look at sort of a toxicant exposure/disease risk

model, this is what you might see. There is an exposure. We

heard this morning about air levels of toxicants. I'll be

talking about biomarkers of exposure, internal dose. And then

there are early biological effects in which there are also some

biomarkers; subclinical health effects, there may be some

biomarkers for that; and then clinical disease.

We really don't have anything yet for passive exposure to

electronic cigarette emissions for early biological effects or

subclinical effects. So I'll talk -- use some of the data we

heard this morning about air exposure and talk about biomarkers

and what we might be concerned about.

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So an overview of my talk. I want to start talking about

secondhand smoke because that's sort of a gold standard for

positive control for disease. We know it causes disease, and

we'll talk about how it does that and what biomarkers we have

of exposure. We'll then talk about the constituents of

cigarette smoke versus electronic cigarette emissions, the

biomarker studies that have been done for secondhand

e-cigarette emissions, and challenges for assessing biomarkers

and concerns for disease risk.

So if we start with just secondhand smoke, these are the

numbers of diseases that have been well established to be

related to secondhand smoke, and they really come into four

categories. There are respiratory infections, cancer,

cardiovascular disease, and reproductive hazards. So it's

clear that secondhand emissions to tobacco smoke constituents

can cause disease.

If we look at tobacco smoke, this is just a small number

of the many toxicants. There are thousands of toxicants in

tobacco smoke. Many of those are carcinogens or reactive

compounds that are involved in causing inflammatory responses.

The ones here that are -- aside from nicotine and minor

alkaloids, virtually all the rest of them are products of

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combustion. And so the big issue is how much of the disease

risk from secondhand smoke is from combustion products versus

the things that might be found in electronic cigarette

emissions.

If we look at electronic cigarettes, we see nicotine,

which is common with tobacco. We certainly heard about

propylene glycol and glycerin. Tobacco-derived nitrosamines,

which are carcinogenic. Some products have them in low levels,

levels much lower than those of cigarettes and secondhand

tobacco smoke.

Particulates still remain a concern. We heard a little

bit this morning about particulates. We heard the question

about metals. And I would just get back to the issue that the

particulate nature may depend on the product and the metals in

the products. It's very difficult to generalize about

e-cigarette emissions when product design influences the

emissions.

Volatile organic compounds are clearly of concern.

Flavorants you heard a little bit about. Cinnamaldehyde should

also be on this list, too, this morning. I thought those data

were very interesting. And then some of the e-cigarettes,

especially the early ones, had a number of different

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contaminants. But there are no combustion products.

So Maciej talked about, on the panel, when you look at

individual constituents, it's hard to assess overall risk

because you're really looking at a combination of things. At

least with e-cigarette emissions, the combination is much

smaller than the secondhand tobacco smoke, where we have

hundreds or thousands of potential toxicants interacting with

one another.

So some comments about what happens to the constituents of

tobacco smoke in the air. So here's a cartoon showing

generation of gases, which include formaldehyde -- I guess it's

also in the particles, as you heard before -- carbon monoxide,

benzene, nitrogen oxides, butadiene, acrolein, et cetera. And

then particles which when they're first generated contain

nicotine and then nicotine rapidly leaves the particles. I

suspect that's true for electronic cigarette particles as well,

because nicotine is extremely volatile. The particles are

alkaline, and some nicotine probably leaves the e-cigarette

particles quickly as well, and there are no data about how fast

and what the partition is.

An important issue is what happens to smoke in a room.

And this is a very important study that was published by Brett

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Singer from Lawrence Berkeley Laboratory in California, and

this was a study done in a chamber that resembled a room. So

it had carpets, it had curtains, it had fabrics.

And he basically looked at the constituents of secondhand

smoke over 2 hours, and this shows what was left 2 hours later.

So you can see some things, like isoprene, acrolein, and

benzene, are mostly still in the air. This is the percentage

of what was present 2 hours ago, so 80% or more. If you look

at nicotine, less than 1% is left.

So nicotine is basically leaving the particles, leaving

the secondhand emissions, and it's going into the room, it's

going into the carpets and the walls and the surfaces. That's

an issue because we know nicotine does go into the environment,

and it stays there and also builds up. So with regular

exposure, nicotine levels build up for months or years.

Another thing about this is that most of the data we have

on secondhand smoke, in terms of biomarkers and disease risk,

relates for cotinine and disease risk. But you can see, if

you're looking at the nicotine levels, which would be the

cotinine exposure, versus another toxicant -- say you look at

benzene, but it could be nitrosamines -- because nicotine

levels drop quickly, nicotine exposure underestimates exposure

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to other toxicants.

And so a study that we did with -- Maciej, I think, was

involved with this as well. We looked at the NNAL, which is a

nitrosamine biomarker to cotinine ratio in people who are

active smokers versus secondhand smokers, and the ratio was

much, much higher in secondhand smokers because nicotine levels

are -- their nicotine exposure is relatively low. So

secondhand smoke gets enriched with other toxicants, so

nicotine underestimates exposure. But still, that's the best

biomarker we have, disease risk from secondhand smoke.

Thirdhand smoke you heard about before. This is really

the residual smoke that remains on the surfaces and dust after

the tobacco has been smoked. You heard again from Maciej that

secondary pollutants can be generated.

Here's also a slide he showed, which basically shows that

with nitrogen oxides and water, you generate HONO, which is

reactive, you know, reacts with nicotine, and generates

nitrosamines on surfaces, including NNA, which is not present

in tobacco smoke. So actually some unique nitrosamines present

in the environment that are markers are thirdhand smoke

exposures.

We've actually been trying to measure this in people, and

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we've not been able to measure it yet. Either levels are low,

or we don't have adequate sensitivity, but we're still trying

to get a sense of what the systemic exposure is from thirdhand

smoke toxicants. But clearly this is a concern with

e-cigarette emissions if there is a lot of cigarettes and a lot

of nicotine exhaled.

So if you look at the toxicants that the World Health

Organization study group for tobacco regulation has identified

as key toxicants for tobacco smoke, and presumably for

secondhand smoke as well -- so it's nitrosamines,

benzo(a)pyrene, other PAHs, carbon monoxide, and then

acetaldehyde, benzene, butadiene, acrylonitrile,

crotonaldehyde.

For e-cigarettes there, in general, is little

nitrosamines, although some products have them; pHs are low;

carbon monoxide is not. The aldehydes clearly are a concern

for e-cigarettes and disease risk.

So let me just talk a little bit about what kind of

biomarker studies you can use for secondhand smoke exposure and

what's the best we can do.

So I'll show you data from a study that we did in San

Francisco, a very sort of semi-real life study. A parked

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automobile in a parking lot with the windows open, variable

degrees. A smoker sitting in the front seat. A nonsmoker in

the back seat. The smoker smokes three cigarettes, one every

20 minutes, in the front seat, and then the nonsmoker gets

submitted to our research ward for 24 hours and we get

biomarkers. So I think this is the most controlled sort of

situation. And we looked at exchange rates and air levels and

whatnot, but I'll just show you the biomarkers.

So the first is cotinine. So you can see that -- and in

terms of the intensity of exposure, the nonsmokers did not find

the secondhand smoke exposure very irritating. So it was not

high enough to be really irritating to the nonsmoker. You can

see, though, there's a very strong cotinine signal, a very

clear effect. The levels are pretty low. We're talking about

an increase from 0.05 to 0.15 ng/mL, where smokers got a level

of 200. So you can see this sort of sensitivity that you need

to measure cotinine levels from secondhand smoke exposure.

Urine cotinine levels are shown here. These levels are

about five times higher because concentrations are higher in

urine. So there are ways that you can look at that as well.

Here is urine NNAL, which again the only two really

specific biomarkers we have for tobacco smoke exposure are

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nicotine and metabolites like cotinine and tobacco

nitrosamines. And you can see a very strong signal for NNAL.

Cotinine is the one biomarker that has been related to

disease risk and for secondhand smoke. NNAL certainly is

thought to play a role, but it's not been directly associated,

and it's not likely to be useful for electronic cigarettes.

The aldehydes, which you've heard a lot about. There are

a number of aldehydes that are measured in -- that are

generated by cigarette smoking and some presumably by

e-cigarette use. These are the ones that are thought to be

toxicants. And a hazard index analysis of these suggests that

these VOCs are actually responsible for the biggest percentage

of cardiovascular and pulmonary disease of all the constituents

of tobacco smoke and a major contribution to cancer as well.

And these can be measured in the urine as mercapturic acid

metabolites.

And so in our car study you can see acrylonitrile, a

carcinogen. Levels increased twofold looking at urine

mercapturic acid metabolites. Benzene causes leukemia and

increases 50%. Butadiene, a carcinogen, also increases as

well.

So, in a carefully controlled situation, you can measure

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exposure to VOCs, even with secondhand smoke exposure, but you

can also see that there's a background level. So these things

are not as specific for tobacco smoke. And as you heard this

morning, there can be quite a lot of variability in the

environment. So whether you could measure something like this

from secondhand exposure to e-cigarette emissions, it's

doubtful.

So, again, to restate what Maciej said this morning,

cigarette smoke -- secondhand cigarette smoke is a combination

of exhaled mainstream smoke and sidestream smoke, and 75% of

the cigarette ends up in sidestream smoke. So most of what

you're exposed to is from sidestream smoke generation. An

electronic cigarette is really exhaled mainstream smoke only.

And I think there have been a number of passive

e-cigarette emission exposure studies that have tried to use

direct emissions, and those would be not appropriate. If

you're going to look at secondhand exposure, we really need to

look at what gets emitted by the smoker -- not a smoker, but

e-cigarette user, because it's not the same thing.

And I'll show you again -- okay, before I get to that, the

question is, well, how much gets exhaled by the user? And it

really depends on the user and how you're using it and why

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you're using it.

So here is an adolescent girl who's playing with smoke.

So she's taking it in and blowing it out, and she's generating

a lot of aerosol. There's probably a lot of nicotine in this

aerosol.

You know, in our lab we do studies a little bit like you

heard this morning from Dr. Pritchard, where we have people use

e-cigarette devices and they use it in a standardized protocol,

so like 15 puffs. And then we have them exhale into a trap

system where we trap nicotine, you know, as well as propylene

glycol and glycerin, in a series of traps and making sure that

we get all of it because the third trap has got nothing. And

then we can measure what we collect in the traps and compare it

to what they're using. So I'll just show data for nicotine.

Here's data from 10 users. We estimate the dose exposure

by how much e-liquid gets used from the device. We measure the

device weight before and afterwards, and that gives us an

effective dose of nicotine. And so we figure out how much

nicotine gets delivered in milligrams, and then we measure what

gets exhaled. So we trap what gets exhaled and figure out what

gets retained. So, in our study, by and large, we find that

more than 95% gets retained by most people, but not everybody.

