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Hazardous Compounds in Tobacco Smoke

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Tobacco smoke is a toxic and carcinogenic mixture of more than 5,000 chemicals. The present article provides a list of 98 hazardous smoke components, based on an extensive literature search for known smoke components and their human health inhalation risks. An electronic database of smoke components containing more than 2,200 entries was generated. Emission levels in mainstream smoke have been found for 542 of the components and a human inhalation risk value for 98 components. As components with potential carcinogenic, cardiovascular and respiratory effects have been included, the three major smoke-related causes of death are all covered by the list. Given that the currently used Hoffmann list of hazardous smoke components is based on data from the 1990s and only includes carcinogens, it is recommended that the current list of 98 hazardous components is used for regulatory purposes instead. To enable risk assessment of components not covered by this list, thresholds of toxicological concern (TTC) have been established from the inhalation risk values found: 0.0018 μg day(-1) for all risks, and 1.2 μg day(-1) for all risks excluding carcinogenicity, the latter being similar to previously reported inhalation TTCs.
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Int. J. Environ. Res. Public Health 2011, 8, 613-628; doi:10.3390/ijerph8020613
International Journal of
Environmental Research and
Public Health
ISSN 1660-4601
www.mdpi.com/journal/ijerph
Article
Hazardous Compounds in Tobacco Smoke
Reinskje Talhout 1,*, Thomas Schulz 2, Ewa Florek 3, Jan van Benthem 1, Piet Wester 1,4 and
Antoon Opperhuizen 1
1 Laboratory for Health Protection Research, National Institute for Public Health and the Environment
(RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; E-Mails: Jan.van.Benthem@rivm.nl
(J.v.B.); Piet.Wester@rivm.nl (P.W.); Antoon.Opperhuizen@rivm.nl (A.O.)
2 Bundesinstitut für Risikobewertung, Thielallee 88-92, 14195 Berlin, Germany;
E-Mail: Thomas.Schulz@bfr.bund.de
3 Laboratory of Environmental Research, Department of Toxicology, University of Medical Sciences,
Dojazd 30, 60-631 Poznan, Poland; E-Mail: eflorek@ump.edu.pl
4 Centre for Substances and Integrated Risk Assessment, National Institute for Public Health and the
Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands
* Author to whom correspondence should be addressed; E-Mail: Reinskje.Talhout@rivm.nl;
Tel.: +31-30-274-4505; Fax: +31-30-274-4446.
Received: 28 December 2010; in revised form: 2 February 2011 / Accepted: 7 February 2011 /
Published: 23 February 2011
Abstract: Tobacco smoke is a toxic and carcinogenic mixture of more than 5,000
chemicals. The present article provides a list of 98 hazardous smoke components, based on
an extensive literature search for known smoke components and their human health
inhalation risks. An electronic database of smoke components containing more than 2,200
entries was generated. Emission levels in mainstream smoke have been found for 542 of
the components and a human inhalation risk value for 98 components. As components with
potential carcinogenic, cardiovascular and respiratory effects have been included, the three
major smoke-related causes of death are all covered by the list. Given that the currently
used Hoffmann list of hazardous smoke components is based on data from the 1990s and
only includes carcinogens, it is recommended that the current list of 98 hazardous
components is used for regulatory purposes instead. To enable risk assessment of
components not covered by this list, thresholds of toxicological concern (TTC) have
been established from the inhalation risk values found: 0.0018 µg day1 for all risks, and
OPEN ACCESS
Int. J. Environ. Res. Public Health 2011, 8
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1.2 µg day1 for all risks excluding carcinogenicity, the latter being similar to previously
reported inhalation TTCs.
Keywords: smoke component; risk assessment; tobacco product regulation; Hoffmann
list; TTC
1. Introduction
Tobacco smoke is a complex, dynamic and reactive mixture containing an estimated 5,000
chemicals [1-3]. This toxic and carcinogenic mixture is probably the most significant source of toxic
chemical exposure and chemically mediated disease in humans [4,5]. According to WHO estimates,
5.4 million premature deaths are attributable to tobacco smoking worldwide [6]. If current trends
continue, 10 million smokers per year are anticipated to die by 2025 [7,8]. The most common tobacco
smoke related causes of death are cardiovascular disease, chronic obstructive pulmonary disease, and
various types of cancer, in particular lung cancer [9]. In addition, environmental tobacco smoke also
significantly increases the risk to develop these and other diseases [10]. Obviously, there is a need for
regulation of this addictive and harmful product as are most other addictive and/or hazardous products
to which the population is exposed. Nevertheless, as yet tobacco products are only loosely regulated
and largely exempt from any safety standards.
The WHO Framework Convention on Tobacco Control (FCTC) provides a comprehensive
framework for global tobacco control efforts. The FCTC covers all aspects of tobacco control,
including tobacco product regulation, advertising, health warnings, price and tax issues, illicit trade
(smuggling) and programs for smoking cessation. Article 9 of FCTC addresses the regulation of the
contents of tobacco products, including their emissions. The implementation of article 9 requires
product regulation measures based on the empirical testing of tobacco products using standardized
methods. It is not feasible to measure all 5,000 cigarette smoke components for product monitoring
and subsequent regulation purposes. Therefore, a list of smoke components needs to be selected with a
sufficiently broad chemical, toxicological, and pharmacological profile.
