On the Safety of E-cigarettes: “I can Resist anything except Temptation” 1

Abstract

Strategic policy decisions are being made about e-cigarettes, based on the
plausibility of their greater safety, rather than on essential scientific evidence
which would permit a proper risk assessment. If e-cigarettes are really ‘safer’,
their use should be recommended, but only after an intelligent analysis of
their risk to human health, based on integrated in silico, in vitro and clinical
studies for both scientific and logistical reasons.

Full text

Concern Raised by Public Health
England’s Proposal for ECs to be
Available on the NHS
In a Comment article published in the September
2015 issue of ATLA,2we expressed our concern
that, although we welcomed the prospect of new
tobacco-related products aimed at reducing
harmful exposures, it appeared that new regula-
tions would require that their relatively greater
‘safety’ would have to be established via complex
testing regimes which would be heavily reliant on
traditional animal procedures of doubtful rele-
vance and reliance. We argued that, instead, the
focus should be on the intelligent and integrated
use of non-animal in silico, in vitro and clinical
studies.
Just before our article went to press for publica-
tion, Public Health England (PHE; a UK executive
agency, sponsored by the Department of Health)
proposed that electronic cigarettes (ECs), a non-
tobacco alternative to smoking, should be made
available via the NHS (National Health Service),3as
a means of reducing the general incidence of disease
and harm attributable to conventional smoking.
We found that there was an increasingly heated
debate about the safety of ECs, between those that
want their use encouraged and endorsed with little
delay, and others who urge caution. The PHE
proposal is a classic example of the temptation of
short-term gain irrespective of the possibility of
long-term pain.4It is dangerous, because the rela-
tively greater safety of ECs has not been scientifi-
cally established — and regrettable, because it is
likely that other authorities, notably those on the
other side of the Atlantic, are likely to insist on the
introduction of complex testing regimes which will
require animal testing, as is the case for new
smoking materials.2
Background
PHE’s proposal is a matter of concern, mainly
because of the lack of safety data and the resulting
inability to perform any sort of risk assessment of
the type normally undertaken for consumer prod-
ucts, as well as doubts concerning the relevance of
the data on the impact of ECs on smoking habits.
In addition, our review was not specifically on ECs,
as a consequence of which there is other, relevant
published information on usage and safety, which
needs to be considered. We now take this opportu-
nity to elaborate on our initial response, and on our
reasons for urging caution, in the light of recent
developments regarding ECs, both at home and in
the USA.
This issue needs to be resolved urgently, since
the popularity of ECs is rapidly gaining ground,
especially with young people, at the expense of
tobacco smoking, largely on the assumption that
ECs either lack many of the toxic constituents,
contaminants and by-products to which conven-
tional smokers are exposed, or that these
substances are encountered at sufficiently low
concentrations so as to cause no health problems.
Moreover, an update on the situation with ECs is
timely since: a) the FDA is about to be charged
with responsibility for regulating ECs in the USA
(http://www.fda.gov/TobaccoProducts/ Labeling/
ucm388395.htm); b) as we write, the Third Sum -
mit on Electronic Cigarettes has just taken place in
London (http://www.e-cigarette-summit.com/); and
c) the UK (via the Department of Health and the
Medicines and Healthcare Products Regulatory
Agency [MHRA]) has a deadline of May 2016 to
complete the process of transposing into its
national legislation, the EU revised Tobacco
Products Directive (http://ec.europa.eu/health/
tobacco/ docs/ dir_201440_en.pdf), which came into
force in May 2014.
ATLA 43, 417–425, 2015 417
Comment
On the Safety of E-cigarettes: “I can resist anything except
temptation”1
Robert D. Combes and Michael Balls
Strategic policy decisions are being made about e-cigarettes, based on the plausibility of their greater safety,
rather than on essential scientific evidence which would permit a proper risk assessment. If e-cigarettes are
really ‘safer’, then their use should be recommended, but only after an intelligent analysis of their risk to
human health, based on integrated in silico, in vitro and clinical studies for both scientific and logistical reasons

The situation regarding ECs is also highly rele-
vant to the Three Rs, since we have the prospect
of significant levels of safety testing, some of
which could involve traditional animal tests,
highly invasive procedures and the use of non-
human primates, to satisfy new regulatory
requirements in Europe and the USA.2Although,
after careful consideration, we believe that more
information is required before ECs become incor-
porated into strategies for tackling the burden of
disease and ill-health due to tobacco smoking, we
feel that most, if not all, of the required data
could be obtained in a more-timely way by imple-
menting a strategy focused on the coordinated
use of chemical, in vitro and clinical methods.