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One person only retained 55%.

So if we're saying this is the source of secondhand

exposure of electronic cigarette aerosol, it really depends on

the user and how they're using, probably what the device is,

and whether they're blowing smoke rings or whether they're

using it to get nicotine. Our people were all pretty solid

electronic cigarette users who were taking in a fair amount of

nicotine.

So I think it is hard to generalize about secondhand

exposure to nicotine because it depends on who's using it and

how they're using it and what device is being used.

Here's some data from Schober's paper. You heard about

this, this morning. I just show this to emphasize the fact

that propylene glycol and glycerin seem to be and should be

present in the environment. Although I should also say I

haven't shown the data now, but people retain 70% to 80% of

propylene glycol and glycerin as well. There's also high

retention of that, and most likely formaldehyde as well. So a

lot of the materials from electronic cigarettes get retained.

This study did not find significant increases in

formaldehyde, acetaldehyde, acrolein, and benzene. PM2.5

obviously gets as well.

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Here's something from Maciej's paper. He also showed that

this morning, suggesting nicotine levels are about 10% in the

air when people are using e-cigarettes compared to regular

cigarettes and higher than background. And PM2.5 was sevenfold

higher. So I think the concerns, at least here, are what are

potential effects of nicotine and what are the effects of

PM2.5?

On the one study, the Ballbe study, which you heard about

again this morning from Maciej -- it's sort of summarized here.

This was a small study. So these were looking at nonsmokers

who lived either with cigarette smokers, e-cigarette users, or

nonusers, the controls. There are only five e-cigarette homes,

so the sample size is small.

What he found looking at air nicotine levels, there's

about a fivefold difference in air nicotine levels where

e-cigarettes were used compared to regular cigarettes. There

was a twofold difference in cotinine, so a much smaller level.

But this is the only biomarker study, so it shows that there

certainly can be some nicotine exposure. Why there's a

discrepancy between air levels and saliva levels, I don't know.

There could be exposure outside the home, which is common in

Spain.

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So it does suggest, if we saw this kind of an effect for

secondhand smoke, we'd say this is consistent with a risk of

cardiovascular disease, at least, you know, and maybe cancer.

However, for secondhand smoke, nicotine is a marker for the

other thousands of toxicants rather than nicotine being a

toxicant itself. And so whether nicotine predicts other

toxicant exposure here is hard to know. So that's one of the

things we have to deal with.

So the challenges in assessing secondhand smoke exposure,

in terms of systemic exposure, the exposure levels are low.

Nicotine is the only specific biomarker, and it underestimates

exposure to other toxicants in general. For e-cigarettes,

there's also the complication that people use different amounts

of nicotine and different e-cigarettes. For tobacco, most

cigarettes contain about 10 mg of nicotine, so nicotine is

pretty consistent. So it's a challenge using that.

Other toxicants of concern, like aldehydes, are

endogenous. So there are natural levels and there are other

environmental sources.

So let me just get -- I'll just go on. So the concerns

for disease risk, so far as I can see from what -- we see

nicotine. Certainly there is potential low-level exposure, not

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likely to have cardiovascular effects.

There are some very interesting data looking at effects of

secondhand tobacco smoke and nicotinic receptors, showing

nicotine can actually activate brain receptors at even

secondhand smoke levels. So there is the possibility that

nicotine could have effects even at low levels.

The particles are clearly there. They're present in lower

concentrations in secondhand smoke. We know that particles

convey cardiovascular risk from cigarette smoke and

carbonaceous particles. We don't know what the risk is of

particles per se from electronic cigarettes.

Carbonyls, if they are present -- and we saw conflicting

data about these -- certainly there is concern for pulmonary

inflammation and asthma.

Propylene glycol. I think there are certainly some animal

studies that show that propylene glycol can cause a pulmonary

inflammatory response, and I think there are concerns, you

know, for both of these in terms of asthma.

And, finally, what's not here are the flavorants. And I

think the data we heard this morning suggesting that there

might be -- 15% of the e-liquid might be a flavorant. So we

need to also look at what the potential presence in the

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environment is of flavorants.

So thank you for your attention.

(Applause.)

DR. DRESLER: We'll do questions after, okay?

Okay, our next speaker is Dr. Donald Graff from Celerion,

discussing on Assessing Second-Hand E-cigarette Aerosol

Exposure using 13C3-labeled Propylene Glycol.

DR. GRAFF: All right, thank you, FDA, for inviting me

here today to speak.

In the way of confidentiality -- not confidentiality,

conflict of interest. Sorry. My general counsel said

something about confidentiality, so that's where that came

from. As a contract research organization, we have performed

services for various companies who are evaluating electronic

cigarettes as well as other tobacco products, but also pharma

companies who are evaluating nicotine replacement therapy

products as well. But the data that I'm going to show you from

the study today was funded solely by Celerion.

Okay. So if we consider the centuries-old adage that it's

the dose that makes the poison, we really need to have an

understanding of not only what e-cigarette chemicals are in the

aerosols, and we did -- there was a fantastic discussion

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earlier today about those -- but we also need to have an

understanding in what amounts bystanders are exposed to, and

have some understanding of what amounts that are in the body at

the site of action, where they can elicit some sort of

physiological response if we're really looking to be able to

establish a cause-and-effect relationship here.

Okay. So at the most basic level of the secondhand

exposure debate, here we have two friends. Friend 1 here is a

vaper. And I'm going to use the term vaper today because --

well, mostly out of habit, but secondly, aerosolizer just

doesn't quite roll off the tongue as well. So Friend 1 here is

a vaper, Friend 2 is not, and when they get together, Friend 2

suggests that Friend 1's e-cigarette is making him sick. But

as Friend 1 questions here, how can we be sure?

And so it sounds like a very simple problem to answer, but

it's really quite complex, as we saw earlier today. Nicotine

and a lot of the other solvents, components of the e-liquids,

are everywhere in the environment. You can get them from food.

You can get them from cosmetics and a variety of other sources.

So what would be useful is if we are able to come up with a way

to establish what actually comes from the e-cigarette as

opposed to some of these other sources. And so the solution

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that we've come up with in the current study was to replace the

solvent -- and in this case, propylene glycol -- with one made

of stable isotopes and then use mass spectroscopy in order to

distinguish the constituents that came from the e-cigarette and

from potential other sources.

So in this case what we've done is Friend 1's e-cigarette

has been loaded with carbon-13 labeled propylene glycol, and as

the only source of carbon-13 labeled propylene glycol probably

that this guy has ever come into contact with, anything that

shows up in this guy's blood likely or definitely came from the

electronic cigarette of his friend.

Okay, just a little bit of chemistry here so that you have

an understanding of what's going on. So the atomic mass of

propylene glycol when we use carbon-12 is 76. And so when we

replace the carbons with carbon-13, we increase the atomic mass

by three, and the mass spec is able to differentiate between

these two.

And so building on something -- some other discussions

that were going on this morning. In addition to other benefits

of using a stable isotope, what we hope to be able to establish

is, is methods that can utilize this labeled propylene glycol

in order to track thermal and metabolic degradation products

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from propylene glycol, so, for example, formaldehyde and

acetaldehyde. Eventually we hope to be able to use this method

for that as well. I'll get to that later.

Okay. So the study that we performed is a small pilot

study, proof-of-concept study, where we took three vapers or we

enrolled three vapers and three non-vapers. The vapers self-

reported a 6-month product use history, daily product use for

30 days prior to the test visit. So they were experienced in

using vaping products. For the non-vapers, we asked that they

had no nicotine product use for 14 days prior to the test visit

and then limited their -- avoided environmental exposure to

nicotine for 48 hours prior to the test visit. We got a very

sensitive nicotine assay, so we wanted to get to have a long

enough washout period for those subjects.

All right. So, in terms of the study design, all six of

these subjects were confined to the test room. It was about

21.5 m3 in size. So we put them in the room about a half hour

before product administration, and they remained in the room

for 2 hours after.

And so at 8 o'clock we asked the vapers to begin using the

product, and we used a controlled administration in this case.

We asked them to take 30 puffs -- 30 3-second puffs at 30-

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second intervals, so about a 15-minute exposure. Kind of short

over that period of time. And then we -- there we go. We drew

blood before exposure and then for 8 hours after exposure.

And at noon, 4 hours after the exposure, we fed the

subjects a meal containing foods that were known to have

propylene glycol in them. So we gave them a Big Mac, a side

salad with 3 ounces of Kraft fat-free ranch dressing, two

chocolate fudge Pop Tarts, and an A&W root beer.

(Laughter.)

DR. GRAFF: So not exactly the lunch of champions, but

you'll see in a minute, it served the purpose for our study.

Actually, it sounds like my college meals that I used to have.

Okay. So for the device that we used, we used the kGo

bottom-feeder tank that we purchased from GNS Vapor there in

Lincoln, Nebraska. For the nicotine solution, we acquired the

pure nicotine from Nicobrand and the carbon-heavy propylene

glycol from Aptochem and then created our own solution. So we

made up a 1.8% nicotine solution and 98.2% propylene glycol

solution. And, of course, this is not a solution that you're

ever going to find in any commercial -- or likely to find in

any commercially available e-liquid.

But that wasn't our purpose here. What we wanted to do

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was to try to maximize the amount of exposure that the vapers

and the non-vapers would have. I actually wanted a higher

concentration of nicotine, but people who use these products

said there's no way. I wanted 5%, but they weren't going to --

that wasn't going to happen.

Okay. So the estimated exposure and the estimated dose to

propylene glycol and nicotine in the vaping subjects. So you

can see here Subjects 1 and 3 had a very similar -- acquired a

very similar dose of both propylene glycol and nicotine. And

the way we did this is we basically took the weight of the

product after, from the weight of the product before, and then

multiplied it by the concentration.

Subject 2, on the other hand, had a much lower exposure.

It was very evident that this guy was having some difficulty

activating the product during the exposure period. I think it

might have had something to do with the viscosity of the

solution, but I'm not 100% sure of that.

And so in terms of nicotine, which is kind of the known

quantity here, we were looking at about just over 4 mg for

Subjects 1 and 3 and then just over 1.5 for Subject 2.

All right. So for the nicotine plasma concentrations,

again, this is the known quantity. Based on the doses that we

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saw, pretty much the peaks that we expected to see, so ranging

from about 7.5 to just under 25 ng/mL. Then, of course, it

dissipated or was eliminated over the remaining 8 hours. And

so that's the vapers.