Currently, both the tobacco industry and authorities strongly focus on the so-called Hoffmann
analytes. Hoffmann and his co-workers have published several lists with varying numbers of
biologically or toxicologically active mainstream smoke components, which are colloquially referred
to as Hoffmann analytes [1,11,12]. The list of Hoffmann analytes is, however, not state-of-the art, as it
is based on research from the early 1990s. Furthermore, the Hoffmann publications give no arguments
for inclusion of the listed components apart from general statements that these components are
biologically active components in mainstream smoke, or that they are carcinogens or major tobacco
smoke components. Finally, no endpoints other than carcinogenicity are specified, whereas cancer is
only one of three major tobacco-related diseases. Other toxicological endpoints such as those related to
cardiovascular and pulmonary disease need to be included as well.
For these reasons we propose that the Hoffmann list needed to be revised. The present paper
describes the development of an up-to-date list of hazardous tobacco smoke components together with
inhalation risk values covering all major tobacco-related diseases. Many literature data are available on
Int. J. Environ. Res. Public Health 2011, 8
615
the presence of chemical components in cigarette smoke, often with concentration ranges and
occasionally with information on the toxic potency of these components. However, to the best of our
knowledge, an exhaustive list of smoke components was not available at the start of the project.
Therefore, a database has been generated by reviewing recent literature on smoke components. From
our database components with known potential health risks for cancer or other endpoints (primarily
cardiovascular and respiratory effects) have been selected as an initial list for regulatory purposes.
2. Experimental Section
2.1. Database Composition
To screen for smoke components, peer-reviewed literature dating back to 1990 has been searched
using PubMed and Scopus. The following search query was used: (―cigarette smoke‖ OR ―tobacco
smoke‖ OR ―mainstream smoke‖) AND (toxin OR analyte* OR constituent* OR deliveries OR
composition* OR component* OR compound* OR ―gas phase‖ OR particulate OR toxin* OR ―smoke
chemistry‖ OR emission*).
In addition, all issues of Recent Advances in Tobacco Science have been checked, as well as all
issues of the journal Beitraege zur Tabakforschung International dating back to 1990. Existing lists
such as the Hoffmann list, the WHO TobReg list [13], the Rodgman & Green list [14], and the Fowles
and Dybing list [15] have also been used. Finally, several textbooks on smoke composition have been
consulted [10,16-22].
Information retrieved from these data sources were entered in an Excel database. The database
contains detailed information on each chemical compound and its levels in mainstream tobacco smoke,
if available. Available human inhalation risk values (cancer and non-cancer risk, safety factors
included) from the International Toxicity Estimates for Risk Assessment (ITER) database have also
been incorporated. ITER is an Internet database of chronic human health risk values and cancer
classifications for over 542 chemicals of environmental concern obtained from several independent
organizations worldwide (http://www.tera.org/ITER). This database is updated on a regular basis and
contains risk values from the Agency for Toxic Substances and Disease Registry of the Centers for
Disease Control of the United States (ATSDR), Health Canada (HC), International Agency for
Research on Cancer (IARC), NSF International, Rijksinstituut voor Volksgezondheid en Milieu
(RIVM; National Institute of Public Health and the Environment, the Netherlands), and the United
States Environmental Protection Agency (U.S. EPA). When more than one of these institutes has
published a risk value, the lowest value was selected for our database. In addition, risk values from the
Californian Environmental Protection Agency (Cal EPA) as listed in the articles of Fowles and
Dybing [23] and Rodgman and Green [14], were included. One NATA (U.S. EPA National-scale Air
Toxics Assessment) and two ORNL (U.S. EPA Department of Energy, Office of Environmental
Management) values listed in Rodgman and Green were also included.
Int. J. Environ. Res. Public Health 2011, 8
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2.2. Derivation of Smoke Components Threshold of Toxicological Concern
From the available inhalation risk values for tobacco smoke components thresholds of toxicological
concern (TTC) have been established. Two TTCs were derived, one from all risk values including
carcinogens, and one for endpoints other than carcinogenicity. To derive the threshold of toxicological
concern, the 5th percentile benchmark dose was taken from the plot of the cumulative probability
versus the inhalation risk values. It should be noted that risk values from different agencies were used,
which may affect the accuracy of our TTC. Agencies often base their risk assessment on different
toxicological data, and apply different safety factors.
3. Results and Discussion
3.1. Database and List of Hazardous Smoke Components
Our literature search resulted in a database of 2,256 different smoke components. For 542 of these
components, yields per cigarette in mainstream smoke were also reported in literature. For the other
compounds, only the presence in smoke was mentioned, but the amount not specified. To assess the
human health risk of a specific smoke component, data on its smoke yield and inhalation risk value are
required. For 98 components, risk assessment authorities have established a human inhalation risk
value for cancer and/or another endpoint: 60 cancer and 48 non-cancer inhalation risk values have
been found. These 98 components were selected for our list of hazardous smoke components, as their
potential hazard contribution can be assessed. Table 1 lists these components, together with their
inhalation risk values and the institute that published this value. Searching the recent publication on
tobacco and tobacco smoke components by Rodgman and Perfetti [24], containing references to
around 5,300 smoke components, may result in hazardous smoke components not yet on our list.
