CHAPTER 7.

POLYCYCLIC AROMATIC
HYDROCARBONS IN AMBIENT AIR
AND CANCER
Erik Dybing, Per E. Schwarze, Per Nafstad, Katarina Victorin, and Trevor M. Penning

Polycyclic aromatic hydrocarbons (PAHs), upgraded to a Group 1 known human carcin-

which are generated from the incomplete ogen (IARC, 2010). Thus there is considerable
combustion of organic (carbonaceous) mate- concern about the relationship between PAH
rial, are ubiquitous contaminants in ambient air exposure in the ambient air and the potential
(IARC, 1983, 1984a, 1984b, 1985, 2010; WHO, to contribute to human cancer incidence. The
1998). Their occurrence in the air we breathe has United States Environmental Protection Agency
been substantial during the past centuries due to (EPA) monitors 16 priority PAHs in air due to
emissions from industrial processes and energy health concerns: naphthalene, acenaphthylene,
production, motor vehicular traffic, incineration acenaphthene, fluorene, anthracene, phenan-
of refuse, and residential heating. threne, fluoranthene, pyrene, chrysene, benz[a]
PAHs consist of two or more fused aromatic anthracene, benzo[b]fluoranthene, benzo[k]
rings made up of carbon and hydrogen atoms. fluoranthene, B[a]P, indeno[1,2,3-cd]pyrene,
The ring systems can be present in multiple benzo[g,h,i]-perylene, and dibenz[a,h]anthra-
configurations and may be unsubstituted or cene (in order of number of aromatic rings per
substituted. PAHs range from semivolatile structure) (Figure 7.1). Of particular note is that
molecules to molecules with high boiling points. several PAHs (naphthalene, chrysene, benzo[b]
Thus, they may be found both in the gas and the fluoranthene, benzo[k]fluoranthene, B[a]P,
particulate phase of ambient air or in mixtures of dibenz[a,h]anthracene, dibenzo[a,e]pyrene and
both phases. About 500 different PAHs have been dibenzo[a,l]pyrene, and anthanthrene) have
detected in air, but often the measurements focus been found to be carcinogenic in experimental
on benzo[a]pyrene (B[a]P) as a representative of animals after inhalation or intratracheal inges-
the whole PAH family (WHO, 1998; Boström tion, increasing concern about the levels of these
et al., 2002). Many of the PAHs in ambient air are carcinogens in ambient air (Figure 7.1).
carcinogenic (IARC, 1983, 1984a, 1984b, 1985,
2010) (Figure 7.1), and a recent reassessment of
their carcinogenic potential led to B[a]P being

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IARC SCIENTIFIC PUBLICATION – 161

Fig 7.1 PAHs in ambient air.

An asterisk denotes a United States Environmental Protection Agency priority pollutant. (C) indicates that the compound is carcinogenic by
inhalation or intratracheal administration in experimental animals. Source: Park and Penning (2008); reproduced with permission from John
Wiley & Sons.

PAH emissions in ambient air emitted from East Asia are transported to the
west coast of the USA, and PAHs emitted in the
A recent global atmospheric emission inven- Russian Federation influence atmospheric PAH
tory of PAHs (Zhang and Tao, 2009) showed concentrations in the Arctic (Zhang and Tao,
that the emission from the 16 priority PAHs 2009). The annual PAH emission from Asian
listed by the EPA was 520 000 tonnes per year. countries is 290 000 tonnes (55% of the total); the
Anthropogenic sources of total PAHs in ambient amounts from China (114 000 tonnes per year)
air emissions are greater than those that come and India (90 000 tonnes per year) are the major
from natural events such as forest fires and contributors. The USA is the third largest emitter
volcanic eruptions. of PAHs, at 32 000 tonnes per year. By contrast,
Apart from localized risk at or near the source European countries account for only 9.5% of the
of emission, PAHs can be dispersed regionally total PAH emissions annually (Zhang and Tao,
and intercontinentally through atmospheric 2009). The contribution of the various anthro-
long-range transport. For example, PAHs pogenic sources of PAHs to the total emission