So the non-vapers, Subjects 4 and 6, we didn't see any

measurable concentrations at our limit of quantitation of 0.2.

Subject 5. Subject 5 had baseline concentrations. So he

came in prior to the exposure with concentrations of about 0.35

ng/mL, and he kind of hovered there for about 2 hours, and then

it went to not measurable. So, you know, this guy, can we 100%

definitively say that he didn't receive any nicotine from the

exposure? Well, no. If we had been able to label the nicotine

in this case, then we could have said that. We wanted to and

we tried, but we couldn't get the nicotine synthesized in time.

But we didn't really see a bump during the exposure either. So

the likelihood of this guy being very different than the other

two is slim, I think.

All right. So unlabeled propylene glycol here. Four of

the subjects had measurable concentrations coming in. I

thought all six would, but not the case. The concentrations

decreased over time to the point where we administered the

meal. And, of course, after that they increased again, and the

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remaining two subjects had measurable concentrations after

that.

So what you can see from this is that, you know, we had

various rates and various extensive propylene glycol

absorption, and so we really have to be careful. And this is a

very good example of why you need to be careful when you're

designing a clinical study to evaluate something that's

ubiquitous in the environment and separating that from your

intervention.

All right. So the 13C3-labeled propylene glycol plasma

concentrations in the vaping subjects. Again, based on the

very high amount of propylene glycol in the solution that we

used, we see peak concentrations in the neighborhood of 2,000

to about 4,000 and then decreasing over time to 8 hours -- to

about 100 to right around 700. And notice that there wasn't a

bump after the meal. So that just kind of speaks to the

specificity of the method that we used in this case.

All right. So back to our two friends here. What's the

verdict? Does this guy -- can his friend -- can Friend 2 here

blame Friend 1 for his whatever it is that he's feeling?

In the three vaping subjects, we found no quantifiable

concentrations at a limit of quantitation of 5 ng/mL. And if

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you think back to the concentrations that we saw in the vapers,

these are orders of magnitude lower -- the limit of

quantitation there is orders of magnitude lower than both the

peak and the trough concentrations that the vapers actually

experienced.

However, if we wanted to -- so that's the limit of

quantitation. Now, with the mass spec we can detect lower

concentrations, and our limit of detection in this case is 0.2

ng. So were we able to -- we can't really quantitate it that

low, but were we able to detect it? And so the answer is yes.

So we were able to detect peak levels at about 1 ng/mL, again,

thousands of times less than the peaks that we saw in the

vaping subjects.

Okay. And so back to the dose makes the poison. In terms

of adverse events, none were reported by the non-vapers.

Again, there were only three, but we had nothing reported by

the non-vapers.

Subject 1, on the other hand, who was a vaper, vomited

about 7 minutes following completion of product use, and upon

questioning, we found out that he hadn't eaten most of the day

prior due to his work schedule and hadn't eaten prior to coming

in that morning. So almost 4.5 mg of nicotine over a 15-minute

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period, it's really no surprise that he had an upset tummy

there.

Okay. And so our conclusions. Again, with the very

specific conditions of our study, non-vapers in close proximity

to the vapers using a highly concentrated propylene glycol

solution experienced very little uptake of 13C3-labeled

propylene glycol during a relatively short exposure period and

reported no adverse events.

And so we believe that stable labeling can be a powerful

tool for testing direct and secondhand exposure to e-cigarette

components, allowing scientists to differentiate exposure from

other sources such as food.

And, finally, the data generated from these kinds of

studies evaluating e-cigarettes that include labeled e-liquid

components may help regulators make informed, science-based

decisions about these products in their efforts to protect the

public health.

And so I'd just like to acknowledge the staff here.

Dr. Michael Gartner, who was the principal investigator on the

study; Stephanie Grone and Holly Lehman, who are basically the

study managers and operationally and logistically made the

study go forward; the bioanalytical staff led by Kirk Newland,

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who was the bioanalytical principal investigator; and then Ray

Farmen, our vice president of bioanalytical sciences, who

basically paid for this study.

That's it.

(Applause.)

DR. DRESLER: Okay, our next speaker, Dr. Collaco -- I

hope I said that correctly -- from Johns Hopkins School of

Medicine. Impact of E-cigarettes on Lung Growth and Behavior

in a Mouse Model.

DR. COLLACO: Thank you. My name is Mike Collaco. I am a

pediatric pulmonologist at Johns Hopkins. I want to thank the

organizers for the opportunity to present some of our data

today. I'm actually presenting on behalf of the principal

investigator, Dr. McGrath-Morrow, who's unfortunately in an NIH

meeting today.

This is where the particular research that you're going to

see has been funded by.

So briefly I'm going to discuss the background and our

study aims; walk you through our mouse model; demonstrate some

of the effects that we've seen on lung growth with e-cigarettes

in our mouse model; demonstrate some of the effects on adult

mouse behavior from prenatal/neonatal exposure; and also

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discuss some future research directions that we're considering.

So as pediatric pulmonologists, Sharon and I are very

interested to know whether there are any adverse consequences

to e-cigarette exposure on the very young, particularly since

that's a critical time for organ development, both prenatally

and in early childhood.

And small children may be exposed to a variety of

constituents from e-cigarettes through multiple routes,

including inhalation, dermal absorption, breast milk, and

possibly thirdhand through contaminated surfaces.

So we have two studies that I'm going to present today.

One has already been published in PLOS ONE, the pulmonary

study. The other is under review.

In our pulmonary study, we wanted to see whether

e-cigarette exposure in early life affects lung growth, using

the mouse model. And in the behavioral study, we wanted to see

if early e-cigarette exposure affects adult mouse behavior,

again in the model.

There we go. So one of our first questions is, you know,

could nonusers of e-cigarettes be exposed potentially to

emissions? This is a study -- it's a theoretical model using a

particle sampler, and they're basically predicting where

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particles might deposit, you know, from an aerosol. And we can

certainly debate the percentages of where we think particles

are ending up, but you know, a substantial fraction of them may

be exhaled by certain e-cigarette users.

Perhaps more telling is this data, which you've heard

referred to twice today. It is a study on a very small number

of individuals, nonusers. The researchers in this study

recruited subjects from households where no exposure took

place, households where e-cigarettes were used, and households

where conventional cigarettes were used. There were no dual-

use households in this particular study.

And, you know, although the salivary cotinine levels are

less, slightly, in the e-cigarette exposure than the

conventional cigarette exposure -- cotinine is again a

metabolite of nicotine -- they're very much similar in urinary

cotinine, and statistically, they're no different, suggesting

at least in this small sample that nicotine is absorbed by

secondhand means.

So this is our mouse model. In the foreground, where the

red arrows are, are the chambers where the e-cigarettes are.

The emissions are drawn in through the pump that you see in the

mid part of the picture and then transmitted via the tubing

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that you can see in the background to the chambers where the

mice are. The mice are exposed 20 minutes per day, either once

or twice a day, depending on the protocol.

Another question is, you know, does a pump generate

similar emissions to a human e-cigarette user? Again, it

probably varies by e-cigarette user. But at least there's one

study that suggests at least the nicotine air concentration and

the aerosol particle concentration are roughly comparable.

So we have three arms in our studies. One is a group of

mice that aren't exposed to any products whatsoever. The

second is a group of mice that are exposed only to the 0%

nicotine-containing e-cigarettes, so that is, they are exposed

to the carrier agent, in which our case is propylene glycol.

And there may or may not be other compounds present there. All

of the e-cigarettes that we used in our study have no

flavoring. And then the third group is either exposed again,

depending on the protocol, either to 1.8% or 2.4% nicotine.

For the purposes of our model, although we know that there

are certainly other compounds present in e-cigarettes, we

assume that they were at low enough concentrations that we did

not think that they affected the mice, but again this is an

assumption.

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The next question then is, you know, in this model, what

are the mice actually being exposed to? Is it something

that's, you know, real life or not? You know, I'm sure you've

all heard about the saccharine studies where mice were exposed

to thousands of levels of -- you know, times the levels that

humans would be exposed to and develop cancer. So we did some

back-of-the-envelope calculations, which you see here, and

based on a previous study by Etter, human e-cigarette users may

inhale up to 24 mg of nicotine per day. In our mouse model,

2.5 mg per mouse entered the chamber. I don't know, obviously,

if all of that was inhaled. I would suspect not, but that

would be the maximum dose.

To confirm this, we looked at plasma cotinine levels in

the mice to get an idea of what type of exposure it is. In our

mouse study data in our pulmonary study, the mice had levels of

62 ng/mL. In the behavioral study it was 23. If you look at

human data from the literature, in adult conventional cigarette

smokers, the levels of plasma cotinine, again a biomarker for

nicotine, are 122.

For secondhand exposure for the type that we're trying to

get at, which is very young children, there are a couple of

studies which have measured newborn levels of plasma nicotine,

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which range from 31 to 76. So, as you can see, our levels are

probably more akin to secondhand exposure in newborns.

So our pulmonary study. The aim is to determine whether

e-cigarette exposure in early life affects lung growth. We

know from conventional cigarette studies that maternal smoking

during pregnancy causes adverse effects on lung function

throughout childhood that can be measured on lung function

testing. We also know that exposure to secondhand smoke during

childhood also causes adverse effects on lung function. And

it's, you know, obviously at this point unknown whether

e-cigarettes have the same effect on infants and children.

So the timing of our exposure in our study. So this is a

timeline for lung development in humans and in mice. E in the

mice column refers to prenatal embryonic days, and PN refers to

postnatal days after birth. In our study, mice were exposed on

Postnatal Days 1 through 9, which corresponds in people to late

fetal development, third trimester, into perhaps infancy.

So before we show you the lung growth data, I just wanted

to bring this slide up because I think it is interesting data.

This is the growth for the mice body weights on the vertical

axis, and on the horizontal axis is days, Day 1 through Day 10.

The white bar represents the mean for room air-exposed

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mice. The light gray is the 0% nicotine, and the dark gray is

the 1.8% nicotine. And what we saw was, with time, the mice

that were exposed to both the 0% as well as the 1.8% weighed

less than the room air mice by about 11 to 12 -- I'm sorry, 11%

to 13%, as you can see on the slide, which suggests, even in

mice that aren't exposed to nicotine-containing e-cigarettes,

that there may be effects on growth.

So this is a slide for lung growth, and I want you to

concentrate on the pictures rather than on the graphs, for

starters. So on the far left -- these are all sample sections

of lung tissue from the mice. The picture on the left is a

sample from mice exposed to room air, representative, and this

represents fairly normal lung architecture. And this is not

that dissimilar to human lung tissue. You have air spaces.