Moreover, because the information will have
largely been obtained by using organotypic tissue
culture systems comprised of cells from the
target tissues and species, it will be of direct rele-
vance to assessing risk levels arising from the
use of ECs.
The Controversy
Understandably, PHE’s suggestion has provoked
considerable discussion and controversy, while
being generally welcomed by those who see ECs as
a quick solution to the smoking and health
problem. To illustrate the type of approach being
taken by some stakeholders to address the EC
issue, we quote the opening sentence of what looks
like an internal report on the burdens of regulating
ECs, but dated September 2013,5which states
that: E-cigarettes are very low risk alternatives to
cigarettes, used by smokers as a pleasurable way of
taking the relatively harmless recreational drug,
nicotine. However, we were unable to find any
evidence, or citations to original articles
presenting toxicity data, in support of such a
potentially far-reaching statement by the authors
in their 26-page document, which, essentially,
urges the UK Government to resist being overbur-
dened with EU regulations for ECs — require-
ments which, in the authors’ opinion, are
unnecessary, because they could delay the take-up
of ECs by the public. The authors qualify the risk
level, by claiming it is ‘very low’, again without any
reference to quantitative hazard data — most
extraordinary!
In direct contradiction, and two years following
publication of that statement, our in-depth
appraisal2of the use, safety assessment and regu-
latory control of tobacco-related products in
general, including ECs, leads us to believe that,
whatever the long-term consequences of any such
policy, or however worthy the ultimate objective of
PHE may be, it is, in the light of current knowl-
edge, a reckless and irresponsible suggestion.
Poor Reporting
PHE’s justification for its proposal relies heavily
on two reports which it commissioned, and which
were not peer-reviewed.6,7 It ignores the possibili-
ties that users might be repeatedly exposed to
hitherto undetected contaminants and by-prod-
ucts, as well as to carcinogenic chemicals, or their
precursors (which have been detected in solvent
extracts and vapours, and which are derived from
tobacco during solvent extraction or generated
during solvent heating), that can have effects at
very low dose levels, following repeat exposures,
which can occur without clear threshold doses,
thus necessitating zero-dose extrapolation.8Also,
the PHE report contains information on the likely
adoption and use of e-cigarettes by existing and
potential smokers that could be of questionable
relevance to the UK. This is because this informa-
tion is derived from experience in other countries,
with differing attitudes to smoking, or it applies to
other tobacco-related products that are used
mainly elsewhere, or it is conflicting, or merely
circumstantial.
On comparing our Comment2with the PHE docu-
ment, as well as looking at data that were
published before the document was released, we
have found that some key references are missing
from it, or have been selectively covered, with the
omission of some important information. For
example, we have previously discussed evidence of
the presence in vapours of some tobacco-specific
nitrosamines (TSNAs), but the PHE report, which
included the same reference,9omitted any mention
of the analytical data for such chemicals. There are
several other reports of the detection of TSNAs in
ECs,10,11 but there is no discussion in the PHE
report of the potential role of such contaminants,
some of which are highly-potent genotoxins12 in
the aetiology of lung cancer. In fact, cancer is not
specifically mentioned anywhere in relation to
safety, and there is no record of published reports
of exposure to additional substances, such as
nanoparticles (NPs) derived from metals13 (also
see Combes and Balls2). NPs, together with certain
other chemicals, have been linked to respiratory
sensitisation and mechanistically-related diseases,
such as chronic obstructive pulmonary disease.
Sensitisation is another endpoint for which clear
thresholds for induction doses are difficult to iden-
tify.14 This might be because they do not exist, as
with genotoxins, or because of technical deficien-
cies, but either way, this complicates risk
assessment.