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 Air pollution and cancer

profile can vary by country and region. The improvements have led to reductions in PAH
global sources of PAH emissions are shown in emissions from this source. Little is known
Table 7.1, and the main sources of PAHs in six about the composition of these PAH emissions
European countries are shown in Table 7.2. (WHO, 1998). In petroleum refining, most of the
The largest emission of PAHs globally comes emissions consist of smaller two- and three-ring
from incomplete combustion of organic mate- compounds (94–99%, depending on the process
rial, and the largest single source is from the studied) (IARC, 1989). Thus, the composition of
combustion of biofuels. Biofuel is a single type PAHs from combustion (pyrogenic) versus the
of primary solid biomass (e.g. animal dung or composition of PAHs from petroleum refining
peat) (Zhang and Tao, 2009). Burning biomass (petrogenic) can be widely different. Other
fuels such as wood on indoor open-pit stoves is industrial sources with significant PAH emis-
common in developing areas, leading to harmful sions are carbon black plants, wood preserva-
exposures to particulate matter < 2.5 µm in tion (creosote) plants, the asphalt and bitumen
diameter (PM2.5), carbon monoxide (CO), and industry, aluminium production (Söderberg
PAHs, which can be significantly reduced by the electrodes), iron and steel production, foundries,
introduction of modern stoves (Li et al., 2011). tyre production, power plants, waste incinera-
Anthropogenic sources include PAHs that come tors, and stubble burning (WHO, 1998). Further
from incomplete combustion processes (espe- restrictions may lead to lower PAH emissions
cially biofuels) and those that are made commer- from these industries (CORINAIR, 1997).
cially, are by-products of industrial processes, or Estimation of the PAH emissions for six
are generated from vehicle emissions, cooking, European countries indicates that the industrial
food preservation, and first- and second-hand sources contribute PAHs in the same range as
cigarette smoke. mobile sources (Table 7.2; data from CORINAIR,
1997).
Anthropogenic sources of PAHs in
Residential sources
ambient air
Domestic heating with oil and wood
Commercial production stoves leads to considerable PAH emissions in
PAHs produced commercially include naph- northern European countries, and especially in
thalene, acenaphthene, phenanthrene, fluoran- Scandinavia (Boström et al., 2002). In Sweden,
thene, and pyrene; however, only naphthalene the emissions from wood-fired domestic heating
is used directly without further processing, as a are estimated to be about 100 tonnes per year,
moth repellent. with minor contributions from oil combustion.
Environmental tobacco smoke is also a consider-
able source of indoor air pollution and contami-
Industrial processes
nation within the home (Hoh et al., 2012).
Many PAHs are released into the atmos-
phere during industrial processes such as coal Motor vehicle emissions
coking and petroleum refining. It is estimated
that coal coking was responsible for the release The amount of PAHs released into the air
of thousands of tonnes of PAHs per year in from vehicles has been reduced considerably
different countries during the 1980s and early by the introduction of three-way converters.
1990s. Reduced coke production and technical However, older diesel and gasoline cars with a

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Table 7.1 Main sources of emission for the United States Environmental Protection Agency 16
priority PAHs in China, India, and the USA

Source Global China India USA

Biofuel 56.7% 66.4% 92.5% 9.1%
Wild fire 17.0% 0% 0% 3.3%
Consumer product use 6.9% 0.9% 0.6% 35.1%
Traffic oil 4.8% 2.0% IS 23.0%
Domestic coal 3.7% 10.7% 1.3% IS
Coke production 3.6% 14.4% IS IS
Petroleum refining 2.4% 1.0% IS 8.7%
Waste incineration 1.9% IS IS 9.5%
Aluminium electrolysis 1.4% IS IS 1.9%
Open straw burning IS 2.0% 3.2% IS
Gasoline distribution IS IS IS 3.0%
Aerospace industry IS IS IS 2.5%
Other 1.5% 2.7% 3.9%
Tonnes in thousands 530 114 90 32
IS, insignificant.
Compiled from Zhang and Tao (2009).