The air spaces allow oxygen to be taken in and carbon dioxide

to be expelled.

And then, as you move across from 0% nicotine to 1.8, you

can start to see some changes in the lung architecture. The

spaces are much bigger, larger. And that's what the graphs

above show. They're measuring something called mean linear

intercept, which is just the measure of how much distance there

is across that air space.

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So what does that mean? So if you have larger air spaces

like this, you have less surface area in your lungs. And the

lung is all about gas exchange. You need surface area to

exchange gas. So if you have a reduced surface area, as you do

in the 1.8% nicotine-exposed mice, that implies that your gas

exchange isn't as efficient.

And those of you who have, perhaps, a medical background

or have looked at lung tissue samples before may have seen

similar sorts of findings in human lung tissue in people with

lung disease, particularly with emphysema or COPD, and they too

have decreased surface area in their lungs. And if you have

decreased surface area, this usually leads to shortness of

breath and/or exercise limitations.

So these studies suggest, at least in mice, that exposure

to e-cigarettes in early life does result in some durable

changes in lung architecture that may have consequences.

The second study I'm going to talk to you today is our

mouse behavioral study. This is currently still under review.

The purpose of the study was to determine whether e-cigarette

exposure in early life affects adult behavior, using a mouse

model. The rationale for this particular study was that ADHD

has been associated with fetal exposure to maternal

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conventional cigarette smoking during pregnancy, and it's

obviously unknown whether e-cigarettes have any such effects.

So mouse brain development does not exactly follow the

same timeline as human brain development. The exposure that we

exposed the mice to in this particular study was the pregnant

mice were exposed from Embryonic Days 15 through 19, and then

the baby mice were exposed from days -- postnatally from 1 to

14, roughly corresponding to the second or third trimester

exposure for humans, as you can see in the graphic above.

Male mice underwent behavioral testing at 3 months of age.

Mice typically become adults somewhere between 28 and 36 days

of life. So at 3 months of age, these are clearly adult mice.

Why only in the male mice? Unfortunately it's another form of

gender bias. There are only validated behavioral standards for

male mice at this time.

The behavioral test, which I'll walk you through in the

subsequent slides, that we performed are standard behavioral

tests for mice, including an open field test, an elevated zero

maze test, rotarod, and light-dark box test, which measure sort

of different parameters of mouse activity.

The open field test is when mice are placed in an open

field chamber and allowed to move freely. The mice that were

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exposed to 2.4% -- we used 2.4% nicotine e-cigarettes in this

particular study -- traveled longer distances, as indicated by

the bar graph on the left, and demonstrated increased rearing

behavior, which is sort of standing on their hind legs. These

are sometimes taken in mouse behavioral studies to represent,

potentially, hyperactivity. We did not see these similar

behaviors in the 0% nicotine-exposed mice, again suggesting

that this is a function of the nicotine exposure.

The zero maze -- I'm sorry, the elevated zero maze test is

when a mouse is placed in a quadrant maze that has open and

closed sections, and typically researchers measure the time in

open sections as a measure of anxiety. We did not see any

differences between the three groups in that. The mice who

were in the -- also were measured for a number of head dips,

which is a measure of exploration. And the 2.4% nicotine-

exposed mice did experience more head dips, which suggests

again, from the mouse behavioral literature, that it may be

associated with less timid behavior and more impulsivity.

The other tests that we did, the rotarod test, where a

mouse is placed on a rotating rod, and it requires locomotion

to avoid falls, we did not see any differences.

We also did not see any differences with a light-dark box

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test, where a mouse is allowed to move freely between lighted

and dark box components as a measure of anxiety.

So, to summarize these results, nicotine exposure via

e-cigarettes with prenatal and early postnatal life in mice is

associated with behavioral changes in later life that appear to

be durable, an increase in what might be considered

hyperactivity or risk-taking behaviors, but no change in

anxiety-related behaviors.

Does this have any relevance to human data for nicotine

exposure? As I said previously, there have been several human

studies that have reported exposure associations between

prenatal nicotine exposure and behavioral changes during

childhood, including ADHD and oppositional defiant disorder.

There is less solid data for whether there's an association

between NRT and ADHD.

Lastly, I just wanted to touch base on this subject of

thirdhand e-cigarette exposure. As has been presented in data

earlier today, nicotine is readily detectable on surfaces of

lab equipment as well as indoor surfaces of e-cigarette users.

Obviously, we cannot exclude the possibility in our study that

mice in our study also absorbed nicotine through thirdhand

routes, but that may also be a possibility.

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So, in conclusion, you know, I think this mouse data

presents some interesting findings that early exposure to

e-cigarettes, at least in mice, does cause changes in lung

growth as well as behavior. You can debate as to what the

specifics of those behavioral changes are, or what they mean on

those tests, but there's clear -- you know, I think our data is

fairly clear that there are at least some behavioral changes

associated with e-cigarette exposure in early life in mice.

We need, obviously, more research to determine the effects

of e-cigarettes on lung function, susceptibility to infections,

whether there are gender differences with e-cigarette exposure

in the extremely young, and obviously human studies are needed

to confirm our research in mice.

Thank you.

(Applause.)

DR. DRESLER: Okay. So we're going to do clarifying

questions now, and if you have any hard questions for

Dr. Benowitz before he leaves, I'll take those too.

So this one is for you, Dr. Benowitz. Considering ENDS do

not contain smoke or combustion, nicotine as a biomarker is not

applicable -- considering ENDS do not contain smoke or

combustion, nicotine as a biomarker is not applicable nor

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comparable to actual cigarette smoke. It is not a good measure

of harm or risk to people. For example, it has been shown that

nicotine is the same in vapers' homes and nonsmokers' homes.

Thus, as a biomarker, it tells us nothing of the constituents

found in vapor exposure. Don't we need new measures developed

for vapor products, considering some vapor products don't

contain nicotine?

DR. BENOWITZ: Yes, that would be a great idea. The

things we would like to have markers for, say, aldehydes,

formaldehyde, acetaldehyde, are difficult. They're endogenous

compounds. I know that there's some work trying to look at

potential adducts of formaldehyde, but we don't really have any

other specific markers.

I certainly agree that nicotine does not say the same

thing with e-cigarette use than it says for cigarette use. And

for cigarettes, nicotine is really a marker for everything

else. For e-cigarettes, it is not that. On the other hand, I

think if a nonuser wants to be nicotine free, they're entitled

to be nicotine free. So even though I don't know what the

disease caused by low-level nicotine might be, I think that

still, you know, a nicotine-free world is desirable.

DR. DRESLER: Wait. So don't sit down. Here's another

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one for you. What constituents in tobacco smoke are of most

concern for cardiovascular health?

DR. BENOWITZ: So, for cardiovascular health, there's

pretty solid evidence that the combustion products are the

things that are responsible for most of the inflammatory

response, the prothrombotic response, the endothelial

dysfunction response.

Nicotine plays a role mostly in the hemodynamic effects,

which means that heart rate goes up, blood pressure goes up,

cardiac output goes up. Those are things that can potentially

cause problems if you already have cardiovascular disease, but

it probably doesn't play a role in the causing of

cardiovascular disease, sort of an aggravator. So I think it's

mostly the combustion products.

You know, for secondhand smoke there is one concern. We

know that secondhand smoke exposure can trigger acute

cardiovascular events. So you can have a myocardial infarction

or sudden death with acute secondhand smoke exposure if you're

not a smoker. We don't think that that's nicotine related, but

nicotine could play some role, and that's something that I

think needs to be thought about.

DR. DRESLER: Thank you.

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Dr. Collaco. So I want to thank you for looking at those

gender differences because I was going to ask Dr. Graff why you

did only men. Just saying. No, just saying. I have to do

that to represent the women, though. I appreciate that it was

a small n. But no, the question, sir, was for you.

If nicotine NRT is not associated with ADHD, would not

that be similarly expected with ENDS? So NRT is not associated

with ADHD.

DR. COLLACO: I think it probably has to do again with the

exposure, how much, how often, when, you know, during

pregnancy, during early childhood. So I think there are a lot

of variables there that still need to be sorted out. And,

again, it's hard for me to comment, you know, exactly the role

of NRT since we didn't have an NRT arm in our study.

DR. DRESLER: Okay, I have a few more for you. So, in the

mouse model, you were testing exclusively developing lungs in

mice and not that of grown adult mice. Does the study provide

any information on the effect on full-grown and developed lungs

in humans? And it would be likely to be smoking and

replacement with ENDS. So what would your studies predict for

adults, could you say?

DR. COLLACO: We actually can't say earlier, so I wouldn't

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feel confident saying something definitive on that. And,

unfortunately, at least in human studies, this may take

decades, you know, for durable or permanent changes to occur.

DR. DRESLER: Okay. A few more for you, okay? How clear

is the mice behavior literature at seeing anxiety behavior?

For example -- and I can tell you guys tried to help me with

this. For example -- can you read what that word is?

DR. COLLACO: Control.

DR. DRESLER: For example, control mouse --

DR. COLLACO: Drops?

DR. DRESLER: Head drops. Okay, control mouse head drops

and standing, can it be just greater curiosity?

DR. COLLACO: It's a good question. I think these tests

have been standardized over decades with the behavioral

literature, and they've been used for a variety of purposes,

and certainly, you know, with other drug exposures in the past,

such as alcohol, methamphetamines, et cetera. Yes. You know,

there is definitely some speculation on my part, from

interpreting mouse behavior to interpreting human behavior.

But I think what you see in the mice studies is that there

is a behavioral change. That's clear. What you interpret that

behavioral change to be is up for debate, but there is a

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behavioral change suggesting that, at least in early life,

these things may not necessarily be benign.

DR. DRESLER: Okay. And I think this one is going to

follow on, on this. Isn't greater activity in open field and

maze movement in the light-dark test often taken as an

indication of lower anxiety? Why did you interpret it as ADHD?

DR. COLLACO: Again, you know, I think these tests are

objective in terms of what they're measuring, subject in terms

of their interpretation. Based on the fact that, you know, the

other anxiety tests did not differ between any of the control

groups or the nicotine or 0% nicotine-exposed mice, we tended

to think that our results are related to more activity levels

or hyperactivity.

DR. DRESLER: Okay, thank you. Let me go to Dr. Graff.

Yeah, sit up front, though, because I know I have another one

for you.

So, Dr. Graff, you measured blood PG levels. Lung

concentrations could be much higher. What can you say about

the pulmonary risk of PG from secondhand emissions?

DR. GRAFF: So based on our study, I can't say anything

about it. But the good thing is, is that using a method -- a

labeled propylene glycol like we have, we certainly could use

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that to assess what the concentrations are at the site within

the lung. But from our study, we really can't say anything

about that.