Emission levels are known from literature for all 98 components except for five that had been
measured but not quantified in smoke. Exposure to the components on this list forms a potential health
risk to develop cancer and/or other diseases, primarily cardiovascular and respiratory illnesses.
Our list of hazardous smoke components includes all nine components reported in mainstream
cigarette smoke that are known human carcinogens (IARC Group I carcinogens), as well as all nine
components that are probably carcinogenic to humans (IARC Group 2A carcinogens) [25,26].
In addition, it contains 34 of the 48 components that are possibly carcinogenic to humans (IARC
Group 2B carcinogens) [27].
The WHO Study Group on Tobacco Product Regulation (TobReg) recently published an expert
advice on smoke component regulation (based on research by a joint WHO and IARC working
group) [13,28]. A list of 43 priority toxicants was composed from three smoke component emission
level datasets which were all based on the Hoffmann list. All components of this TobReg initial group
of priority toxicants are present on our list, with the exception of catechol, crotonaldehyde,
hydroquinone, and NNK. Those components are not on the current list as no human inhalation
risk values were found. Catechol has been classified by IARC as possibly carcinogenic to humans
(Group 2B); hydroquinone and crotonaldehyde have been classified by IARC as not classifiable as to
its carcinogenicity to humans (Group 3).
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. List of hazardous tobacco smoke components with their cancer and non-cancer inhalation risk values.
Smoke component
Cancer risk value 1
(mg m3)
Institute
Non-cancer risk value 2
(mg m3)
Institute
1,1,1-Trichloro-2,2-bis(4-chlorophenyl)ethane
(DDT )
1.0E-04
U.S. EPA
1,1-Dimethylhydrazine
2.0E-06
ORNL
1,3-Butadiene
3E-04
U.S. EPA
2E-03
U.S. EPA
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TEQ)
2.6E-04
Cal EPA
2-Amino-3-methyl-9H-pyrido[2,3-b]indole
(MeAaC)
2.9E-05
Cal EPA
2-Amino-3-methylimidazo[4,5-b]quinoline (IQ)
2.5E-05
Cal EPA
2-Amino-6-methyl[1,2-a:3',2"-d]imidazole
(GLu-P-1)
7.1E-06
Cal EPA
2-Aminodipyrido[1,2-a:3',2"-d]imidazole
(GLu-P-2)
2.5E-05
Cal EPA
2-Aminonaphthalene
2.0E-05
Cal EPA
2-Nitropropane
Cal EPA
0.02
U.S. EPA
2-Toluidine
2.0E-04
Cal EPA
3-Amino-1,4-dimethyl-5H-pyrido
[4,3-b]indole (Trp-P-1)
1.4E-06
Cal EPA
3-Amino-1-methyl-5H-pyrido[4,3-b]-indole
(Trp-P-2)
1.1E-05
Cal EPA
4-Aminobiphenyl
1.7E-06
Cal EPA
5-Methylchrysene
9.1E-06
Cal EPA
7H-Dibenzo(c,g)carbazole
9.1E-06
Cal EPA
2-Amino-9H-pyrido[2,3-b]indole (AaC)
8.8E-05
Cal EPA
Acetaldehyde
4.5E-03
U.S. EPA
9.0E-03
U.S. EPA
Acetamide
5.0E-04
Cal EPA
Acetone
30
ATSDR
Acetonitrile
0.06
U.S. EPA
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Smoke component
Cancer risk value 1
(mg m−3)
Institute
Non-cancer risk value 2
(mg m−3)
Institute
Acrolein
2.0E-05
U.S. EPA
Acrylamide
8E-3
Acrylic acid
1.0E-03
U.S. EPA
Acrylonitrile
1.5E-04
U.S. EPA
2.0E-03
U.S. EPA
Ammonia
0.1
U.S. EPA
Aniline
B2probable human
carcinogen
U.S. EPA
1E-3
U.S. EPA
Arsenic
2.3E-06
U.S. EPA
Benz[a]anthracene
9.1E-05
Cal EPA
Benzene
1.3E-03
U.S. EPA
9.8E-03
ATSDR
Benzo[a]pyrene
9.1E-06
Cal EPA
Benzo[j]fluoranthene
9.1E-05
Cal EPA
Beryllium
4.2E-06
Cadmium
5.6E-06
U.S. EPA
Carbazole
1.8E-03
NATA
Carbon disulfide
0.1
HC
Carbon monoxide
10
Cal EPA
Chloroform,
4.3E-04
U.S. EPA
0.1