The omission by PHE of several key papers and
information from a report that was intended to be
used to determine public health policy on the basis
of the evidence available, is completely inexcus-
able. This is especially the case, as the above facts
combined suggest that there is a tangible, and, at
418 Comment

present, unquantifiable, risk that repeated and
prolonged exposure to even low doses of such
chemicals, as would be expected to occur as a
result of using ECs, could be sufficient to trigger
cellular changes eventually culminating in serious
conditions, sometimes not manifested until some
considerable time following the onset of exposure.
With regard to the possibility of the presence of
undetected chemicals, some of which could be
toxic, it is worth noting that very few of the analyt-
ical methods in use have been validated for the
purpose in question, which could, in part, explain
the relatively high levels of variation seen between
EC brands, and which also could account for the
variation experienced within experiments.
The PHE report also fails to mention one of the
main findings of the earlier investigations into the
safety of ECs, namely, that different brands can
vary substantially in the levels of contaminants,
by-products and active components (e.g. nicotine),
such that there is an urgent need for more harmon-
isation of the different products available.3
A reminder of how difficult it can be to predict
the adverse effects of complex mixtures, such as
EC aerosols and liquids, is provided by a recent
study15 on the potential modulating influence of
nicotyrine, a product present in tobacco which also
arises in EC fluids as a result of slow oxidation of
nicotine. This chemical is an inhibitor of
cytochrome (CYP) isozymes (CYP P450 mixed
function oxidases), which clear nicotine from the
body and are active in both hepatic and extrahep-
atic systems. The authors noted that the metabo-
lism of all of the substrates of the respective
isozymes will be affected by nicotyrine. It so
happens that one of these substrates is the TSNA,
nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanone (NNK),12 one of the most potent of the
known lung carcinogens in tobacco smoke. This
substance is activated in airway cells, both in vitro
and in vivo, by CYP2A13,12 suggesting a potential
anti-carcinogenic effect of nicotyrine, at least for
this particular mechanistic pathway.
Neither our Comment,2nor the PHE report,
referred to a review, published in April 2014, on
the toxicity of ECs.16 The authors of this review
concluded that: The available evidence suggests
that these products are by far a less harmful alter-
native to smoking and significant health benefits
are expected in smokers who switch from tobacco to
electronic cigarettes. However, while this seems to
be good news, the authors admitted that only very
few toxicological studies were available to them.
Also missing from the PHE report is reference to
an unpublished, but comprehensive 19-page
document, available on the Internet,17 which
summarises various aspects of ECs, including
safety issues.
The PHE report went considerably further than
merely saying that ECs are safer than conven-
tional smoking, by providing a quantitative esti-
mate of the extent of this alleged greater safety. It
claimed that ECs are up to 95% safer than conven-
tional smoking, and that: Best estimates show e-
cigarettes are 95% less harmful to your health than
normal cigarettes, and when supported by a
smoking cessation service, help most smokers to
quit tobacco altogether. Later on, the report states
that: Acknowledging that the evidence base on
overall and relative risks of EC in comparison with
smoking was still developing, experts recently iden-
tified them as having around 4% of the relative
harm of cigarettes overall (including social harm)
and 5% of the harm to users.
Misuse of Information
While these two statements are not referenced, it
emerges later in the report that they are based on
the outcome of a multi-criteria decision analysis
(MCDA) study, in which a small group of experts
considered the harms to human health and well-
being posed by using a wide range of tobacco prod-
ucts.18 Each product was ranked on a scale which
put cigarette smoking top at almost 100% for
several properties, including addiction and cancer.
The authors stated that: Within the tobacco prod-
ucts there was a gradual reduction in harm from
water pipe, smokeless unrefined, smokeless refined
to snus that has 5% of MRH. Among the purer non-
tobacco vehicle products ENDS were rated to have
only 4% of MRH and for the even purer NRTs the
MRH was only rated at about 2%. [where ENDS =
electronic nicotine delivery systems; MRH =
maximum relative harm; and NRTs = pharmaco-
logical replacement products.]
PHE then used the outcome of this study, as if it
were equivalent to experimental data, to derive the
95% figure. Apart from being baffled by how any
quantitative risk assessment can be made with the
paucity of available hazard data, we are uncertain
as to how to interpret the intended meaning of
such a statement, other than by concluding that
PHE believes that ECs are almost twice as safe as
tobacco smoking. The quantification of risk in toxi-
cology, although not a precise process by any
means, implies some greater confidence in a partic-
ular prediction than is conveyed by a mere quali-
tative statement, and it has to be derived from
detailed quantitative hazard data. However, in
this case, the information was merely generated by
an ad hoc group of experts, and was based on opin-
ions, rather than being grounded in scientific
observation.