DR. DRESLER: Okay. In the mouse model of lung toxicity,

the PG alone caused increased air space. So was it the

nicotine or was it the PG?

DR. COLLACO: That's a very good question. We did several

different trials or repeated trials. In one trial, we did see

a difference between room air and 0% nicotine in terms of the

air space. In the second trial, it was not statistically

significant. So being conservative, when we did report it to

the journal, we said that we did not see a difference.

DR. DRESLER: So here's another one for -- if nicotine has

been reported to be used to relieve negative mood anxiety in

schizophrenics, could you comment on why such changes in mouse

anxiety behavior were not seen?

DR. COLLACO: Yeah, I'm not sure I can speculate on the

role of nicotine and schizophrenics related to our mice study,

unfortunately.

DR. DRESLER: Okay. Dr. Benowitz, I'm going to ask you

this one. So since I know that you're going to have to leave,

we may come back to this question for some of the others too.

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So what about in pregnant women that are exposed to this

aerosol? We kind of touched on this in the earlier session.

What is the best way to better understand potential adverse

health outcomes of e-cigarettes in the pregnant women, and

especially on the impact on the fetus?

DR. BENOWITZ: Well, certainly for active exposure. And I

think the study that you just heard, in the mice, raises real

concerns that if the mother is using e-cigarettes during

pregnancy, it certainly could have adverse effects. So I

think, to me, that's pretty clear.

Secondhand emissions, it's not so clear. I think there

could be some nicotine levels. What those levels mean, you

know, it's hard to say. We do have studies with NRT during

pregnancy, where at least NRT compared to cigarette smoking

appears to be less harmful. The levels from e-cigarettes are

certainly going to be lower than levels from secondhand --

levels from secondhand e-cigarette emissions are certainly

going to be lower than NRT levels.

So I would guess that you probably are not going to see

adverse effects, but there are some effects of nicotine that

occur at incredibly low concentrations that we don't

understand. So I would say probably not, but not definitely

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not.

DR. DRESLER: Okay, all right. Any other questions

because Dr. Benowitz is going to have to leave?

(No response.)

DR. DRESLER: So okay, thank you. And we'll come back for

more panel questions after the next two speakers.

So the next speaker is Dr. Jeannie Limpert. She's from

the FDA Center for Tobacco Products. She's going to be

speaking on Electronic Nicotine Delivery Systems: Nonuser

Adverse Experiences Reported to FDA/CTP.

DR. LIMPERT: Good afternoon. My name is Jeannie Limpert,

and I'm a medical officer with FDA/CTP Office of Science. I

don't have any financial conflicts -- financial disclosures or

conflicts of interest. I look forward to providing a brief

summary of the adverse experiences related to e-cigarettes and

other electronic nicotine delivery systems, or ENDS, in

nonusers that have been reported to CTP.

I will first provide a brief overview of the process for

reporting an adverse experience to CTP. CTP receives voluntary

reports of adverse experiences involving tobacco products from

consumers, healthcare professionals, and members of the public.

Reports are received via the Safety Reporting Portal, MedWatch,

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mail, and e-mail. And voluntary reports have described adverse

experiences not only in users but also in nonusers.

In January of 2014, CTP launched a web-based reporting

system called the Safety Reporting Portal, featuring tobacco

product-specific queries to streamline the incoming

information. The portal can be accessed via the FDA website or

directly via the web address noted here on the bottom of this

slide.

The goal of the Safety Reporting Portal is to identify

previously undetected health concerns and take appropriate

action to prevent further adverse experiences and to educate

consumers about health risks. Reports submitted are reviewed,

evaluated, and where appropriate, issues are addressed to

ensure the protection of the public health.

Reports may be about tobacco products currently regulated

by CTP as well as those that are not currently under CTP

jurisdiction, such as ENDS products.

This is a screenshot of the first page of the tobacco

product-specific Safety Reporting Portal, and the portal takes

reporters through screens designed to gather information both

about the tobacco product and the issue of concern.

So I will now move on to review the voluntary adverse

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experiences associated with ENDS, reported to CTP, in nonusers.

This graph depicts the number of adverse experience reports

related to ENDS, broken down by whether the report identified

an adverse experience in a user or nonuser. So for each year,

the number of reports in dark red and on the left represent

users, and the number of reports in pink and to the right

represent nonusers.

So, as you can see, while the number of reports -- while

the overall number of reports is small, the number of reports

that we received have increased, including the number of

reports in nonusers.

The highest number of nonuser reports are related to

passive exposure to exhaled aerosols. We've also received

reports of device malfunction, choking, dermal exposure, and

e-liquid ingestion.

So as per the previous slide, the highest number of

nonuser reports are related to exhaled aerosols, and reports

have described symptoms, including dizziness, eye irritation,

headache, nausea, racing and irregular heartbeat, chest

discomfort, respiratory complaints, and sore throat. And

respiratory complaints were the most frequently reported

symptoms. And some examples of the types of respiratory

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complaints received include asthma exacerbation, difficulty

breathing, pneumonia, and coughing.

Of note, reporters frequently reported more than one

symptom or adverse experience. These exposures were typically

in indoor spaces such as apartments and homes or public

settings such as offices or restaurants. Some reports included

information about recurrent adverse experiences after repeat

exposure, symptoms in more than one person, medical attention

and treatment received, and history of underlying conditions.

Other exposure reports have included four reports of burns

due to device overheating and device explosion and two reports

of death. The first was an infant who died after choking on an

e-liquid cartridge, and the second report was a toddler who

ingested e-liquid containing nicotine and died. We also

received one report of lip cheilitis, or local inflammation,

that developed after the reporter had kissed someone who had

used an e-cigarette.

So these reports provide important information about

potential health risks. However, interpretation of these

reports has important limitations. Reporting adverse

experiences to CTP is voluntary. So reports received likely

underestimate the true number and types of adverse experiences

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associated with these products. Data cannot be used to

calculate incidence or to estimate risk, and experiences

reported may not have a causal relationship to product

exposure.

Additionally, the launch of the Safety Reporting Portal in

2014 may have affected trends in reporting and content.

So, in conclusion, although small in number, adverse

experiences associated with ENDS have been reported in

nonusers. Most commonly, these reports are associated with

passive exposure to aerosols and most commonly identify

symptoms consistent with respiratory tract irritation. Some

symptoms may suggest nicotine exposure and potential toxicity

and suggest that passive aerosol exposure is not completely

innocuous.

Adverse experience reports also include injuries related

to device explosion and overheating, and deaths from accidental

exposure in children have been reported.

Thank you.

(Applause.)

DR. DRESLER: Okay, our next speaker is Dr. Kevin Chatham-

Stephens from the Centers for Disease Control and Prevention,

and he'll be presenting on Calls to U.S. Poison Centers

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Involving Exposure to Electronic Cigarettes.

DR. CHATHAM-STEPHENS: Thank you for the opportunity to

discuss our projects.

So I think there have been several descriptions of the

rising incidence of e-cigarette use, so I'm just going to fast-

forward through these slides.

Given the increasing use of these relatively new devices,

there have been questions regarding the safety of e-cigarettes

and e-liquid. So who is being exposed and how are they being

exposed? And are the exposures leading to health effects?

So some of the acute health effects that may occur

following nicotine exposure include vomiting, headache,

agitation, seizures, and death. Many of these questions were

raised when, in December 2014, the media reported that a

1-year-old child died after ingesting e-liquid.

Given the questions regarding the safety of e-cigarettes

and e-liquid, we sought to quantify calls to U.S. poison

centers reporting exposures to e-cigarettes and e-liquid and

describe the associated acute adverse health effects.

There are currently 55 poison centers in the United

States. When someone calls a poison center, poison center

staff collect standardized information, including information

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about the exposed person, the substance or medication to which

the person was exposed, and any resulting symptoms. These data

are actually uploaded within minutes to the National Poison

Data System, or NPDS, which serves as a national data

repository and surveillance system for poisonings. Each

substance or medication has a unique code in NPDS.

The code for e-cigarettes was released in 2010. So we

searched NPDS from September 2010 through December 2014 for

calls involving e-cigarettes or e-liquid. We combined those

calls and refer to those calls in this presentation as

e-cigarette calls. And to provide a comparison to a

conventional established product with known toxicity, we also

searched for calls involving conventional tobacco cigarettes.

We excluded calls involving multiple exposures, such as to

ethanol and e-cigarettes.

We quantified the number of calls involving e-cigarettes

or e-liquid and conventional tobacco cigarettes. We also

compared e-cigarettes to conventional tobacco cigarettes by age

of the exposed person, using chi-square tests, considering a

p-value of less than 0.05 significant.

In NPDS, health effect severity is categorized as minor,

such as a transient cough; moderate, such as vomiting causing

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dehydration; major, such as respiratory failure or death.

In NPDS, we are unable to tell whether exposures in adults

result from direct use of e-cigarettes or from secondhand

exposures, such as through secondhand aerosol. Since this

particular session focuses on potential health effects in

nonusers of e-cigarettes, I'll present the total number of

calls for all ages and then focus on the effects in children

under the age of 11 years, assuming that these individuals are

not directly using e-cigarettes.

So during the study period, poison centers received 5,970

human exposure calls involving e-cigarettes or e-liquid. And

of these, 163 were excluded for involving exposure to multiple

substances, leaving a total of 5,807 e-cigarette calls.

Poison centers received 21,106 human exposure calls

involving conventional tobacco cigarettes. And of these, 751

were excluded for involving multiple exposures, leaving a total

of 20,355 human conventional tobacco cigarette calls.

Annual e-cigarette calls increased from 238 in 2011 to

3,692 in 2014, which represents a greater than 1,400% increase.

Monthly e-cigarette calls increased from 1 in September

2010 to a peak of 401 in April 2014, followed by a decline to

295 in December 2014, while conventional tobacco cigarette

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calls ranged from 302 to 514 per month.

Here I show the age groups for e-cigarettes and

conventional tobacco cigarettes; 58% of e-cigarette exposures

occurred among the 0- to 5-year age group, and 35% of exposures

occurred among the greater than or equal to 20-year age group,

while 95% of conventional tobacco cigarette exposures occurred

among the 0- to 5-year age group.

So, for the remainder of the presentation, I'll focus on

the 3,449 calls involving children younger than 11 years of age

who were exposed to either an e-cigarette or e-liquid. Just

over half of the e-cigarette calls involved males.

In terms of the location of calls, 17% of e-cigarette

calls came from the healthcare facility. For the 2,713 calls

that originated outside of a healthcare facility, the majority

of e-cigarette calls (69%) were managed on site. An additional

30% of e-cigarette calls were referred to a healthcare facility

or already en route to a healthcare facility.