ATSDR
Chromium VI
8.3E-07
U.S. EPA
1.0E-04
U.S. EPA
Chrysene
9.1E-04
Cal EPA
Cobalt
5.0E-04
RIVM
Copper
1.0E-03
RIVM
Di(2-ethylhexyl) phthalate
4.2E-03
Cal EPA
Dibenzo[a,i]pyrene
9.1E-07
Cal EPA
Dibenzo[a,h]acridine
9.1E-05
Cal EPA
Dibenzo[a,h]anthracene
8.3E-06
Cal EPA
Dibenzo[a,j]acridine
9.1E-05
Cal EPA
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Smoke component
Cancer risk value 1
(mg m−3)
Institute
Non-cancer risk value 2
(mg m−3)
Institute
Dibenzo[a,h]pyrene
9.1E-07
Cal EPA
Dibenzo[a,l)pyrene
9.1E-07
Cal EPA
Dibenzo[a,e]pyrene
9.1E-06
Cal EPA
Dibenzo[c,g]carbazole
9.1E-06
Cal EPA
Dimethylformamide
3.0E-02
U.S. EPA
Ethyl carbamate
3.5E-05
Cal EPA
Ethylbenzene
0.77
RIVM
Ethylene oxide
1.1E-04
Cal EPA
Ethylenethiourea
7.7E-04
Cal EPA
Formaldehyde
7.7E-04
U.S. EPA
1.0E-02
ATSDR
Hexane
0.7
U.S. EPA
Hydrazine
2.0E-06
U.S. EPA
5E-3
ATSDR
Hydrogen cyanide
3.0E-03
U.S. EPA
Hydrogen sulfide
2E-3
U.S. EPA
Indeno(1,2,3-c,d)pyrene
9.1E-05
Cal EPA
Isopropylbenzene
0.4
U.S. EPA
Lead
8.3E-04
Cal EPA
1.5E-3
U.S. EPA
Manganese
5.0E-05
U.S. EPA
m-Cresol
0.17
RIVM
Mercury
2.0E-04
U.S. EPA
Methyl chloride
0.09
U.S. EPA
Methyl ethyl ketone
5
U.S. EPA
Naphtalene
3E-3
U.S. EPA
N-nitrosodi-n-butylamine (NBUA)
6.3E-06
U.S. EPA
N-nitrosodimethylamine (NDMA)
7.1E-07
U.S. EPA
Nickel
9.0E-05
ATSDR
Nitrogen dioxide
1.0E-01
U.S. EPA
Int. J. Environ. Res. Public Health 2011, 8
620
Table 1. Cont.
Smoke component
Cancer risk value 1
(mg m−3)
Institute
Non-cancer risk value 2
(mg m−3)
Institute
N-nitrosodiethanolamine
1.3E-05
Cal EPA
N-nitrosodiethylamine
2.3E-07
U.S. EPA
N-nitrosoethylmethylamine
1.6E-06
Cal EPA
N-Nitrosonornicotine (NNN)
2.5E-05
Cal EPA
N-Nitroso-N-propylamine
5.0E-06
Cal EPA
N-nitrosopiperidine
3.7E-06
Cal EPA
N-nitrosopyrrolidine
1.6E-05
U.S. EPA
n-Propylbenzene
0.4
U.S. EPA
o-Cresol
C- possible human
carcinogen
U.S. EPA
0.17
RIVM
p-, m-Xylene
0.1
U.S. EPA
p-Benzoquinone
C- possible human
carcinogen
U.S. EPA
0.17
RIVM
p-Cresol
C- possible human
carcinogen
U.S. EPA
0.17
RIVM
Phenol
0.02
RIVM
Polonium-210
925.9
ORNL3
Propionaldehyde
8.0E-03
U.S. EPA
Propylene oxide
2.7E-03
U.S. EPA
Pyridine
0.12
RIVM
Selenium
8E-4
Cal EPA
Styrene
0.092
HC
Toluene
0.3
ATSDR
Trichloroethylene
82
HC
0.2
RIVM
Triethylamine
7.0E-03
U.S. EPA
Vinyl acetate
0.2
U.S. EPA
Vinyl chloride
1.1E-03
U.S. EPA
1 Cancer inhalation risk values provide an excess lifetime exposure risk, in this case the human lung cancer risk at a 1 in 100,000 (E-5) level.
2 Noncancer inhalation risk values indicate levels and exposure times at which no adverse effect is expected; here values for continuous lifetime exposure are listed.
3 Unit risk in risk/pCi = 1.08E-08.
Int. J. Environ. Res. Public Health 2011, 8
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Considering this classification, these components probably do not form the highest carcinogenic
risk of all components in tobacco smoke. Only NNK, that has been classified as Group 1 since 2007
(before 2B) would be worthwhile to include after determining a risk value. In the TobReg article, no
non-cancer hazard indices are mentioned. Thus, our shortlist of 98 potentially hazardous smoke
components includes all important smoke components from these previous lists. Compared to the
Hoffmann list, our list includes many new components including acetone, acetonitrile, cadmium,
methyl chloride, methyl ethyl ketone, propionaldehyde and toluene.
