E-Cigarette FAQs
The increasing use of
e-cigarettes, particularly in our pediatric population is of concern primarily because
of uncertainties surrounding chronic exposures to nicotine and other chemicals. A recent rule finalized by the FDA in August
8, 2016 will likely affect manufacturers, retailers and consumers of
e-cigarettes and e-liquids as follows. Below are a few FAQs regarding e-cigarettes.
1. How do the FDA rules affect e-cigarette
manufacturers?
If you make,
modify, mix, manufacture, fabricate, assemble,
process, label, repack, relabel,
or import any “tobacco
product,” then you are considered a tobacco product manufacturer. If you are
a tobacco
product manufacturer, then you
must:
2016
·
Stop distributing products with
modified risk claims (other
than “light,” “low,” or
“mild”) by August 8, 2016.
2017
o February 8,
2017 or
o February 8,
2017 or
2018
2019
2.
How do the FDA rules affect e-cigarette retailers?
If
you sell e-liquids, pipes or cigars, but do NOT mix
or prepare e-liquids, make or modify
vaporizers, or mix loose tobacco,
then you are considered a tobacco retailer. Requirements for retailers include:
Beginning August 8, 2016:
·
Only sell tobacco products
to customers age 18
and older.
·
Check photo ID of everyone under
age 27 who attempts to purchase
tobacco products.
·
Do NOT give away
free samples, including any components or parts.
·
Do NOT sell in
a vending machine unless in an adult-only facility.
Beginning May 10, 2018:
·
Do NOT sell, distribute, or display advertisements for any tobacco product without a health
warning statement on the package.
3. How do the FDA rules affect e-cigarette
consumers?
People
who buy or use e-cigarettes will also be affected by this new regulation. These
new rules are focused on preventing the use of these products by young
people. They “…prohibit false and misleading product
claims, and prevent new tobacco products from being marketed unless a
manufacturer demonstrates that the products meet the relevant public health
standard.” E-cigarette users appearing to be under the age of 27 will have to present photo ID’s when purchasing
tobacco products or components to the e-cigarette. If
consumers are making, modifying
or mixing e-liquids, they will
have to comply with
the same requirements as the manufacturers.
References:
4.
What are the average nicotine
levels and range of nicotine levels that users of e-cigarettes exposed to?
E-cigarettes
typically come in 3, 6, 12, 18, 24, 36 and in some cases up to 54 mg/mL of
liquid nicotine. The dosing corresponds
to the level of liquid nicotine. The 18 to 24 mg/mL doses are most comparable
to regular cigarettes. It has been found in one study that on average, 50-60%
of the nicotine from a cartridge is vaporized although different models of e-
cigarettes differ in their efficacy (Goniewicz, et al. 2013). A
review on electronic cigarettes
stated one study that found
the average aerosolized nicotine level in a 18 mg nicotine
cartridge was
82.8 µg nicotine/100 mL aerosol
(Schroeder and Hoffman, 2014). According
to an article published in 2013 that
analyzed sixteen popular
e-cigarettes, a range of 0.5
to 15.4 mg from 300 puffs (calculates out to
1.67-51.3 µg/puff) of nicotine
was measured in the vapor (Goniewicz
et al., 2013). It is estimated
that e-cigarettes can deliver 0.35-43.2
µg nicotine/100 mL puff
whereas a Marlboro cigarette
delivers 152-193 µg
nicotine/100 mL puff
(Schroeder and Hoffman, 2014). Differences in puffing duration when
comparing experienced consumers (those using e-cigarettes) and naïve users
(regular smokers) also contribute to nicotine level differences in plasma.
E-cigarette users were shown to have longer puff durations (4.2 seconds)
whereas smokers using the e-cigarette exhibited a similar puffing patter as
when they smoke and actual cigarette (approximately2.4 seconds) (Konstantinos,
et al. 2015).
References:
Farsalinos,
K.E., et al., (2015). Nicotine
absorption from electronic cigarette use: comparison between experienced
consumers (vapers) and naïve users (smokers).
Scientific Reports 5.
Schroeder, M. J.,
and Hoffman, A. C. (2014)
Electronic cigarettes and nicotine.
Clinical Pharmacology,Tobacco control 23 Suppl
2, ii30-35.
Goniewicz, M. L., Kuma, T.,
Gawron, M., Knysak, J., and
Kosmider, L. (2013) Nicotine
levels in electronic cigarettes, Nicotine
& tobacco research
: official journal of
the Society
for Research on Nicotine
and Tobacco 15, 158-166.