The most common route of exposure for e-cigarette calls

was ingestion at 80%, followed by multiple routes of exposure

at 10%, inhalation/nasal exposure at 4%, skin exposure also at

4%, and eye exposure at 2%.

To determine the medical outcome, poison center staff must

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collect sufficient information about the exposure, route, and

health effect. Of the 3,449 e-cigarette calls, sufficient

information was available for 69%. And of these calls with

sufficient information, 37% of e-cigarette calls reported an

adverse health effect. And of the calls reporting an adverse

health effect, 92% were categorized as a minor effect, 7% as a

moderate effect, 0.3% as a major effect, and there was one

death reported to U.S. poison centers.

For the e-cigarette calls reporting a health effect, the

eight most common effects were vomiting, drowsiness, eye

irritation, nausea, cough, tachycardia, agitation, and red eye.

This analysis is subject to several limitations. Because

reporting to poison centers is voluntary, we likely

underestimate the total number of e-cigarette and conventional

tobacco cigarette exposures. And, in fact, the Institute of

Medicine estimates that less than half of all poisonings are

reported to poison centers.

The type of e-cigarette device involved in each exposure

was also unknown, which may limit our ability to generalize the

results of this analysis, given the variety of devices that are

available and the rapidly changing e-cigarette market. We also

have limited data on the concentration of the e-liquid involved

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in each of these exposures.

As I mentioned earlier, in NPDS, we are unable to

differentiate primary exposures from secondary exposures. So

this analysis likely misses adults who experience secondhand

exposures.

In addition, almost one-third of the e-cigarette calls did

not have outcome data. And the lack of data on monthly

e-cigarette use meant that we were unable to calculate rates of

adverse health effects.

To conclude, annual e-cigarette calls increased by greater

than 1,400% from 2011 through 2014, with 60% of the calls

involving children less than 11 years of age. Most of the

health effects commonly reported in the e-cigarette calls were

consistent with nicotine exposure. And the majority of

e-cigarette calls resulted in minor adverse health effects.

Given the overall increase in e-cigarette calls to U.S.

poison centers and predictions of e-cigarette use continuing to

increase, healthcare providers and the public should be aware

of the potential for acute adverse health effects from

e-cigarettes.

Developing strategies to monitor and prevent adverse

health effects from these novel devices is critical. Some

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strategies may include CDC continuing to use NPDS for

surveillance of e-cigarette calls; manufacturers evaluating the

potential use of child-resistant containers for e-liquid;

manufacturers considering implementation of clear, standardized

labeling for e-cigarettes and e-liquid; and public health

messaging to e-cigarette users regarding safe handling of

e-liquid as well as appropriate storage of the devices and

e-liquid around children.

I would like to thank our collaborators at CDC, including

the Office on Smoking and Health, and FDA as well as the

AAPCC/local poison centers. Thank you.

(Applause.)

DR. DRESLER: So could we have the presenters come up to

the front, and we'll go for clarifying questions and other --

so please send your questions over. Yes, sir, it's coming.

Diane Ashton. Diane Ashton, are you coming over here or

is it going to be down there? Wherever you would like.

Okay. And for our transcriber, Dr. Chatham-Steffens --

Stephens, Steffens. Okay. Dr. Graff, Dr. -- oh boy, Collaso.

I know I haven't got this pronunciation; Collaso?


DR. DRESLER: Colloso. Okay, thank you. Dr. Phillips and

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Diane Ashton, right? Dr. Ashton. Yes, thank you.

Okay. So could we have, please -- so the last two, could

you please say where you're from and your declaration of

interests, please?

DR. PHILLIPS: Sure. I'm Carl V. Phillips. My research

is focused on tobacco harm reduction for 15 years, first as a

professor and now with CASAA. I'm here under the auspices of

CASAA, which represents its 60,000 members and other consumers

and would-be consumers of low-risk tobacco products. I would

say this is not a conflict of interest because consumers are

the one group whose interest is to understand, without spin or

hype, the real health effects of the products.

I wanted to note that this marks the first time that any

public meeting in the history of CTP, that a representative of

the primary stakeholder, the consumers, has been given a seat

at the table, which appears to be a small step in the right

direction, though since I'm here in my role as a scientific

expert rather than consumer advocate, it's not clear whether it

should really count.

In terms of my personal funding outside of CASAA, at one

time or another I received research grants or consulting

contracts from most everyone with a financial interest in this

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matter. That includes companies that sell e-cigarettes. It

also includes those that benefit from the sale of competing

products, pharmaceuticals, smokeless tobaccos, and cigarettes.

In particular, I received funding from those who profit the

most from the sale of cigarettes, which of course is the

government of the United States and other jurisdictions as well

as those who manufacture those products.

DR. DRESLER: So your declaration of interest, please,

Dr. Ashton.

DR. ASHTON: I am an obstetrician-gynecologist. I'm the

Deputy Medical Director at the March of Dimes, Vice President

for Health Equity, and I too am, I guess, representing the

consumer interest.

The mission of the March of Dimes is to improve the health

of babies by preventing birth defects, prematurity, and infant

mortality. And one of our earliest interventions when we began

our prematurity campaign in 2003 was smoking cessation and the

impact of tobacco on preterm birth and adverse birth outcomes.

So we definitely have an interest in the use of e-cigarettes

and potential for adverse outcomes.

DR. DRESLER: Okay. All right, the first question is for

you, Dr. Graff. If glycerin is added, would it be more or less

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likely to see bystander absorption due to the variation of

particle size or viscosity of the carrier liquid? So if

glycerin is added.

DR. GRAFF: That's a great question, and I don't think

that I have an answer for it. I do know that, you know, the

composition of our liquid that we used in our study is

obviously not standard, and so there could be a lot of

different characteristics upon heating, that when you add

glycerol, you could see something completely different.

DR. DRESLER: Okay. Even though e-cigarette aerosols

appear to be less toxic than secondhand smoke, how can we be

sure they don't pose any additional risk to bystanders,

especially children? So what evaluations should be conducted?

So, in this area looking at bystanders such as children,

infants, what evaluations should be conducted?

DR. COLLACO: Well, I think there's -- you know, obviously

there are a lot of ethical issues about researching children.

I mean, I don't think I know any parents who would voluntarily

expose their child to e-cigarettes as part of a research study.

So sometimes, you know, we're left with either modeling through

animal models or other types of studies to get at secondhand

exposure effects or, you know, retrospective studies,

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observational studies of the health effects of e-cigarettes in

children. And to the best of my knowledge, there aren't any

large-scale studies of that sort that have been started yet.

DR. GRAFF: So I think when you talk about a prospective

clinical trial, then yes, you're not going to find any parents

who are not consumers that are going to, you know, expose their

children. However, if you look at some of the work that EPA

has done with pesticides and some of the natural exposures in

epidemiological-type studies, something like that might provide

some of that information. It's just a matter of who's willing

to do that, perform those studies.


DR. PHILLIPS: One important point that's getting lost

here in terms of the importance of this information is that

supposedly a ban of e-cigarettes is not actually on the table,

and that means that from a policy and regulatory perspective,

we're talking about whether we're going to be imposing exposure

bans in adult venues, like bars and offices, whereas the

exposures to children are mostly in the home. And so, yes, it

would be tremendously useful to be able to advise consumers as

to whether they're causing harm for their children. But from a

regulatory perspective, it's not one of the relevant questions.

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DR. ASHTON: I think there is also the question of

exposure in pregnant women. And, anecdotally, looking at blogs

on the Internet, you do understand that there are pregnant

women who do use e-cigarettes and may not be aware of what

their potential for adverse outcomes are. I think there may be

an opportunity in that population to be able to at least gather

some information about what possible birth outcomes these women

are experiencing, not in a randomized clinical trial. But at

least there would be the opportunity for some information.

DR. DRESLER: Dr. Chatham-Stephens, in poison center

calls, do you differentiate between adverse events of the

device or the liquid?

DR. CHATHAM-STEPHENS: So currently there are two

different codes that we use to differentiate, or the American

Academy of -- American Association of Poison Control Centers

uses for e-cigarettes, and there's one code for e-cigarettes

and one code for the e-liquid. And so up until this point, all

of our analyses have looked at those two codes combined,

because we have some concern regarding the accuracy of those

codes differentiating between exposure to the e-liquid itself

versus the actual device. And it's something that we talked

about with our colleagues, moving forward and starting to look

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at that and see if there is any difference in terms of health

effects surrounding exposure or anything like that.

DR. DRESLER: Okay, and this sort of follows up with this.

Since e-liquid is a liquid and tobacco cigarettes are solid, is

this a good comparison for poisoning for ingestion? So

wouldn't a product like laundry detergent pods be more

applicable for a similar type of vector? A liquid's path can

be oral and through the skin, and tobacco cigarettes have no

path through the epidermis but could cause choking.

DR. CHATHAM-STEPHENS: So, yes, I think at the beginning

of the project we spent quite a bit of time trying to figure

out (1) should we have a comparison group, and (2) what would

be the optimal comparison group? And we talked about several

different things, including laundry pods. Our group was the

group that authored the MMWR a couple of years ago on laundry

pod poisonings.

So I think the reason why we chose to go with the

comparison to conventional tobacco cigarettes was the fact

that, at that point, there was a lot of talk of individuals

switching from conventional tobacco cigarettes to e-cigarettes,

and we thought that they are products that are relatively used

similarly. And so we thought, at that point, that the best

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comparison was conventional tobacco cigarettes, but it's

definitely something that we're continuing to reevaluate.

DR. DRESLER: Okay. Dr. Ashton, this is a question about

the March of Dimes, and what is the official stance of the

March of Dimes related to e-cigs, and perhaps compare that with

what you do for cigarettes or something.

DR. ASHTON: Well, our official stance in terms of tobacco

is that there is no known safe level for women during

pregnancy, and we would certainly extrapolate that same opinion

to be used with e-cigarettes.

DR. DRESLER: Okay. Dr. Chatham-Stephens, taking into

account the number of people who smoke cigarettes versus those

who use e-cigarettes, how do the numbers of calls to the poison

center compare; i.e., there are more smokers than people who

use e-cigarettes? So can you account for that, and how do the

numbers look?

DR. CHATHAM-STEPHENS: Sure. So one of the graphs that I

showed had the number of calls involving e-cigarettes or

e-liquid, and you saw that dramatic increase and then the

slight decline as well. And then the following slide was the

chart showing the conventional tobacco cigarette calls. And at

one point the number of e-cigarette calls actually surpassed

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the number of conventional tobacco cigarette calls, which I

think we were all quite surprised by.