3.2. Threshold of Toxicological Concern in Smoke Risk Assessment
As human health inhalation risk values have been found for only 98 of the 2,256 smoke components,
the potential hazard contribution can only be assessed for these components when using classical risk
assessment criteria. An alternative approach is to look at smoke components with an emission level
below the threshold of toxicological concern (TTC). The TTC refers to a human exposure threshold
below which there would be no appreciable risk to human health, despite the absence of
chemical-specific toxicity data [29,30]. When a chemical would be present at concentrations below
this level, it can be exempted from further hazard consideration. The TTC is usually a cut-off value
based on a set of experimental data, e.g., the 5th percentile value of the distribution of a set of
no-observed effect levels (NOEL). TTCs can be defined for several endpoints, the most sensitive
being mutagenicity.
The inhalation exposure-based TTC for tobacco smoke components was established at
0.0009 µg m3 for all risk values including those for carcinogens (5th percentile benchmark dose), and
0.06 µg m3 for risk values excluding carcinogenic components. These concentrations can be
remodeled to daily doses of respectively 0.0018 and 1.2 µg day1 by assuming a default breathing rate
of 20 m3 day1. It should be noted that the compounds for which we found human inhalation risk
values have been assessed because they are known or suspected toxicants (selection bias). This means
that, had our entire dataset been tested for toxicity, the TTC would have turned out higher. Below, our
TTC for non-carcinogenic effects is compared to inhalation exposure based TTCs found in literature.
Escher et al. report an inhalation TTC for non-carcinogenic endpoints of 4180 µg day1
(depending on the Cramer class of the component) based on repeated dose toxicity studies from the
REPDOSE database [31,32]. No observed effect concentrations (NOECs) have been normalized to
daily exposure, and converted to daily doses using a default breathing rate of 20 m3 day1 and a safety
factor of 25; organophosphates and compounds with a genotoxic structural alerts were excluded. Their
value is comparable in magnitude to our TTC for non-carcinogenic components.
Carthew et al. derived a TTC for inhalation exposure to aerosol ingredients in consumer products
from an inhalation toxicology database of over 100 rodent studies [33]. Using a safety factor of 25,
they derived a TTC of 300 µg day1 for systemic effects and a TTC of 1,000 µg day1 for local effects.
Genotoxic carcinogens and in vivo mutagens have been excluded from their analysis, as well as heavy
metals, dioxins, polychlorinated biphenyls, organophosphates and polymers. This may explain why
their TTC values are higher (250 and 830 times) than our TTC for non-carcinogenic components.
Int. J. Environ. Res. Public Health 2011, 8
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Based on analysis of toxicological data for hundreds of carcinogenic and noncarcinogenic
substances, the FDA derived a human TTC for oral exposure of 1.5 µg day1. Drew and Frangos
remodeled this value to an air guideline TTC of 0.03 µg m3 assuming default breathing factors, and
100% absorption in the lungs [34]. Next, they compared this inhalation TTC to air guideline values
established by reputable authorities. Their air guideline database was comprised of organics only and
did not include carcinogens, sensory irritants, metals, particulates, and dioxins. For the chronic air
guideline values established by risk assessment authorities, there are three guideline values lower than
the TTC and 280 at or above the TTC. For 3,274 acute air guideline values established by various
authorities and from occupational exposure limits, only one value was below the TTC. Thus, the FDA
human TTC for oral exposure, 1.5 µg day1, seems to result in a reasonable estimation for inhalatory
exposure to non-carcinogens, as well. Our TTC for non-carcinogens (1.2 µg day1) is almost equal to
the FDA value.
Thus, the non-carcinogens TTC we derived from inhalation risk values for smoke components is
comparable to previously reported inhalation TTCs for non-carcinogenic effects. For 542 components
in our database, a concentration range in smoke is known. As a smoker consumes on average
20 cigarettes per day, these levels have to be multiplied by 20 to estimate a smoker‘s daily exposure.
For 81 of these components, the concentration in smoke is lower than the TTC for all endpoints
including carcinogenicity. If the TTC approach would also be valid for the complex mixture of tobacco
smoke, this means that for 15% (81/542) of the components with known concentration in smoke, there
would be no appreciable risk for any disease including cancer. As a first approximation, these
components could be exempted from further hazard consideration, especially if one considers that as
many as 461 (542 81) smoke components with known concentration levels are present at levels
above the TTC and would therefore have a higher priority for hazard characterization anyway.
However, one has to take into account that the TTC approach has been developed for exposure to
single components or simple mixtures. The complex tobacco smoke mixture, on the other hand,
contains more than 5,000 components. Any effects of these components could be antagonistic,
independent, additive, or even synergistic, depending on the specific mechanisms of toxicity.
Price et al. modeled an independent and an additive approach for some simple model mixtures [35].
Further research could study this problem for the much more complex tobacco smoke mixture.
For 172 of these components, the concentration in smoke is lower than the TTC for endpoints other
than carcinogenicity. Thus, for 32% (172/542) of the components with known concentration in smoke,
there would be no appreciable risk at diseases other than cancer. These components could be exempted
from further hazard consideration if they are proven non-carcinogens and/or have no structural alerts
for carcinogenicity.