5. What is the target of nicotine and
how does it signal?
Nicotine is a tertiary amine
consisting of a pyridine and a pyrrolidine ring. (S)-nicotine, found in
tobacco, binds stereoselectively to nicotinic cholinergic receptors (nAChRs).
(R)-nicotine, found in small quantities in cigarette smoke owing to
racemization during the pyrolysis process, is a weak agonist at nAChRs. When a person inhales smoke from a cigarette,
nicotine is distilled from the tobacco
and is carried in smoke particles into the lungs, where it is absorbed rapidly
into the pulmonary venous circulation. It then enters the arterial circulation
and moves quickly to the brain. Nicotine diffuses readily into brain tissue,
where it binds to nAChRs, which are ligand-gated ion channels. When a
cholinergic agonist binds to the outside of the channel, the channel opens,
allowing the entry of cations, including sodium and calcium. These cations
further activate voltage-dependent calcium channels, allowing further calcium
entry. The nAChR complex is composed of
five subunits and is found in both the peripheral and central nervous systems.
In the mammalian brain, there are as many as nine α subunits (α2 to α10) and
three β subunits (β2 to β4). The most abundant receptor subtypes in the brains
of humans are α4β2, α3β4, and α7 (homomeric). The α4β2* (asterisk indicates
possible presence of other subunits in the receptor) receptor subtype is
predominant in the human brain and is believed to be the main receptor
mediating nicotine dependence. In mice, knocking out the β2 subunit gene
eliminates the behavioral effects of nicotine, such that nicotine no longer
releases dopamine in the brain or maintains self-administration. Reinserting
the β2 subunit gene into the ventral tegmental area of a β2 knockout mouse
restores behavioral responses to nicotine. The α4 subunit appears to be an
important determinant of sensitivity to nicotine. In mice, a single nucleotide
point mutation in the pore-forming region results in a receptor that is
hypersensitive to the effects of nicotine. This mutation makes mice much more
sensitive to nicotine-induced reward behaviors, as well as to effects on tolerance
and sensitization. The α3β4 nAChR is believed to mediate the cardiovascular
effects of nicotine. The homomeric α7 nAChR is thought to be involved in rapid
synaptic transmission and may play a role in learning and sensory gating. The
α4 β2* receptor may include α5, α6, and/or β3 subunits, which may modulate the
sensitivity and function of the receptor. For example, α5 knockout mice are
less sensitive to nicotine-induced seizures and hypolocomotion. Brain imaging studies demonstrate that
nicotine acutely increases activity in the prefrontal cortex, thalamus, and
visual system, consistent with activation of corticobasal ganglia-thalamic
brain circuits. Stimulation of central nAChRs by nicotine results in the
release of a variety of neurotransmitters in the brain, most importantly
dopamine. Nicotine causes the release of dopamine in the mesolimbic area, the
corpus striatum, and the frontal cortex. Of particular importance are the
dopaminergic neurons in the ventral tegmental area of the midbrain, and the release
of dopamine in the shell of the nucleus accumbens, as this pathway appears to
be critical in drug-induced reward. Other neurotransmitters, including
norepinephrine, acetylcholine, serotonin, γ-aminobutyric acid (GABA), glutamate,
and endorphins, are released as well,
mediating various behaviors of nicotine.
Reference:
Benowitz, Neal L. "Pharmacology of nicotine:
addiction, smoking-induced disease,
and therapeutics." Annual
review of pharmacology and toxicology 49
(2009): 57.
6.
Chronic exposure to nicotine poses a number of adverse effects with
addiction being the most prevalent. In
addition, however, nicotine also acts as a tumor promoter. What are the mechanisms by which nicotine is
thought to exert its tumor promoting effects.
Nicotine
can contribute in a variety of ways to cancer survival, growth, metastasis,
resistance to chemotherapy, and create a tumor-supporting microenvironment, thus
implementing a "second hit" that aggravates aberrant signaling and
elicits survival and expansion of cells with genomic damage. The list of
cancers reportedly connected to nicotine is expanding, and presently includes
small- and non-small cell lung carcinomas as well as head and neck, gastric,
pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and
kidney cancers.
Nicotine
can displace the autocrine and paracrine hormone-like molecule acetylcholine
(ACh) from the nicotinic class of ACh receptors (nAChRs) expressed in lung
cells due to its higher receptor-binding affinity. ACh is produced practically
by all types of human cells, and is remarkably abundant in the lung epithelium.
