Policy Watch
Carcinogenicity of polycyclic aromatic hydrocarbons
Kurt Straif, Robert Baan, Yann Grosse, Béatrice Secretan, Fatiha El Ghissassi, Vincent Cogliano,
on behalf of the WHO International Agency for Research on Cancer Monograph Working Group
In October, 2005, 24 scientists from
nine countries met at the International
Agency for Research on Cancer, Lyon,
France, to assess the potential carcino-
genicity of 60 polycyclic aromatic
hydrocarbons and several occupational
exposures involving coal-derived poly-
cyclic aromatic hydrocarbons. These
assessments will be published as
volume 92 of the IARC Monographs,1
the first of several volumes that will
cover topics on air pollution.
Polycyclic aromatic hydrocarbons are
formed during the incomplete com-
bustion of organic material. Environ-
mental sources of polycyclic aromatic
hydrocarbons include industrial air
pollution, urban air pollution, tobacco
smoke, and diet (which is commonly
the main source of exposure in non-
smokers who are not exposed to such
hydrocarbons through their occu-
pations). High occupational exposure
can arise during the conversion of coal
to coke and coal tar, and during the
processing and use of products derived
from coal tar. Workplace concentrations
of benzo(a)pyrene, a polycyclic aro-
matic hydrocarbon commonly used as a
marker of exposure to polycyclic aro-
matic hydrocarbons, can be as high as
0·1 g/L compared with typical
ambient air concentrations of less than
0·01 ng/L. The highest benzo(a)pyrene
concentrations have been measured in
the aluminium-production industry
when the Söderberg process is used.
After metabolic activation, many
polycyclic aromatic hydrocarbons have
been shown to induce lung tumours
and skin tumours in animals. The main
enzymes of activation (phase I) that
catalyse the mono-oxygenation of
these hydrocarbons to form epoxides
are cytochromes P450 1A1, 1A2, and
1B1. Epoxide hydrolase forms inter-
mediate transdihydrodiols, which are
converted by specific cytochrome
http://oncology.thelancet.com Vol 6 December 2005
isoenzymes to reactive diolepoxides
that are one class of ultimate carcino-
genic metabolites of polycyclic aromatic
hydrocarbons.2,3 Cytochromes and
peroxidases catalyse one-electron oxi-
dation of some polycyclic aroma-
tic hydrocarbons depending on their
ionisation potential to form reactive
radical cations.4 The intermediate trans-
dihydrodiols can also be oxidised fur-
ther by aldoketo reductase isoforms to
generate reactive and redox-active
polycyclic aromatic hydrocarbon or-
thoquinones.5 The main enzymes of
detoxification (phase II) that conjugate
metabolites of polycyclic aromatic
hydrocarbons include the glutathione
S-transferases GSTM1, GSTP1, and
GSTT1; UDP-glucuronosyltransferases;
and sulphotransferases. Polymorph-
isms in several of these enzymes have
been identified in human beings, some
of which could modulate cancer sus-
ceptibility.6,7
The working group discussed several
mechanisms that could contribute to
understanding the carcinogenesis of
polycyclic aromatic hydrocarbons. The
diolepoxide mechanism involves for-
mation of stable and unstable DNA
adducts, mainly at G and A, which can
lead to mutations in proto-oncogenes
(RAS) and tumour-suppressor genes
(P53). Many polycyclic aromatic hydro-
carbon diolepoxides and their precursor
diols and epoxides are tumorigenic in
animals.2,3,8
The radical cation mechanism invol-
ves generation of unstable adducts at G
and A, leading to apurinic sites and
mutations in HRAS.4
Orthoquinone formation could lead
to stable and unstable DNA adducts
and generation of reactive oxygen spe-
cies, inducing mutations in P53.9 Aryl-
hydrocarbon receptor mechanisms and
immunological mechanisms were also
discussed.
The most widely investigated poly-
cyclic aromatic hydrocarbon is benzo-
(a)pyrene, which induces tumours
in mice, rats, guineapigs, hamsters,
rabbits, monkeys, newts, and ducks.
In mice, strong evidence shows that
benzo(a)pyrene causes lung tumours
through the diolepoxide mechanism,
and skin tumours through the diole- Upcoming meetings
poxide and radical-cation mechanisms. Feb 7–14, 2006
Important steps of these mechanisms, Carbon black, titanium dioxide,
non-asbestiform talc
including the complete activation path-
June 14–21, 2006
ways, have been reported in individuals Ingested nitrates and nitrites,
exposed to polycyclic aromatic hydro- and blue–green algae toxins
carbons. G to T transversions in the Kras including microcystin-LR and
nodularin
proto-oncogene identified in lung
Oct 10–17, 2006
tumours from mice treated with benzo- Indoor air pollution from
(a)pyrene are causally associated with household combustion and
formation of DNA adducts derived heating
from the diolepoxide.8 Human beings http://monographs.iarc.fr
exposed to benzo(a)pyrene activate
this molecule metabolically to diole-
poxides that form DNA adducts. One of
these adducts has been measured
in chimney sweepers and coke-oven
workers, who are frequently exposed to
mixtures of polycyclic aromatic hydro-
carbons that contain benzo(a)py-
rene.10,11 Similar mutations in KRAS were
found in lung tumours from non-
smokers exposed to coal com-
bustion products rich in polycyclic
aromatic hydrocarbons containing
benzo(a)pyrene.12
The working group classified benzo-
(a)pyrene as carcinogenic to human
beings (IARC group 1), based on
sufficient evidence in animals and
strong evidence that the mechanisms
of carcinogenesis in animals also ope-
rate in exposed human beings. Use of
mechanistic data to classify benzo-
(a)pyrene in group 1 indicates the
increasing strength of mechanistic data
to contribute to the identification of
human carcinogens that cannot be
studied as single agents in epidemio-
logical studies.