In conclusion, we have derived two inhalation TTCs, one for all risks, including carcinogenicity,
and one for endpoints other than carcinogenicity, the latter being well comparable to previously
reported inhalation TTCs for non-carcinogenic effects. Only a small part of the smoke components
with known yields have emission levels below these TTCs.
Int. J. Environ. Res. Public Health 2011, 8
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3.3. How to Use the Initial List for Tobacco Product Regulation?
Our list of 98 smoke components provides a scientific basis for the progressive reduction in the
level of toxic chemicals in tobacco emissions. The WHO TobReg expert advice on smoke component
regulation proposed lowering of toxicants levels per mg nicotine in cigarette smoke [13,28]. First, the
levels for selected smoke components would need to be established and second, sale or import of
cigarette brands that have yields above these levels could be prohibited. The Centre for Disease
Control in Atlanta already implemented a similar approach by monitoring the levels of three categories
of chemicals (tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, and volatile organic
compounds) in tobacco smoke and setting a target to reduce the unit-based sales-weighted average
levels of each category by 10% [36].
As the risk for tobacco smoke-related diseases appears to be dose-dependent, reducing the
concentration of the most important toxicants in smoke may lower the risks related to tobacco
smoking [37]. This harm reduction approach is interesting because in many countries smoking
prevalence seems to stabilize after an initial steep decline secured by various policy measures.
However, the effect on mortality and morbidity of lowering (classes of) toxins in cigarette smoke has
not been clarified yet, one of the reasons being the relatively long lag time for developing
tobacco-related diseases. Additional studies are required to assess individual- or population-level
reductions in exposure or in adverse health effects. For instance, the consumption of modified
cigarettes cannot be linked easily to a reduction in disease risk or even to significant reductions in
carcinogen exposure biomarkers [37]. Second, past experiences with the introduction of low-yield
tobacco products showed unforeseen effects that counteracted any harm reduction effects. The
resulting products did not lead to reduced exposure as consumers adapted their smoking behavior such
as frequency and intensity of use to inhale sufficient nicotine to satisfy their craving and addiction
[38,39]. On the other hand, consumers did perceive these products to be less hazardous due to
marketing health claims, such as ‗light‘ and ‗mild‘ [40-42]. As these circumstances may lead to a
negative health impact, TobReg also advised to report toxicant levels normalized for nicotine level and
to prevent marketing of products with reduced toxicant levels as such. Such normalization may lead to
less focus on the quantity of smoke generated per cigarette, and on TNCO values as misleading
measures of human exposure and risk. On the other hand, toxicant emission levels for cigarettes with
different nicotine emission levels can be better compared. According to TobReg, normalization may
shift the interpretation of the measurement towards product characterization of smoke toxicity
generated under standardized conditions.
In addition to the potential health effect of a smoke component, other criteria are important in
selecting components for regulation (e.g., [13,28]). First, the component must have substantial
variability in its yield across brands on the market to allow for banning of part of the products. Second
and somewhat related, the variation across brands should be substantially greater than the variation in
repeat measurement for the component for a single brand. Otherwise, large numbers of measurements
would be required for each component in order to tighten the estimation of the mean value, and the
cost of testing would increase proportionally. Third, compounds from different chemical classes need
to be included. Analyses of variation in brands of 13 mainstream smoke emissions suggests the
occurrence of risk swapping (in which one specific exposure is reduced within a group at the cost of
Int. J. Environ. Res. Public Health 2011, 8
624
another's exposure increasing) and risk shifting (in which a specific exposure is reduced within a group
at the cost of that exposures increasing within another group) [43]. For instance, when polycyclic
aromatic hydrocarbons are reduced by enhancing nitrate content in tobacco, more tobacco specific
nitrosamines are generated in smoke. Therefore, it is warranted that marker components of all relevant
chemical classes are included on a list for regulatory purposes.
A final consideration to select smoke components for regulation is the availability of technology, or
other approaches, that can reduce the level of specific smoke components, as setting limits on these
toxicants then becomes feasible and therefore of higher priority. Some smoke component emission
levels may be lowered by adapting agricultural practices, plant characteristics, tobacco blending, and
cigarette design (for example additives, filters, papers) [44]. For instance, parameters which influence
heavy metal concentration in tobacco include growing conditions (e.g., soil type and pH), agricultural
practices (e.g., use of metal-containing pesticides and fertilizers), genotype, stalk position, and
processing of tobacco leaves [45]. Another example is the formation of carbonyls in tobacco smoke by
the pyrolysis of tobacco components, including celluloses and sugars. Sugar levels in tobacco can be
reduced by using different curing methods, and regulating the amount that is added in the
manufacturing process [46]. A third example is the yield of many organics in smoke that can be
influenced by the type of filter, e.g., charcoal filters remove up to 70% of benzene from cigarette
smoke [11].