Moreover, there are many difficulties with the
MCDA approach in general, and in particular,
with the above application of it.2,19 This implies
that the validity of its outcome is very question-
able, being dependent on the amount and rele-
Comment 419

vance of pre-existing information, subject to much
value judgement, and difficult to reproduce with a
different set of experts, and with the same ill-
defined criteria used to assess relative harm. We
also noted one inescapable problem, which relates
to the large bias in the overwhelming amount of
available data on cigarette smoking compared to
that on ECs. It is difficult to see how such an
imbalance could be compensated for in practice,
but it greatly complicates any comparison of the
two types of products. The results from an MCDA
study should be used only for what they are, that
is, predictions, rather than as novel experimental
data, which they certainly are not. MCDA is part of
the analysis of evidence, rather than being an
additional source of evidence per se.
Another UK study, investigating the perception
of relative harm from the use of ECs,20 involved
recording the views of cohorts of smokers and ex-
smokers given ECs, and involved standard statis-
tical methods to estimate changes in perception
over a three-year period. It was found that the
proportion perceiving ECs to be less harmful than
cigarettes decreased significantly over the period
2013 to 2014. Unsurprisingly, a major preliminary
conclusion of the study was that: Clear information
on the relative harm of cigarettes and e-cigarettes is
needed. Another human study, a randomised
controlled trial,21 found that ECs, with or without
nicotine, were only moderately good at assisting
smokers to quit. The authors noted that:
Uncertainty exists about the place of e-cigarettes in
tobacco control, and more research is urgently
needed to clearly establish their overall benefits
and harms.
Like McKee and Capewell,22 we doubt that the
95% figure can be given any scientific credibility,
mainly due to the way in which it was derived. We
go further, in saying that the statement is
misguided and misleading. It is tempting to even
suspect that the latter was used intentionally, as
intimated by Kirby,23 who summed up the situa-
tion well, if somewhat rather benevolently, thus:
While the PHE report contains many caveats, albeit
subtle and largely missing from the media
coverage, it has uniformly adopted the most
favourable interpretation of the very limited
evidence, rejecting the precautionary principle.
In response to criticism of the 95% figure,24
Professor John Britton (chair of the Royal College
of Physicians Tobacco Advisory Group and co-chair
of the PHE Tobacco Control Implementation
Board, and also a co-author of one of the reports on
ECs that was commissioned by PHE), suggested
that, rather than dwell on an exact percentage
figure, the real point is that ECs are substantially
safer than tobacco smoking.25 This begs the
following question: If the 95% figure is not meant
to be interpreted literally, why include it in the
report, unless the aim was to have a headline for
gaining publicity, with a view to persuading us all
to accept the proposal without further questioning?
However, in truth, as we have argued above, there
is no evidence for the 95% estimate. Moreover,
doubts have been expressed about the integrity
and objectiveness of the MCDA study, due to the
alleged conflicts of interest of some of its authors.26
Unfortunately, little further information is avail-
able, and this fact, together with the other general
drawbacks of implementing MCDA, discussed
earlier, suggest that extreme caution should be
exercised when considering the outcome. A similar
issue with conflict of interest was encountered by
Pisinger and Døssing,27 when they found the
problem to have arisen in some 34% of the 76
studies relating to EC safety that they reviewed.
These authors could draw no firm conclusions from
the information, due to high levels of data incon-
sistency, but they did state that: Electronic ciga-
rettes can hardly be considered harmless. This
study, incidentally, is yet another key publication
missing from the PHE document.
What is Needed is a Role for
Alternative Methods
Predictably, few, if any, of the small number of
toxicity studies that have been published to date
consist of medium-term to long-term investiga-
tions. The issue of chronic toxicity due to vaping
has been noted by others, including, for example,
Rowell and Tarran,28 who recently discussed the
lack of data relating to the ability of chronic expo-
sures to ECs to induce serious lung disease. The
need to take into account long-term consequences
of EC use also applies to efficacy as well as safety,
as Unger notes in a recent editorial: Longitudinal
studies are not yet available to assess the long term
effects of e-cigarettes on health or their usefulness
as a cessation tool.29 Some four years ago, Etter et
al.30 stated that ECs had not been adequately
tested for safety or efficacy, and the situation has
not altered very much since then. Until further
studies of high quality and integrity are conducted,
the marketing of ECs poses unknown health and
safety concerns, particularly because the products
available are extremely diverse, many of them on
the market are not regulated, and no oversight of
quality control is in operation.