catalytic converter of outmoded design have B[a]P is the traditional marker for PAH expo-
5–10 times higher PAH emissions than modern sure. Several additional PAH components have
cars. In addition, cold start at temperatures been proposed as emission markers, for example
below the standardized cold start (23 °C), and fluoranthene, B[a]P, and benzo[b]fluoranthene.
especially at temperatures below 0 °C, results in Boström et al. (2002) suggested the use of the
a several-fold increase in PAH emissions. Several following set of PAHs as emission and effect
other technical variations lead to varying emis- markers for monitoring air pollution: B[a]P,
sions, for example spark ignition engines (WHO, fluoranthene, phenanthrene, methylanthracenes/
1998). The total amounts of PAHs emitted from phenanthrenes, pyrene, benzo[b]fluoranthene,
vehicles vary between countries; in the USA benzo[k]fluoranthene, indeno[1,2,3-cd]pyrene,
this can be as high as 6000 tonnes per year, and benzo[g,h,i]-perylene, dibenz[a]anthracene, and
in six European countries the amount is about dibenzo[a,l]pyrene. This list is quite similar to the
400 tonnes per year (Table 7.1 and Table 7.2). 16 priority PAHs listed by the EPA (Figure 7.1). In
As might be expected, not all PAHs contribute some studies, the total PAH exposure is given as
equally to the emissions into ambient air. Table 7.3 B[a]P toxic equivalency concentrations. In this
lists a typical PAH profile in ambient air arising approach, individual components are measured
from different sources. and ranked relative to B[a]P in terms of carcino-
genicity. For example, chrysene has 1/1000th
Human exposure of the carcinogenicity of B[a]P and has a toxic
equivalency concentration of 0.001. These calcu-
PAHs may be found in the gas and particu- lations are used to estimate human health risk
late phases (see Chapter 1). The levels given below and can be used to calculate incremental lifetime
frequently reflect the levels of discrete PAHs in cancer risk (ILCR). ILCR = exposure (μg/kg/day)
the particulate phase and are often given as the × cancer slope factor (μg/kg/day). The ILCR is
sum of a limited number of PAH components. considered negligible when it is less than 1 in 105

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Table 7.2 Main source sectors for PAHs in 1994 in six European countries (Austria, Denmark,
Germany, Luxembourg, Norway, and the United Kingdom)

Sector PAH emissions

Amount (tonnes per year) Percentage of total
Combustion of energy and transformation industries 6.1 0.3
Non-industrial combustion plants plus wood burning 1120 60
Combustion in manufacturing industry 63 3.4
Production processes 248 13
Road transport 383 20
Other mobile sources 10 0.5
Waste incineration 30 1.6
Agriculture and forestry 1 < 0.1
Natural sources 8 0.4
Total (approximately) 1900
Reproduced from Boström et al. (2002).

(less than 1 additional cancer case per 100 000 equivalency concentrations were found to be
persons), and the cancer slope factor is based on 3-fold higher in the winter months (Gaga et al.,
the extrapolation of a dose–response curve for 2012). A similar outcome was observed in a study
tumorigenicity seen at high dose in experimental of children aged 5–6 years (n = 260) in New York
animals. City when measurements were conducted in the
Background levels of PAHs in remote loca- heating and non-heating seasons (Jung et al.,
tions have been measured between 0.01 ng/m3 2010). In the United Kingdom, the Toxic Organic
and 0.1 ng/m3 for individual PAH components Micropollutants programme measured temporal
(WHO, 1998). In rural districts the levels were trends in PAH in the atmosphere from 1991 to
approximately 10 times higher, whereas in 2005 at six different sampling sites. Most showed
city streets levels may amount to 50 ng/m3 or a reduction in PAH levels and had concentra-
more of the more abundant individual PAHs tions that were lower than the new air quality
(Boström et al., 2002). Total PAHs in the centre standard of 0.25 ng/m3. However, this value was
of Stockholm, Sweden, ranged from below exceeded in urban areas in the winter months
100 ng/m3 to 200 ng/m3. The most abundant (Meijer et al., 2008).
PAH was phenanthrene. In other cities higher Indoor PAH levels usually range from 1 ng/m3
levels of individual PAHs have been measured to 50 ng/m3 due to tobacco smoke and residen-
(WHO, 1998; Binková et al., 2003). PAH was tial heating with wood, coal, and other materials
measured in the gas and particulate phase over (WHO, 1998). Environmental tobacco smoke is
summer and winter sampling periods in Kocaeli, a major contributor to air pollution and dust,
Turkey. Σ13PAH in the gas and particulate phases and surfaces remain contaminated long after the
ranged from 6.2 ng/m3 dibenz[a,h]anthracene smoking has ceased (called third-hand smoke).
to 98.6 ng/m3 phenanthrene in the winter, and Measurement of PAHs in settled household
from 3.0 ng/m3 benz[a]anthracene to 35.1 ng/m3 dust in 132 homes showed that total PAHs were
phenanthrene in the summer. The most abundant 990 ng/g in smoking households versus 756 ng/g
PAH in both sampling periods was phenanthrene, in nonsmoking households, and when corrected
followed by fluoranthene and pyrene. B[a]P toxic

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Table 7.3 Mean profiles of individual PAHs in ambient air (relative to benzo[a]pyrene = 1.0)