The current shortlist is solely based on toxicity data from publicly available databases. Thus, other
toxic smoke components may be present in our database, but do not appear on the shortlist due to lack
of an inhalation risk value. Apart from that, additives and their resulting smoke components may also
increase tobacco-related harm by making cigarettes more palatable, attractive, or even addictive to
consumers. From a regulatory point of view, identifying smoke components that influence
addictiveness of tobacco products is also essential. In addition, smoke components that increase the
attractiveness of a tobacco product by affecting e.g., taste, smell and other sensory attributes also need
to be cautiously regulated as these may entice more individuals to start or to continue smoking.
Some of the components in Table 1 or in our database are not only toxic, but also increase the
addictiveness or the attractiveness of a cigarette. For instance, aldehydes such as acetaldehyde may
play a role in cigarette addiction as do the components harman and norharman present in our database
[47]. Other components may affect the taste of tobacco smoke to a high extent and thus its
attractiveness. One example is 5-hydroxymethylfurfural, a characteristic taste component of Maillard
reactions [48]. Unfortunately no sufficient evidence is available on smoke components‘ addictiveness
or attractiveness or on appropriate methods to acquire these data [49]. Therefore, future research
should also focus on these two aspects of tobacco smoking.
In conclusion, our initial list of 98 smoke components can be used for regulatory purposes like the
progressive reduction in the level of toxic chemicals in tobacco emissions. A further selection from
these 98 components can be made based on criteria such as the variability of the toxicants across
brands, the potential for the toxicant to be lowered, the need to include components from different
chemical classes, and any attractiveness- or addictiveness-enhancing effects of components.
Int. J. Environ. Res. Public Health 2011, 8
625
4. Conclusions
Here we provide a list of 98 hazardous smoke components (Table 1) which is based on an extensive
literature search for known smoke components and their human health inhalatory risk. This list
provides a scientific basis for the progressive reduction in the level of toxic chemicals in tobacco
product emissions, through periodic setting of standards. It is advised to replace the Hoffmann list by
the current list of hazardous smoke components. As components with potential cardiovascular and
respiratory effects have also been included, the three major smoke-related causes of death are all
covered by the list. Future updating of this list can be carried out as needed. Based on the inhalatory
risks, we also derived two thresholds of toxicological concern (TTCs), one for all risks including
carcinogenicity, and one for endpoints other than carcinogenicity, which is well comparable to
previously reported inhalation TTCs for non-carcinogenic effects. Only a small part of the smoke
components with known yields has emission levels below these TTCs.
Many components on our list (e.g., styrene, acetamide, and methyl chloride) have not been
systematically studied in benchmark experiments comprising a variety of brands available on the
market, and should therefore be monitored. When these data have been generated, the variability of the
toxicants across brands, and the potential for the toxicant to be lowered, can be evaluated. It is
therefore recommended that the list of hazardous smoke components be monitored in several brands
using different smoking regimes. For many components validated methods are already available from
e.g., International Organisation for Standardization (ISO) or Health Canada. For other components,
such methods need to be developed or modified from other applications. In the framework of FCTC,
harmonized and validated standards will be developed for measuring NNK, NNN, acetaldehyde,
acrolein, benzene, benzo(a)pyrene, 1,3-butadiene, carbon monoxide, and formaldehyde.
Once the list of components has been further studied and monitored, and the results have been
evaluated, a further selection from the shortlist can be made for regulatory purposes. Here, other
criteria such as the variability of the toxicants across brands, the potential for the toxicant to be
lowered, the need to include components from different chemical classes, and any attractiveness- or
addictiveness-enhancing effects of components can be incorporated. Routine collection and analysis of
selected smoke components will accelerate advancement in tobacco control.
Acknowledgements
The Executive Agency for Health and Consumers (EAHC) is gratefully acknowledged for
co-financing this project. The assistance of Jens Schubert (BfR) in the evaluation of Beitraege zur
Tabakforschung International is gratefully acknowledged.