While we understand that there is an urgent
need to have more safety information, we believe
that there is a better way of obtaining it than
having several individuals sitting at a table trying
to predict the harms of these products, when they
have very little reliable information on which to
base their decisions. Instead, we suggest the
strategy which we have outlined previously,2
involving an intelligent, integrated testing scheme,
comprised mainly of chemical analysis, in vitro
420 Comment

methodologies and human/clinical studies. Such
an approach would also expedite testing, particu-
larly since traditional in vivo methods are often
lengthy and their relevance and reliability are
highly questionable.
The numbers of publications on in vitro studies
with EC vapours are increasing (http://www.ash
scotland.org.uk/what-we-do/supply-information-
about-tobacco-and-health/tobacco-related-
research/research-2015/e-cigarettes-2015/). In gen -
eral, the data are promising, in that, for example,
one paper31 shows that several vapours exhibit
substantially less activity in cytotoxicity testing
and in a range of genotoxicity assays, compared
with that exhibited by cigarette smoke. Other,
more-recent studies, one involving the MatTek™
epithelial airway model, confirm the substantially
lower cytotoxicity of vapours, and also demon-
strate that this applies to airway cells in culture32
(http://vaperanks.com/big-tobacco-study-claims-e-
cigarette-vapor-is-as-harmless-to-human-airway-
tissue-as-plain-air/).
However, while all this is encouraging, a glance
at the Vape Ranks website (presenting news on
ECs, rankings and reviews [www.http://vaperanks.
com/]) shows that there is no shortage of other
reports which raise legitimate safety concerns
relating to ECs, that warrant further investiga-
tion. Among such reports are an increasing
number of cases where ECs are being used to
‘smoke’ marijuana, a potentially worrying develop-
ment (see, for example, Murphy33). Some of the
investigations conducted in vitro also suggest that
acute toxic effects could be caused by vaping. For
example, a study in which cultures of human
gingival fibroblasts were exposed to nicotine-
containing or nicotine-free EC fluids, increased the
production of reactive oxygen species (ROS) after
24 hours, along with an elevated expression of the
Bax gene (an early indicator of apoptosis), followed
by apoptosis itself, after 48 hours of exposure.34
The authors concluded that such exposures could
lead to periodontitis, but, in addition, the induction
of such cellular changes could presage other, more-
serious long-term toxicity.
An important part of the integrated testing
strategy that we have proposed, involves human
clinical studies, which have been undertaken for
both efficacy and safety testing (the latter uniquely
possible with tobacco and tobacco-related products,
at an early stage), rather than following extensive
preclinical testing, as with pharmaceuticals (see
Combes and Balls2). Encouraging results were
obtained in some of the first human studies
(reviewed in Caponnetto et al.35), with high levels of
tolerance and acceptance of the new products by
existing smokers and non-smokers, as well as low
incidences of side-effects or of overt signs of toxicity.
However, some subsequent studies have
revealed several potential effects which cause
concern. One example is an investigation36 with
smokers and non-smokers that involved moni-
toring changes in plasma nicotine and carbon
monoxide (CO) concentration, and heart rate. One
brand of ECs increased each of these parameters
within the first five minutes of administration, an
example of an acute adverse effect caused by
vaping. Other evidence that ECs can exert acute
effects on users, following brief exposures, was
clearly demonstrated in a clinical study,37 in
which: a) non-smokers, using an EC for ten
minutes, experienced elevated airway resistance;
b) current regular smokers exhibited a significant
rise in airway resistance after using an EC for ten
minutes; and c) neither COPD nor asthma patients
were affected (www.medicalnewstoday.com/arti-
cles/ 249784.php). In a blog, Phillips has ques-
tioned the relevance of these results.38 However,
although chemicals causing this effect may not
elicit an immune response, the changes seen serve
as biomarkers of lung exposure and of changes
therein that could result in serious health
consequences.