You know, from our standpoint, it's been difficult to find

numbers that you can cite in a medical journal, but some of the

numbers that we found for overall sales was tobacco sales were

about $80 billion, and e-cigarettes sales were about

$2 billion. So there's quite a discrepancy between the sales.

And then what we saw in our findings was that the e-cigarette

calls were actually approximating the tobacco cigarette calls.

DR. DRESLER: So there's a whole bunch more people who

smoke cigarettes than there are e-cigarettes, but about an

equal number --

DR. CHATHAM-STEPHENS: Correct. If you look, there's

still a greater number of tobacco cigarette calls, but the

e-cigarette calls were approaching and surpassed it for 1 month

before tapering off a little bit.

DR. DRESLER: Okay. And the next question has to do with

that the last two speakers showed graphs that showed a drop-off

and compared it to the increased rates per annum, but in 2014

it started to look like there was dip down. What would you

attribute that dip down in adverse events to be?

DR. CHATHAM-STEPHENS: We're not quite sure. So it could

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be that users are becoming more accustomed to e-cigarettes and

they're just not calling poison centers as frequently because

they aren't having as many acute health effects. It could be

some other factor.

We do know that there's some seasonality in all calls to

poison centers. So calls to poison centers are more common

during the summer months, and then they seem to taper off a

little bit in the winter months and then pick back up. So

there is that seasonality effect, and so we stopped looking at

calls through December of last year. So one of the things that

we're hoping to do is update the analysis once we're able to

and see if that seasonality effect continues.

DR. DRESLER: Okay. Yes.

DR. PHILLIPS: I could suggest that within the consumer

community, there was a dramatic increase in awareness about the

possible risks of exposures. And, of course, this is an easily

preventable exposure, through simple physical distance.

There's also been a gratifyingly higher percentage of e-liquid

that's sold in child-resistant containers.

DR. DRESLER: Do you know what percentage that is that are

sold in child-resistant versus other?

DR. PHILLIPS: No, I really don't know what the percentage

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is, but almost all responsible dealers are now going to all

child-resistant. And a lot of that has changed over the last

year and a half or so. So we would have expected to see that

drop-off, just like we did.

DR. DRESLER: Okay. And this question goes to overall,

for poison centers. Actually, I'm forgetting that number,

3,449. Do you remember that? Okay. So what share of total

calls to the poison centers do the 3,449 represent? So I think

the question is what proportion of poisons overall are from

that?

DR. Chatham-Stephens: So each year there are millions of

calls to U.S. poison centers. I believe it's somewhere around

two million, give or take. So if you look at any individual

substance or medication, they account for a very small

proportion. I can't do that math off the top of my head, but

it would be 3,449 divided by all the calls to U.S. poison

centers, so about a couple million.

DR. DRESLER: Okay, all right. So this question goes to

child-resistant packaging, but it seems like additional

measures are needed to adequately protect children. What else

could be done to mitigate the risk of these accidental

poisonings?

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DR. PHILLIPS: Well, I mean, just to repeat what I pointed

out earlier, it's a relatively simple technology to keep that

from happening: child-proof containers and keep out of the

reach of children, exactly what you would do with a bottle of

Tylenol. And, you know, it's useful to have that message out

there, and it's unfortunate that it isn't completely obvious to

everybody even without having the message out there. But

there's just a lot of success in getting it out there. I mean,

obviously nobody wants it to happen, and it's easy to avoid.

DR. DRESLER: So this is a question that -- are any

government agencies working on a rule to require child-

resistant packaging for liquid, like nicotine?

DR. PHILLIPS: Well, there's a bill in Congress right now

that would do it as a one-off regulation at that level. Other

than that, I'm not aware of anything. Individual states have

made some moves, too.

DR. DRESLER: Anybody else?

(No response.)

DR. DRESLER: Dr. Chatham-Stephens, were you able to

ascertain whether the liquids versus devices involved in

incidents as marketed were child resistant? So do you have any

information on your reports of those ingestions, whether they

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were packaged in child-resistant packaging?

DR. CHATHAM-STEPHENS: We do not. So, in NPDS, the

primary purpose behind the AAPCC poison centers is just to

serve as a clinical resource for parents and providers

regarding poisonings. And so we kind of piggyback off of that

for a public health surveillance factor. So right now there

isn't any way to discern whether or not that packaging is child

resistant in NPDS.

DR. DRESLER: Are you planning on doing that, capturing

it?

DR. CHATHAM-STEPHENS: I'm not aware of any proposed

changes, but I would have to touch base with AAPCC.

DR. DRESLER: Okay, all right. So this one is for

Dr. Limpert. Were adverse event reports made by healthcare

professionals, and does the database collect information on

specific products?

DR. LIMPERT: So, for the first question, anyone can

submit a report to the Safety Reporting Portal. The majority

were from consumers, but I know of at least one that was from a

healthcare professional.

And then in terms of specific products, currently in the

dropdown, it's the products that are regulated by CTP, but

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there's an "Other" category where people can report any tobacco

product, and there are plans to add more in the future.

DR. DRESLER: Okay. Then, do you want to address what was

the -- because this is a question about how are you getting the

information about the awareness of the adverse event portal?

Do you want to talk about the rollout and the information that

was shared about the rollout of AE? Is there going to be

information shared about the AE? How do people find out about

the AE profile portal?

DR. LIMPERT: So we've done some presentations about the

Safety Reporting Portal. We haven't done like a PSA about it.

So we hope to kind of raise awareness through these

presentations.

DR. DRESLER: Okay, good. All right, thank you.

Dr. Chatham-Stephens, can you please provide more details

about the three serious cases and the one death case?

DR. CHATHAM-STEPHENS: So, in terms of the death, I think

most -- we didn't gather any additional information from NPDS

than what was portrayed in the media, and that is a 1-year-old

child with ingestion of the e-liquid. So we don't have any

details in NPDS regarding the specifics of the circumstances of

how the child got exposed to it and what else is going on at

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that point.

And then, for the other three, there were three major

effects, and from my recollection, it was a combination of

respiratory effects. As I mentioned, respiratory failure was

one of the defining criteria for major effects. So if I recall

correctly, it's a combination of respiratory effects and then

neurological effects as well.

DR. DRESLER: Okay. For the panel, how can the risk

associated with involuntary exposure to these products be

communicated to the public? How do we let the public know?

DR. PHILLIPS: Well, the question assumes that there's a

risk from the involuntary exposure, and you know, based on the

numbers that we saw from all the credible presenters today, it

doesn't appear that there's any serious risk. The numbers are

in the order of three orders of magnitude lower than the

exposure to the vapors themselves, and we haven't seen much of

a problem there. We aren't entirely sure that there is one,

although certainly we have to keep in mind that there might be.

So, you know, what's to communicate?

I mean, we saw the information yesterday about marketing

and propaganda and so forth that showed that people

overwhelmingly overestimate the risks from the exposure. So I

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suppose, if anything, we need to be communicating to people

that there's far less risk than they might think there is.

DR. DRESLER: I'm going to ask you to go ahead, because

you said the credible ones. So who are the credible ones or

who were the non-credible ones?

(Laughter.)

DR. PHILLIPS: The majority of the presentations, in

keeping with the rest of the science that's out there that

looked at actual measures of environmental exposure, found that

they were trivial. They found that, you know, the nicotine was

being retained by the vapor, the propylene glycol was being

retained by the vapor and so forth, just as we would expect and

just as everything has pointed to already.

There was one exception, but it's a good general rule that

if you think you've discovered something that lots of smart

people are working on who have missed it for a very long time,

there's a 1% chance you're an outstanding genius and a 99%

chance you're from San Francisco.

(Laughter.)

DR. DRESLER: Or we could think of Sir Richard Doll in the

1950s, right? He was that outstanding genius.

Yeah, Dr. Ashton.

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DR. ASHTON: I think there's a lot that's still unknown.

We don't know what long-term exposure is. We still are looking

for questions about what the exact secondhand and thirdhand

exposure is, because these residues, at least these thirdhand

residues, are thought to accumulate over time. And we

certainly don't know what the impacts are as far as fetal

effects, what the thresholds are as far as maternal effects

during pregnancy.

So there are a lot of unknowns, and I think it behooves us

to at least let the consumers know that there are a lot of

unknowns, and if they have the opportunity to avoid exposure,

that we would certainly encourage them to do that. And

hopefully, you know, there will be more research and more

confirmatory research where we're finding consistent results

and we will have more information to be able to counsel

patients more appropriately. But until then I think there's

still a lot that's unknown.

DR. PHILLIPS: Actually, I'd like to clarify my previous

answer and respond to that, because, yes, I was talking about

all the circumstances in the world except pregnancy, and there

is definitely a legitimate concern there that we should be

paying more attention to, you know, either for humans or larval

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mice.

DR. DRESLER: Dr. Collaco.

DR. COLLACO: Yeah, I think it's not just also for

pregnant women, but there's also, you know, a variety of

vulnerable populations out there, you know, where the effects

may be more substantial than for the average otherwise healthy

e-cigarette consumer that we don't know the effects on. And

these vulnerable populations may have, you know, durable

changes to a variety of end organs that we don't know yet, and

that may take some time to develop. Just because we don't see

anything over the 5- or 6-year lifespan of e-cigarettes in the

United States so far, as in terms of long-term health

consequences, doesn't mean they don't exist.

DR. DRESLER: Dr. Graff.

DR. GRAFF: So I guess my opinion on this is that it's an

individual's choice. And so just as use of the products is an

individual's choice, some people are going to take a more

conservative approach to their position on whether or not they

want to be present where these products are used.

And so, on the one hand, you don't want to, you know, use

scare tactics and make something -- make it sound like

something is there that's not. But, at the same time, you

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know, how do you convey that, well, we don't know? We don't

know enough at this point, and we need to continue to evaluate,

and it might take a long time before -- you know, the 5 years

that they've been on the market perhaps isn't long enough.

But, again, I do go back to it's a personal choice, and

you know, if people want to use the products, great. If they

don't want to be in the presence of people who use -- involved

where the products are being used, you know, that's their

personal choice.

DR. CHATHAM-STEPHENS: So just a follow-up point. So as

pediatricians, we often provide anticipatory guidance to our

families on creating a safe and healthy home, and part of that

is simply having our parents be aware of potentially dangerous

substances that are in the house, and that ranges from anything

like their prescription medications to gasoline for the lawn

mower to pesticides for their backyards.

So I think from our standpoint, a very simple thing is

just for parents to be aware that if they do have e-cigarettes

or e-liquid in the house, that it could potentially be

dangerous to infants and young children.