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These are curious times. The Canadian government has passed legislation that requires cigarette manufacturers to routinely test and publish the amounts of 44 toxic substances in cigarette mainstream smoke (MSS). Following in the footsteps of their northern neighbor, various US legislators and regulators are considering modifications to their cigarette testing and reporting programs that will also list toxicants in MSS. Across the Atlantic Ocean, the European Commission has passed a directive that may also follow the North American lead for public disclosure of MSS toxic chemicals for each brand of cigarette sold in the marketplace. United Kingdom authorities have also expressed their intention to follow this mandate. It is difficult to understand the motivation and value of these existing or potentially forthcoming legislative actions. 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Assuming that the current situation is approximately as described above, the authors of this paper critically examined the existing lists of MSS toxicants. They discarded chemicals that are no longer relevant, e.g., DDT, N-nitrosodiethanolamine, added known smoke constituents that are glaringly absent, e.g., dioxins, and replaced the existing 1950-60s era nonfiltered cigarette MSS yields with those more representative of the present-day marketplace. Data for the Kentucky reference 1R4F cigarette smoked under standardized smoking conditions, i.e., those established by the International Organization for Standardization (ISO) and the Federal Trade Commission (FTC), are used as a surrogate for the modern-day cigarette whenever possible. A list of smoke toxicants and their approximate concentrations in today's cigarettes is nearly useless without an appropriate ranking of their relative toxicity. Unfortunately, the toxicological data for ranking importance are available for fewer than 5% of the approximately 4800 reported smoke constituents. Although neither of this paper's authors presumes to be a toxicologist, we cite in our discussion several published attempts at ranking smoke toxicants. Specifically, ranking by US Occupational Safety and Health Administration (OSHA) permissible workplace exposure levels, use of US Environmental Protection Agency (EPA) toxicity criteria supplemented with California EPA criteria, and use of the Human Exposure - Rodent Potential methodology and database developed by AMES et al. when data are available. There appears to be a wide divergence in the permissible exposures allowable in the workplace and those advocated by environmental regulators. Thus, it is expected that rankings such as those presented herein will ultimately form the basis of MSS toxic chemical prioritization for either attempts at reduction by product developers or development of standardized analytical methods. This review of MSS toxicants also explores the limitations of toxicological evaluations. The toxicity data used in the above ranking are derived wholly from studies of pure compounds. It is highly improbable that extrapolation of bioassay results determined on an individual compound to that compound when it is a component of a mixture as complex as cigarette MSS is valid. For example, several decades of research involving numerous investigators reported that the benzo[a]pyrene (BaP) content of cigarette smoke condensate (CSC) accounts for only a few percent of the tumor-bearing animals in the skin-painting bioassay. Subsequently they asserted that the tumorigenic polycyclic aromatic hydrocarbons (PAHs) in CSC could account for no more than 3 to 4% of the tumor-bearing animals. Inclusion of promoters, e.g., phenols, raises the level to about 5%. However, several of the same investigators recently claimed that BaP is one of two smoke components responsible for lung cancer in cigarette smokers. While much is written about the hundred or so toxic components in cigarette smoke, little is published about the numerous nontoxic smoke components that have been shown in various bioassays to counteract the effects of the toxic ones. In some cases the inhibiting components are also listed as toxic, e.g., nicotine inhibits the mutagenicity of N-nitrosodimethylamine; the promoter phenol inhibits the tumorigenicity of BaP; the weakly tumorigenic benz[a]anthracene negates the potent tumorigenicity of BaP. On a one-to-one molar basis, many bicyclic, tricyclic, and tetracyclic nontumorigenic PAHs counteract the tumorigenicity of BaP and dibenz[a,h]anthracene. To further illustrate this murky toxicological situation, the history and current knowledge of the importance of tobacco-specific nitrosamines (TSNAs) to the hazards of smoking is reviewed. In brief, these compounds were discovered in tobacco products and found to transfer to MSS (and sidestream smoke). Toxicological evaluations on the pure compounds demonstrated that they are potent carcinogens. Some public health scientists believed that if the levels of TSNAs could be reduced or lowered in MSS, then this would lead to a ‘less hazardous’ cigarette. Once given this assignment, agronomists discovered that at least for flue-cured tobaccos, the levels of TSNAs can be greatly reduced through the use of indirect heating in the curing barns. This was wonderful news. However, toxicologists soon conducted experiments comparing the toxicity of MSS from flue-cured cigarettes containing high and ultra-low concentrations of TSNAs. It must have been a surprise to these investigators when they could find no significant difference between the toxicities of the two smokes. Some public health scientists have asserted that the reduction of the per cigarette ‘tar’ delivery below 15 mg/cig does not reduce the risk from smoking because of the hazard resulting from the higher levels of additives used to maintain consumer acceptability. Although no data in support of this assertion have ever been offered, much data generated during the past decade contradict the assertion. Ingredient addition at the usual level or at levels several times greater than normal does produce some minor changes in the smoke chemistry, but these changes do not result in any adverse biological response as measured in various bioassays to determine mutagenicity, tumorigenicity, etc. From our review of the literature gathered to prepare this paper, we have come to several conclusions. These include the following: 1. It is possible to prepare a list of the known toxicants in MSS and to prioritize some of them based upon existing biological data. However, for more than 95% of the known constituents in MSS, there are no biological data. 2. Even if there were biological data for most MSS components, extrapolation of this pure-compound knowledge to the biological properties of a mixture containing them is beyond our scientific ability. 3. At our current state of scientific knowledge, no one will ever be able to legitimately claim the development of a ‘less hazardous’ cigarette based solely on the reduction of known toxic chemicals in MSS. 4. The approach of reducing ‘tar’ yields of cigarettes appears in retrospect to be the most practical means of producing a ‘less hazardous’ cigarette, because when product developers reduce ‘tar', both the known and unknown toxicants are reduced. 5. The ranked toxicants in MSS contain both gas-phase and semi-volatile constituents that appear to be important determinants of toxicity. Some of these constituents, e.g., N-nitrosodimethylamine, phenols, are reduced by triacetin-plasticized cellulose acetate filters. These filters also reduce ‘tar'. Additionally, it is well known that charcoal-containing filters have a high efficiency for removing carbonyl compounds from MSS. Development of more consumer-acceptable products that reduce gas-phase toxicants appears to be another route to a ‘less hazardous’ cigarette.
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