Another investigation, still ongoing, involves
cohorts of smokers and non-smokers. At the 12-
month stage, the results suggest that vaping has
little effect on helping smokers to quit.39 However,
the trial is not scheduled to be completed until
2019. It is monitoring self-reported side-effects,
and, hopefully, will include an assessment of
biomarkers of disease and toxicity.
Nowhere are conflicting views regarding the
safety of ECs more sharply delineated than by the
different approaches to their use and regulation
that are emerging in markets on either side of the
Atlantic (reviewed in Combes and Balls2). On the
one hand, in the UK, some Government agencies
appear too ready to approve and promote the use of
such products, without going through the neces-
sary standard checks and balances, while, on the
other hand, in the USA, the FDA is about to take
over the regulation of ECs by subjecting them to a
rigorous and formal assessment.
It was on 25 April 2014 that the FDA published
a proposed rule, Deeming Tobacco Products to be
Subject to the Federal Food, Drug, and Cosmetic
Act. The period between then and now has been
taken up by: a) a 75-day public comment period,
which ended on 9 July 2014; b) an extension of the
public comment period by 30 days, taking us to 8
August 2014; c) an unknown time delay for consid-
eration and decision by the Agency of additional
requests to extend the comment period a second
time (which was not granted); and d) the analysis
of comments (undisclosed time). Despite these
delays, the question concerning the FDA’s regula-
tion of ECs is ‘when’, rather than ‘if’. The latest
information we can find is an entry in The Hill (the
website presenting news of US Congress activities)
in May 2015, where it is reported that Senator
Comment 421

Richard Blumenthal (D-Conn.) is giving the FDA
until the end of the summer 2015 to finalise its
deeming regulations for all tobacco products,
including ECs and cigars (http://thehill.com/regu-
lation/242125-fda-has-summer-to-finalize-tobacco-
deeming-regs-sen-dem-says).
Once the FDA assumes responsibility for ECs for
recreational use (it already regulates such prod-
ucts intended for therapeutic purposes), its
approach to ECs would appear to be clear from its
website (http://www.fda.gov/NewsEvents/Public
HealthFocus/ucm172906.htm). This states that: E-
cigarettes have not been fully studied, so consumers
currently don’t know: the potential risks of e-ciga-
rettes when used as intended; how much nicotine or
other potentially harmful chemicals are being
inhaled during use, or whether there are any bene-
fits associated with using these products.
Additionally, it is not known whether e-cigarettes
may lead young people to try other tobacco prod-
ucts, including conventional cigarettes, which are
known to cause disease and lead to premature
death.
This viewpoint is essentially one that we share,
and, although we are not in favour of testing just
for the sake of it, we fervently believe that it is very
simplistic and premature, at this time, to base
important public health decisions of the sort
currently being proposed by PHE, on inadequate
evidence of safety and/or potentially irrelevant and
unreliable extrapolation. On the other hand, while
we concur with FDA’s overall assessment of the
situation regarding ECs, we take issue with the
way in which the Agency intends to regulate
tobacco-related products, especially via the use of
the substantial equivalence concept.2In addition,
our views on the availability of data are shared by
other organisations, notably the American
Association for Cancer Research and the American
Society of Clinical Oncology,40 and the BMA.41
The official EU position on ECs is not clear at
this time. The revised EU Directive on the
marketing and use of tobacco products merely
requires that manufacturers take responsibility for
the safety of such products. However, we under-
stand that, in the UK, once the Directive has been
transposed into UK legislation, a process that will
be facilitated by the Department of Health, the
MHRA will become the competent authority (Dr
Ian Hudson, personal communication, 2015) for
ECs intended for medicinal purposes, which
include quitting smoking. Accordingly, the MHRA
will regulate such products in the same way that it
does medicines. Indeed, the MHRA website has
now documented data requirements for ECs
(http://www.mhra.gov.uk/home/groups/comms-
ic/documents/websiteresources/con454361.pdf),
where it is stated (for preclinical studies) that: The
potential transformation of the formulation on
thermal decomposition, and the potential for the
heating element and associated components
(including adhesives and solder) to shed metallic
and other particles on heating, would warrant
further investigation by the applicant to assess the
inhalation safety risks and to limit exposure where
necessary. In addition, the applicant should
provide a detailed safety review of all the compo-
nents in the formulation from the available litera-