Increasingly, a wider role for ACh in cell biology is being recognized,
including proliferation, differentiation, apoptosis, adhesion and motility. The
final cellular response to ACh is determined by the delicate balance between
the growth- promoting and inhibiting signals. The extracellular pool of ACh is
replenished by vesicular ACh transporter secreting the ACh-containing vesicles,
whereas the intracellular pool is represented mainly by free cytoplasmic ACh.
In human bronchioalveolar carcinoma cells, nicotine upregulates choline
acetyltransferase and vesicular ACh transporter, thus increasing production and
secretion of ACh. Nicotine also can upregulate nAChR expression, thus shifting
ACh signaling in lung cells toward the nicotinic vs. muscarinic physiological
signaling pathways. The nAChR subunit proteins can physically associate with
both protein kinases and protein tyrosine phosphatases in large multimeric
complexes. Even a short-term exposure to nicotine activates mitogenic signaling
pathways involving signaling kinases. The nAChRs mediate the nicotine- dependent
upregulation of genes contributing to progression of lung cancer. Nicotine can
permeate lung cells and activate the mitochondrial (mt-)nAChR subtypes found on
the mitochondrial outer membrane of lung cells. Activation of these receptors
may inhibit opening of mPTP, which can block the initial step of intrinsic
apoptosis. The mPTP is a multi-component protein aggregate comprised by
structural elements of the inner as well as outer mitochondrial membrane that
form a non-specific pore permeant to any molecule of <1.5 kDa in the outer
mitochondrial membrane under conditions of elevated matrix Ca2+.
mPTP opening causes massive swelling of mitochondria, rupture of outer membrane
and release of intermembrane components that induce intrinsic apoptosis, such
as cytochrome c (CytC). Mitochondria become depolarised causing inhibition of
oxidative phosphorylation and stimulation of ATP hydrolysis.
Reference:
Chernyavsky, Alex I et al.
“Mechanisms of Tumor-Promoting Activities of Nicotine in Lung Cancer: Synergistic
Effects of Cell Membrane and Mitochondrial Nicotinic Acetylcholine Receptors.”
BMC Cancer 15 (2015): 152. PMC. Web. 15 Sept. 2016.
7.
What are some of the most popular flavors of e-cigarettes?
One website lists the most popular
flavors as: Fruit (30%), Tobacco (22%), Dessert/Bakery (19%), other – DIY or
flavorless (7%), Menthol (mint/peppermint) (6%), Spicy/Savory (5%), Candy (4%),
Menthol (3%), Beverage (3%), all (1%).
Reference:
http://ecigclopedia.com/10-most-popular-e-liquid-flavors-used-by-vapers/
8.
In addition to nicotine, what
other chemicals can be found in e-cigarettes?
Chemicals detected in e-cigarette
liquid include, but not limited to: propylene glycol, 3,4-
dimethoxybenzaldehyde, methyl cyclopentanolone, ethyl maltol,
3-methylcycopentane-1,2-dione, 5- methyl-2-phenylhex-2-enal,
2,5-dimenthylpyrazine, formaldehyde, acetaldehyde, nitrosoamines (NNN, NNK, NAT, and NAB). Chemicals detected in e-cigarette vapor
include, but not limited to: p,m-xylene, glycerine, acrolein, toluene,
nitrosamines, pyrene, 1-methyl-phenanthrene, phenanthrene, cadmium, nickel,
lead, chromium, formaldehyde, acetaldehyde, acetone, NNN, and NNK. Of these, those of the most concern include nitrosamines,
heavy metals and formaldehyde.
References:
Kavvalakis, M. P., Stivaktakis, P. D., Tzatzarakis, M.
N., Kouretas, D., Liesivuori, J., Alegakis, A. K.,
Vynias, D.,
and Tsatsakis, A. M.
(2015) Multicomponent analysis of replacement liquids of electronic cigarettes
using chromatographic techniques, Journal of analytical
toxicology 39, 262- 269.
Cheng, T. (2014)
Chemical evaluation of electronic cigarettes, Tobacco control
23 Suppl 2, ii11-17.
Goniewicz, M. L., Knysak,
J., Gawron, M., Kosmider, L., Sobczak,
A., Kurek, J., Prokopowicz, A.,
Jablonska-Czapla, M., Rosik-Dulewska, C., Havel,
C., Jacob, P., 3rd, and
Benowitz, N.
(2014) Levels of selected
carcinogens and toxicants
in vapour from electronic cigarettes, Tobacco control
23, 133-139.