DR. DRESLER: Okay.

DR. Phillips: Just to pick up on some of that. You know,

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there's this chorus of "we don't know." On my live blog, they

had turned it into a drinking game. But we actually know quite

a lot more than is being implied because, as was pointed out by

a couple of speakers -- Dr. Sarkar, I think -- these are not

novel exposures. We know about the exposure to nicotine

ex-smoke from lots of people who have used smokeless tobacco

for a very long time. We know about exposures to humectants.

We know about exposures to most of these constituents from

plenty of studies of other products.

And so to pretend that we are completely ignorant about

all of that and that we have to only study the exposure to this

one particular product means that we never know anything. I

mean, by that logic, we don't know that smoking in the 21st

century is bad for you. I mean, we have a lot of evidence that

it was bad for you in the 20th century, but we don't have that

evidence about the 21st century yet. Oh, but we can

extrapolate from what we already know, and we need to do that.

That's what science does, it tries to make the best use of the

available information, not to throw up our hands and say we

don't have the perfect information, so we don't know anything.

DR. DRESLER: So I think that's a good segue into the next

question. So we know from secondhand smoke laws that not only

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did that protect the nonusers, but it also impacted initiation

in youth, that they were less likely to start smoking if they

were in an environment with secondhand smoke laws. So how does

this exposure now to e-cigarettes and their use impact

initiation, especially in youth and nonsmokers, and does it

renormalize tobacco use?

DR. GRAFF: I think somebody mentioned yesterday, in one

of the presentations, there was a question like this, and the

expectation, I think, is probably going to be just based on

logic and human nature that kids are going to do what their

parents do. And so it wouldn't surprise me a bit, and I think

the speaker yesterday -- and I've forgotten who it was -- said

pretty much the same thing. You know, if you see your parents

smoking, history tells us that your kids are going to smoke.

If your parents are using these products, I would assume that

there's a pretty good likelihood that the kids will as well.

DR. DRESLER: Anyone else? The pediatricians not going

near that?

DR. COLLACO: You know what we're going to say on that.

DR. DRESLER: Maybe they don't.

DR. COLLACO: Well, I think -- you know, I think everyone

in the room would agree that youth not initiating these

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products is a good idea. You know, I don't think anyone would

disagree with that. And certainly there is a debate about how

best to achieve that, but at the end of the day, I think we

share that goal. You know, as a pediatrician, I think at least

my primary intervention is counseling in the office. But, you

know, certainly there are other avenues for getting that

message out.

DR. DRESLER: Okay.

DR. PHILLIPS: Just on the renormalizing trope, because we

hear that all the time, but it's very difficult to understand

how ostentatiously not smoking, which is what vapers are doing,

can tend to convince people that smoking would be a good idea.

DR. DRESLER: Smoking e-cigarettes?

DR. PHILLIPS: Yeah. So vaping is very obviously not

smoking. Ninety-nine percent of those who are doing it did it

to quit smoking, and that's a signal that smoking is not a good

idea and you should try to avoid it, rather than a signal that

smoking is normal.

DR. DRESLER: So why are the youth rates going up so much?

DR. PHILLIPS: Youth rates of smoking are not going up.

DR. DRESLER: No, for e-cigarette use. No, it's the issue

of renormalizing inhalation of a nicotine delivery device.

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DR. PHILLIPS: Well, that's a different question than the

usual claim, and the way you phrased your question --

DR. DRESLER: That's what they meant, though, it's

renormalizing. So that was what -- because the issue is, is

that e-cigarette use in kids is going up. And so would that

normalize inhalation of a cigarette or e-cigarette?

DR. PHILLIPS: Well, to some extent. Of course, those

numbers are exaggerated also. We heard plenty about people

finally coming around and recognizing that ever tried is not

used. Tried in the last 30 days is not current use. So we

have grossly exaggerated numbers there. But, of course, it is

increasing exactly as you would expect for any normal -- for

any novel product.

I mean, the fact is that a substantial portion of the

human population likes the effects of nicotine. A substantial

but fortunately much smaller portion of kids are going to go

out and use some drug, whatever it is. If it's this one, it's

almost certainly better than whatever their second choice was

going to be for them.

And the reality is that -- you know, I make no secret of

my predictions in this. You know, I predict that in 2050, half

the population is going to be using nicotine again, like they

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once were, because they can be using it in forms that are very

low risk, and they will know that they are very low risk as

opposed to the misinformation that's widespread today. In

fact, we don't know if the risk is positive at all from this.

There are certainly benefits too.

And so, yeah, we have a new normal. It's like the normal

of coffee drinking or the unfortunate normal of cigarette

smoking 50 years ago. What's left out of that worry is why

that's a bad thing.

DR. DRESLER: Dr. Ashton, what is the March of Dimes

recommendation for breastfeeding and nicotine or e-cigarette

use?

DR. ASHTON: That's a good question. I mean, I can't say

that we have a firm policy, but at least as far as good medical

advice, we know that nicotine is transmitted through breast

milk, and we would sincerely recommend that mothers do not

smoke and breastfeed. The American College of Obstetricians

and Gynecologists very clearly recommend that we take active

measures to counsel women and work with pregnant women on

behavioral modification. We know that pregnancy is a time

where there is a high motivation to quit smoking among mothers,

and we certainly try and take advantage of that.

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So at this point we would, you know, recommend that women

undergo behavioral modification to stop smoking during

pregnancy and especially be cognizant that it is being

transmitted in their breast milk.

DR. DRESLER: Okay. So the question came up about choice,

personal choice. So personal choice is not relevant in

secondhand and thirdhand exposure. Please comment on how to

minimize risk exposures to others' risk of nicotine. So, in

those who are -- it's not a choice in second- and thirdhand.

Please comment on minimizing the risk. This was in response to

you.

DR. GRAFF: Yeah.

DR. DRESLER: No, you go ahead and address it, even though

it said not for you because you're --

DR. GRAFF: Okay.

DR. DRESLER: -- the one who brought it up. But you can

go ahead. Go ahead.

DR. GRAFF: So I think it is a personal choice, and I go

back to I'm from Lincoln, Nebraska, and for a number of years

in my college days and maybe post-college days, you know, there

were certain establishments that didn't allow smoking. And so

I chose those establishments if I didn't want to be around

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smokers. So it's the same thing here. I think a lot of the

laws these days are sort of bringing electronic cigarette use

into the indoor smoking regulations, and so I do think that

it's a personal choice.

DR. DRESLER: So is that limiting? Because this does get

into the choice argument, and I think that's why the person is

suggesting not going, too, because it does limit the choices of

people who want to go into that establishment but can't because

they have asthma. So you couldn't go --

DR. GRAFF: Well, I suppose, yes.

DR. DRESLER: Yeah.

DR. GRAFF: Yes.

DR. DRESLER: Okay.

DR. GRAFF: Yeah.

DR. DRESLER: I think that's probably what they were going

to.

Anybody else want to address that?

(No response.)

DR. DRESLER: No? Okay.

With nicotine addiction often characterized in research as

more difficult to quit than heroin, why would we want 50% of

the population addicted to nicotine?

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DR. PHILLIPS: Well, it's not a matter of what we want;

it's a matter of what individuals want for themselves. But the

premise of the question is a little sketchy because there's

very little evidence that nicotine ex-smoke causes this thing

that sometimes gets called addiction.

You know, incidentally, by NIDA's definition, which is the

only official government definition of addiction I'm aware of,

smoking isn't addictive. It doesn't fit their description but

take as the vague definition of addiction that which is

experienced by smokers.

There is no evidence that e-cigarette users or users of

other low-risk products have the same experience. NRT is

officially non-addictive. It's a nicotine delivery system.

Most people who switch from smoking to vaping, people who

thought, oh, I can never quit smoking and, you know, believed

that that was their feeling switched to vaping and find in 6

months they can take it or leave it. Usually they keep taking

it because they like it. It's a choice. There's not a single

case study reported of anyone reporting saying I have become

addicted using e-cigarettes as a never smoker.

So the assumption that this experience, call it addiction,

which isn't really a very good term, or whatever you want, this

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experience of smokers translates to these other products

appears to be wrong.

DR. DRESLER: So e-cigarettes are not addicting?

DR. PHILLIPS: Well, again, by NIDA's definition, neither

are cigarettes. It's a very fuzzy term. What I would say is

that that which is experienced by cigarette smokers, and it

sometimes gets called addiction, does not seem to be present,

certainly not to the same extent and potentially not at all

among exclusive users of e-cigarettes.

DR. DRESLER: Anybody else want to address whether

e-cigarettes or nicotine or smoking is addictive?

DR. GRAFF: I'm pretty sure that nicotine is addictive.

(Laughter.)

DR. DRESLER: Okay, I noticed -- this is for Dr. Chatham-

Stephens. I noticed high rates of calls to poison centers from

a group of nonusers about 20 years old. What kind of adverse

events were reported in this age group and what routes of

exposure? So, in the people that were nonusers over 20, what

were those adverse events and routes of exposure?

DR. CHATHAM-STEPHENS: Sure, just to clarify. So when I

showed all the ages, that was the entire cohort or the entire

group of calls to poison centers, so that didn't exclude

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adults. So when I showed that table with individuals over 20

years, those were adults who reported some health effect from

e-cigarettes, and it could have been users or nonusers. We

can't tell for sure in NPDS.

What we do know is that, not surprisingly, the majority of

calls for the 0- to 5-year age group were mostly ingestion.

And as you get up into the older age groups, then you find that

the proportion of individuals reporting an ingestion exposure

decrease and the inhalation/nasal exposure increases.

DR. DRESLER: Okay.

DR. CHATHAM-STEPHENS: Which is not surprising given the

exposures.

DR. DRESLER: Okay. Are there any other questions?

Questions? No?

(No response.)

DR. DRESLER: Any other questions from the panelists to

the other panelists? No?

(No response.)

DR. DRESLER: Well, very good. Thank you so very much for

the presentations and for all of the panelists. Thank you.

(Applause.)

DR. DRESLER: Thank you for sticking it out through the

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second day and staying on. And we conclude our series of

e-cigarettes. Thank you.

(Whereupon, at 2:44 p.m., the meeting was concluded.)

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301-924-1556

C E R T I F I C A T E

This is to certify that the attached proceedings in the

matter of:

ELECTRONIC CIGARETTES AND THE PUBLIC HEALTH:

A PUBLIC WORKSHOP

June 2, 2015

Hyattsville, Maryland

were held as herein appears, and that this is the original

transcription thereof for the files of the Food and Drug

Administration, Center for Tobacco Products.

_______________________

CATHY BELKA

Official Reporter

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