ture; in particular a review of the safety following
inhalation exposure (including long-term exposure)
would be relevant. A comprehensive evaluation of
the potential extractables and leachables origi-
nating from all components of the electronic ciga-
rette should also be provided, with associated
toxicological review. For clinical studies, for some
unaccountable reason, the focus is on the levels of
nicotine in the body and its pharmacodynamics, to
ensure that endogenous levels do not exceed
maximum safe levels. We feel that this represents
a missed great opportunity for undertaking
biomarker and biomonitoring safety studies on
vapours in the clinical setting, as we have
explained in more detail elsewhere.2
How these regulations are going to be applied in
practice after the various stakeholders and pres-
sure groups, including the tobacco industry, have
argued their various standpoints remains to be
seen. However, if the MHRA sticks to its proce-
dures and requirements for new medicines, it
should be the case that: a) if the supporting toxico-
logical data are deemed relevant and suitable,
there will be no need for further testing and/or
review; and b) where this is not so, or where data
are missing, such information would have to be
obtained by toxicity testing, according to
International Conference on Harmonisation (ICH)-
approved regulatory test methods for new medic-
inal products. Whether any products currently on
the market will receive exemption is a matter of
conjecture at this time. Therefore, we are now
confronted by a ludicrous situation, whereby two
UK Government authorities, the MHRA and PHE,
both with the responsibility for safeguarding
public health, are giving out different messages —
the former has the remit of controlling the sale of
the ECs according to international regulatory
requirements, while the latter endorses the use of
ECs now. Furthermore, the PHE report and its
associated documents can be downloaded from the
MHRA website — no wonder there is so much
confusion!
Some notes on the presentations given at the
Third E-Cigarette Summit, have been posted on the
web (http://www.ecigarettedirect.co.uk/ashtray-
blog/wp-content/uploads/2015/11/E-Cig-Summit-3-
PDF.pdf). The notes provide a preliminary impres-
sion that the debate shows no signs of letting up,
although it would appear that there is a growing
admission among the protagonists that ECs are not
harmless, and, among those looking at health
422 Comment

effects, that they are probably safer than smoking,
but by how much it is difficult to tell. Perhaps we
could be heading in the right direction, after all. We
should get a better idea once the presentations have
been uploaded to the resources section of the
summit’s website.
Concluding Comments
We are puzzled by: a) why there is such a gulf
between the UK and the USA in approaches to
regulating ECs; and, more importantly, b) why the
fundamentals of toxicology, underpinning public
health and safety, involving hazard identification
and risk assessment,42 seem to have been ignored
by PHE, and are being overlooked in the ongoing
debate by a growing number of stakeholders and
so-called experts, when the same are usually so
rigorously applied to other consumer products.
Calls endorsing the wider usage of ECs are being
driven by two main factors, both of which cannot
be supported on scientific grounds: a) an under-
standable, but misguided, wish for having a quick
fix for the major health problems associated with
smoking; and b) a mistaken belief that there is no
need to test complex mixtures, such as EC liquids
and vapours, when the levels of ingredients, whose
presence and contribution to toxicity are known,
are at very low concentrations. If this were
possible, most of toxicology would now merely
consist of chemical analysis of test samples, except
in rare cases where the threshold of regulation
concept43 can legitimately be applied — for
example, when synergistic or antagonistic effects
between constituents can be accommodated.
One way in which risk assessment can be
approached is to derive likely exposure levels from
analytical data on the constituents of vapours and
compare them with recommended maximum
allowable daily intake figures for humans,
obtained from safety tests. However, since most of
the information relates to data obtained under
laboratory conditions, mainly with rodents, some-
times involving different routes of exposure, it has
to be extrapolated and scaled up to be relevant to
human populations, and adjusted to provide for an
extra margin of safety. Moreover, predicting expo-
sure levels is confounded by individual differences
in the way in which ECs are used, the extent to
which they are used, the differences in design and
composition of ECs, the degree of vapour inhala-
tion, and variation in the biotransformation of
inhaled constituents, and also by the possible
endogenous generation of more TSNAs from vaped
nicotine.44
It has been noted elsewhere (http://www.