Compound Point source Near mobile source Home heating Transport Geometric mean
Anthracene 5.5 7.6 1.0 1.8 2.9
Phenanthrene 38 200 39 43 60
Fluoranthene 14 48 12 13 18
Pyrene 9.3 28 11 7.1 12
Benz[a]anthracene 1.4 0.82 1.0 0.78 0.97
Perylene 0.33 0.25 0.22 0.24 0.26
Benzo[e]pyrene 1.5 1.3 1.6 1.4 1.4
Benzo[g,h,i]perylene 1.4 1.5 2.4 1.3 1.6
Indeno[1,2,3-cd]pyrene 1.5 1.3 1.5 1.4 1.4
Anthanthrene 0.19 0.15 0.13 0.20 0.17
Chrysene and triphenylene 3.0 2.7 3.5 2.9 3.0
Benzofluoranthene 3.6 2.9 3.6 4.4 3.6
Source: WHO (1998); reproduced with permission from the publisher.

for loading (dust/m3), the fold change was greater the winter the levels of low-molecular-weight
than 2-fold (Hoh et al., 2012). PAHs are increased compared with the summer
PAHs in the ambient air can react with (Prevedouros et al., 2004).
nitrates, hydroxyl radicals, or ozone, leading to
the production of more water-soluble compounds.
These compounds are rarely included in routine
Biomonitoring
PAH measurements. However, nitro-PAHs have Significant progress has been made in
been detected on soot, and the formation of biomonitoring of human exposure to PAH.
B[a]P-nitroquinone has been identified (Schauer External dose can be measured using personal-
et al., 2004). Exposure levels of nine different ized air monitoring devices where PM is trapped
nitroarenes resulting from diesel and gasoline on filters and then analysed for PAH content.
exhaust have recently been reviewed by the Internal dose can be assessed by measuring blood
International Agency for Research on Cancer; and urinary biomarkers of exposure. Different
diesel exhaust was ranked as a Group 1 known analytes have been used as biomarkers of PAH
human carcinogen (Benbrahim-Tallaa et al., exposure and effect. These include measuring
2012). PAH metabolites in the urine and intermediate
Generally the mobile sources differ in their biomarkers of effect (e.g. DNA and haemoglobin
PAH profile, with the heavy diesel vehicles being adducts). Analysis using urinary metabolites
characterized by lower-molecular-weight compo- has given the most clear-cut results. Particulate
nents than gasoline vehicles. However, per driven pyrene is well correlated with total PAH in the
kilometre, total emissions from a gasoline-fuelled breathing zone.
car are much lower than emissions from a diesel Urinary 1-hydroxypyrene may also reflect
car. The three-way converter does not change the inter-individual variation in PAH metabolism.
PAH profile of a gasoline-fuelled car significantly Occupational exposure has been found to lead
but reduces the total levels considerably. PAH to a 10–100 times greater urinary 1-hydroxy-
levels vary with season, with higher levels being pyrene content. Danish bus drivers excreted
observed in the winter than in the summer. Data more 1-hydroxypyrene than mail carriers did,
from Stockholm, Sweden, indicate that during but outdoor working mail carriers had more