931
 Policy Watch
Monograph Working Group
Members
D Krewski—Chair (Canada);
T Partanen (Costa Rica);
K Vähäkangas (Finland); I Stücker
(France); J Borlak (Germany);
V J Feron (Netherlands);
M M Marques (Portugal); P Gerde,
P Gustavsson (Sweden);
T Fletcher (UK); J Arey, F A Beland,
S Burchiel, L Flowers, R A Herbert,
H Mukhtar, S Nesnow (USA);
T M Penning, R Sinha (not present
for evaluations; USA); T Shimada
(unable to attend; USA)
After the meeting, a member of
the Working Group did not agree
with the outcome and asked to
be removed from any resulting
publications. For this reason, the
participant’s name is not
included in the above list
Conflict of interest
The working group declares no
conflicts of interest.
Invited Specialists
H Kromhout (Netherlands);
R Herrick, T Junghans, S Olin
(USA)
Conflict of interest
HK has received funding from the
Dutch Pavers’ Association. RH
has received funding from the
National Asphalt Pavement
Association, USA
Representatives of health
agencies
C De Rosa (ATSDR, USA); J A Ross
(EPA, USA); V Loch, A Ullrich
(WHO, Switzerland)
Observers
G Granville (CONCAWE—the
European oil companies’
association, Belgium);
D L Williams (Michelin, France)
932
The working group also classified
cyclopenta(c,d)pyrene, dibenz(a,h)an-
thracene, and dibenzo(a,l)pyrene as
probably carcinogenic to human beings
(group 2A), on the basis of sufficient
evidence in animals and strong mecha-
nistic data. Several other polycyclic
aromatic hydrocarbons were assessed
as possibly carcinogenic to human
beings (group 2B): benz(a)anthracene,
benzo(b)fluoranthene, benzo(j)fluoran-
thene, benzo(k)fluoranthene, chrysene,
dibenzo(a,h)pyrene, dibenzo(a,i)pyrene,
indeno(1,2,3-cd)pyrene, and 5-methyl-
chrysene on the basis of sufficient
evidence in animals; and benz(j)acean-
thrylene and benzo(c)phenanthrene on
the basis of limited evidence in animals
and on strong mechanistic data.
A few polycyclic aromatic hydro-
carbons seem to be more potent
carcinogens than benzo(a)pyrene. Of
particular concern is dibenzo(a,l)pyrene,
which seems to be more than ten times
more potent than benzo(a)pyrene in
rats.13,14 The Working Group recom-
mended that this potent polycyclic
aromatic hydrocarbon compound be
measured routinely in the workplace
and the environment. Another highly
potent polycyclic aromatic hydrocarbon
compound is dibenz(a,h)anthracene.15,16
On the basis of increased risks of lung
cancer or skin cancer, the working group
confirmed previous conclusions17–19 that
occupational exposures during coal
gasification, coke production, coal-tar
distillation, paving and roofing, alu-
minium production, and chimney
sweeping are carcinogenic to human
beings (group 1), and that exposure to
creosotes is probably carcinogenic
to humans (group 2A). Occupational
exposure during carbon-electrode
manufacturing20,21 was assessed for the
first time and classified as probably
carcinogenic to human beings (group
2A). The working group also concluded
that exposure to mixtures of coal-
derived polycyclic aromatic hydro-
carbons in these industries contributed
to increased cancer risks, but could not
define the role of individual polycyclic
aromatic hydrocarbons.
The working group assessed several
new studies of dietary exposure to
polycyclic aromatic hydrocarbons in hu-
man beings that suggest an association
between consumption of polycyclic
aromatic hydrocarbons in foods and
increased risks of colorectal adenoma
and pancreatic cancer.22,23 A substantial
source of exposure to polycyclic
aromatic hydrocarbons in non-smokers
who are not exposed through their
occupation is consumption of some
foods, notably grain products and
grilled meats. These foods contain
measurable amounts of benzo-
(a)pyrene and other polycyclic aro-
matic hydrocarbons, which can induce
tumours of the upper digestive tract in
animals by ingestion. These new
epidemiological studies, however, are
restricted to the USA, and are too small
to be conclusive. Large-scale, inde-
pendent cohort studies are needed to
investigate these associations more
definitively.
The authors declare no conflicts of interest.
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non-heterocyclic polycyclic aromatic
hydrocarbons and some related exposures.
Lyon: International Agency for Research on
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2 WHO. IPCS environmental health criteria 202,
selected non-heterocyclic polycyclic aromatic
hydrocarbons. Geneva: World Health
Organization, 1998.
3 Xue W, Warshawsky D. Metabolic activation of
polycyclic and heterocyclic aromatic
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4 Cavalieri E, Rogan E. Mechanisms of tumour
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5 Penning TM, Burczynski ME, Hung C-F, et al.
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6 Bartsch H, Nair U, Risch A, et al. Genetic
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23 Anderson KE, Sinha R, Kulldorff M, et al. Meat
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