tobacco.ucsf.edu/9-chemicals-identified-so-far-e-
cig-vapor-are-california-prop-65-list-carcinogens-
and-reproductive-t) that nine constituents var -
iously found in EC fluids and/or aerosols, are listed
by the Environmental Protection Agency (EPA) of
the US State of California as being of concern with
regard to human safety, as part of the Agency’s
drive to improve and simplify the regulation of
environmental chemicals. These chemicals are:
acetaldehyde, cadmium, formaldehyde, isoprene,
lead, nickel, nicotine, N-nitrosonornicotine (NNN)
and toluene. NNN is widely considered to be a
carcinogen in tobacco smoke. As a worse-case
scenario, we have taken the threshold value of
concern for this chemical (which the EPA has iden-
tified from rodent carcinogenicity studies, after
adjustments for species and test system extrapola-
tion), to have a NSRL (non-significant risk level) of
0.5μg/day (NSRL is the level of exposure that
would result in no more than one excess case of
cancer in 100,000 individuals exposed to the chem-
ical). We have compared this figure with the
amount of NNN that different ECs users might be
expected to be exposed to, based on the maximum
levels of chemical reported in Gureckis and Love,4
which is 4.3μg/150 puffs (equivalent to 14.3μg/day
for a user taking 500 puffs/day). As the respective
NSRL value is 0.5μg/day, the expected exposure
under these conditions exceeds the level of concern
by almost 30-fold. Presumably, such a result would
raise the possibility that ECs with similar
constituent profiles could prompt the EPA in
California to require appropriate product labelling
as a precondition for marketing approval. We
stress, however, that these are preliminary data,
subject to several uncertainties, not the least of
which are vaping behaviour and individual suscep-
tibility, and we plan to investigate risk assessment
in more detail for more ECs, and also for other risk
assessment methods, such as the Margin of
Exposure (see Hahn et al.45).
The more and more we read, the more convinced
we are that the whole debate about ECs is prema-
ture, and would not be happening with other,
equally dangerous consumer products, in the
absence of powerful lobbying on behalf of industry.
The title of the PHE report includes the phrase
...foundation for evidence-based policy and prac-
tice. This sounds great, until one realises that the
foundation is very weak indeed, having been built
on sand, in the words of McKee and Capewell,22
and that the evidence used was incomplete,
conflicting, and used selectively. It is crucial that
these new types of products are labelled appropri-
ately and accurately, not only with regard to their
benefits, but also with appropriate and propor-
tionate warnings of any hazards to which users
may be exposed. This will only be possible after
there has been a full and scientifically-sound
investigation of the toxicity of these products.
We seem to be living in a world now where the
term evidence-based increasingly seems to be being
used to imply some new revelatory approach to
Comment 423

scientific activity that guarantees high quality. We
have ‘evidence-based medicine’ and, more-recently,
‘evidence-based toxicology’, and now: ‘evidence-
based public health’ and ‘evidence-based regula-
tion’. But, in truth, of course, evidence-based is not
a new concept, nor is it a panacea for quality —
any thorough scientific piece of work is only as
good as the evidence on which it is based. What
does appear to be new is the attempt to use the
phrase as a smokescreen for sub-standard scien-
tific investigation, otherwise there would be no
need to use it at all!
We leave the last word to the British Heart
Foundation (BHF), by quoting from a booklet enti-
tled 10 Minutes to Change Your Life — Time to
Quit, which is available in its high-street charity
shops or from its website (https://www.bhf.org.
uk/~/media/files/publications/smoking/g925_time_
to_quit_01_14_booklet_chart.pdf). This states that:
E-cigarettes allow you to breathe in nicotine
vapour. Unlike tobacco smoke, this nicotine
[vapour] doesn’t contain many of the chemicals that
cause cancer and heart disease. But scientists don’t
know yet if e-cigarettes can help you quit or if they
cause any long-term damage to your health.
Simple, clear, informative and correct — this is
where the debate needs to start and it is why the
temptation for a quick fix to the smoking issue
must be resisted!
Author for correspondence:
Robert D. Combes
Independent Consultant
Norwich
UK
E-mail: robert_combes3@yahoo.co.uk
Michael Balls
c/o FRAME
Russell & Burch House
96−98 North Sherwood Street
Nottingham NG1 4EE
UK
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Comment 425