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PAH metabolites in their urine than those increases when children were actively exposed
working indoors, indicating the impact of (Suwan-ampai et al., 2009).
outdoor air pollution (Hansen et al., 2004). The As there is compelling evidence for the
use of 1-hydroxypyrene as a biomarker of PAH conversion of PAH to diol-epoxides as an activa-
exposure has been criticized on the grounds that tion pathway (see below), there have been recent
pyrene is not a carcinogenic PAH. This has led advances in measuring their corresponding
to the substitution of 3-hydroxy-B[a]P, but sensi- tetraol hydrolysis products in humans. Progress
tive methods of detection have been a challenge. has been made in developing stable isotope dilu-
The detection of 3-hydroxy-B[a]P has also been tion liquid chromatographic mass spectrometric
criticized as a biomarker since this metabolite is methods to detect phenanthrene tetraols (Hecht
not derived from any of the known pathways of et al., 2010; Zhong et al., 2011). Phenanthrene
B[a]P activation. contains a bay region and undergoes similar
Measurements of urinary 1-hydroxypy­rene- metabolic transformation to B[a]P to form
glucuronide, 2-naphthol, and malondialdehyde diol-epoxides, which hydrolyse to tetraols. The
by synchronous fluorescence spectroscopy or detection of phenanthrene tetraols has also
high-performance liquid chromatography were been criticized, since it is not a carcinogenic
used to evaluate seasonal and regional variations PAH. Recently, methods have been developed
in PAH exposure and oxidative stress in Korean to measure urinary B[a]P tetraols with femto-
adults and women. Higher levels were found mole sensitivity (Hecht et al., 2010), and these
in individuals from industrialized areas and techniques can now be applied to biomonitoring
in the winter. Further elevation of 1-hydroxy- studies.
pyrene-glucuronide was observed in children Efforts have also been made to detect
exposed to environmental tobacco smoke (Yoon stable covalent diol-epoxide DNA and haemo-
et al., 2012). In a study in Chinese children from globin adducts in exposed humans. Repaired
polluted and non-polluted areas, the levels of diol-epoxide DNA adducts in blood can be
nine urinary monohydroxylated PAH metabo- measured using ELISA and chemilumines-
lites and 8-oxo-2′-deoxyguanosine (8-oxo-dG) cence-based methods, while unrepaired DNA
were compared. Children from the polluted adducts can be measured in lymphocytes by
area had a higher PAH burden than those from [32P]-postlabelling methods. For example,
the non-polluted area, but no significant differ- (+)-7β,8α-dihydroxy-9α,10α-oxo-7,8,9,10-tetra-
ence in 8-oxo-dG levels was noted (Fan et al., hydro-B[a]P-N2-deoxyguanosine [(+)-anti-
2012). The effect of involuntary tobacco smoke B[a]PDE-N2-dGuo] adducts have also been
exposure on urinary levels of 23 monohydrox- detected in human maternal and umbilical
ylated metabolites of PAH in 5060 subjects aged white blood cells after exposure to air pollution,
> 6 years was studied in the National Health using ELISA-based methods (Whyatt et al.,1998;
and Nutrition Examination Survey (NHANES). Santella, 1999). Total DNA and B[a]P-like DNA
After correcting for other confounders, signif- adducts were measured by [32P]-postlabelling
icant increases in urinary 1-hydroxypye- in lymphocytes of nonsmoking policemen in
rene, 2-hydroxyfluorene, 3-hydroxyfluorene, Prague (n = 109) working 8 hour shifts. While
9-hydroxyflourene, 1-hydroxypyrene, and there was no significant change in total DNA
1-2-hydroxy-phenanthrene were observed. adducts, there was a marked increase in B[a]P-like
Increases of 1.1–1.4-fold for involuntary expo- DNA adducts correlated to personal exposure to
sure were noted, which increased to 1.6–6.9-fold PAHs collected on respirable particles (Topinka
et al., 2007). Diol-epoxide DNA adducts are

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short-lived; therefore, attention has also focused involving oxidation and hydrolysis reactions
on the development of methods to detect haemo- (Figure 7.2). In the first step, B[a]P is converted
globin diol-epoxide adducts since the half-life of preferentially in the lung by the cytochrome P450
the red blood cell is 7–10 days (Day et al., 1990). isozyme P4501B1 to the major (+)-7R,8S-epoxide
and minor (–)-7S,8R-epoxide. In the second step,
the 7R,8R-trans-dihydrodiol is predominately
Toxicokinetics, including metabolic formed by the action of epoxide hydrolase. In the
activation third step, diol-epoxide diastereomers are gener-
Parent PAHs have low chemical reactivity ated by another oxidation reaction via various
and must be metabolically activated to elec- P450 enzymes, including P4501B1 (Thakker
trophilic intermediates to exert their carcino- et al., 1985; Petruska et al., 1992; Guengerich,
genic effects (Sims and Grover, 1974; Conney 1993; Constantin et al., 1994; Cavalieri and
1982; Thakker et al., 1985). Three pathways Rogan, 1995; Shimada et al., 1999, 2001).
of PAH activation have been proposed in the Diol-epoxides have been studied in various
literature and are best exemplified with B[a]P animal carcinogenicity models. It has been
(Figure 7.2). In the first pathway, B[a]P is meta- revealed that the diol-epoxides with the highest
bolically activated by either P450 peroxidase or carcinogenic activity are in general the anti-di-
another peroxidase by acting as a co-reductant astereomers and especially the enantiomers with
of complex-1 (FeV). This leads to a radical cation R-absolute configuration at the benzylic arene
on the most electron-deficient C6 atom, which is carbon (Thakker et al., 1985; Glatt et al., 1991).
highly reactive and capable of forming unstable In studies of interactions of diol-epoxides with
C8-guanine [8-(benzo[a]pyren-6-yl)guanine)], DNA, they demonstrate a high preference for the
N7-guanine [7-benzo[a]pyren-6-yl)guanine], exocyclic amino group of deoxyguanosine and
and N7-adenine [7-benzo[a]pyren-6-yl)adenine] deoxyadenosine, where the major adduct derived
depurinating DNA adducts (Cavalieri and from B[a]P is (+)-anti-B[a]PDE-N2-dGuo (Jeffrey,
Rogan, 1995). Evidence for this pathway comes 1985; Gräslund and Jernström, 1989; Jerina
from in vitro reactions with B[a]P, microsomes, et al., 1991; Geacintov et al., 1997). This pathway
and a peroxide substrate, which has led to the of metabolic activation has been observed for
trapping of DNA adducts, as well as from mouse many PAHs in ambient air, including 5-methyl-
skin studies (Cavalieri et al., 1990, 1991). Data chrysene (Melikian et al., 1983, Koehl et al.,
exist that B[a]P and dibenzo[a,l]pyrene can exert 1996), benz[a]anthracene (Cooper et al., 1980),
their tumorigenicity through this mechanism in benzo[b]fluoranthene (Ross et al., 1992), B[a]P
mouse skin and rat mammary gland (Cavalieri (as outlined above), dibenz[a,h]anthracene (Platt
et al., 1991, 2005) In addition, trace amounts et al., 1990), and dibenzo[a,l]pyrene (Luch et al.,
of B[a]P-depurinating DNA adducts have been 1997, 1999), in in vitro systems (cell extracts,
detected in the urine of smokers and in women microsomes, and cell culture systems), and in
exposed to household smoke (Casale et al., some cases in in vivo studies in animals and
2001). However, apart from this single study, the humans. For example, PAHs within airborne
evidence to support this mechanism due to inha- PM2.5 produced DNA bulky stable adducts in
lation exposure to PAH is not strong. human lung cell co-cultures (Abbas et al., 2013).
In the second pathway, B[a]P is metaboli- In the third pathway, PAHs are metabolically
cally activated to vicinal diol-epoxides (Jerina activated to o-quinones by the action of aldo-
et al., 1991) formed through a three-step process keto reductases (AKRs) (Penning et al., 1999;
Penning, 2004). For B[a]P, the sequence involves

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 Air pollution and cancer

Fig 7.2 Pathways of PAH activation using benzo[a]pyrene as an example.

Source: Park and Penning (2008); reproduced with permission from John Wiley & Sons.

the NAD(P)+-dependent oxidation of the 7R,8R- which NADPH is depleted and ROS is amplified
trans-dihydrodiol to a ketol catalysed by AKR1A1, (Shultz et al., 2011). This pathway of metabolic
AKR1C1–AKR1C4 (Figure 7.2). The ketol then activation has been observed for several PAHs in
spontaneously rearranges to a catechol, which ambient air, including phenanthrene, chrysene,
undergoes air-oxidation to yield B[a]P-7,8-dione 5-methyl-chrysene, benz[a]anthracene, and
and reactive oxygen species (ROS) (Palackal et al., B[a]P in in vitro systems (recombinant enzymes)
2001, 2002; Penning et al., 1996). B[a]P-7,8-dione and cultures of human lung cells (Palackal et al.,
is both electrophilic (will react with DNA) and 2001, 2002; Park et al., 2008b).
redox-active. In the presence of reducing equiva- Efforts have been made to assess the contri-
lents and NQO1, AKRs themselves, and carbonyl bution of each of these pathways to the meta-
reductase, the quinones can be reduced back to bolic activation of B[a]P in human lung cells.
the corresponding catechols, and if they are not Using a stable isotope dilution liquid chromato-
intercepted a futile redox cycle will ensue in graphic mass spectrometric method, signature

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metabolites of each of the three pathways were the 12th and 61st codons, which could explain
measured: B[a]P-1,6-dione and B[a]-3,6-dione the transformation potential of the diol-epoxide.
(radical cation metabolites), B[a]P-tetraol-1 The dominant mutation observed was a G → T
(diol-epoxide metabolites), and B[a]P-7,8-dione transversion, consistent with DNA-adduct
(o-quinone metabolites) in human bronchoepi- formation on deoxyguanosine (Marshall et al.,
thelial (H358) cells in the presence and absence 1984). One of the most compelling pieces of
of the aryl hydrocarbon receptor (AhR) agonist data has shown that by using ligation-mediated
TCDD. It was found that each of the pathways polymerase chain reaction, the (+)-anti-B[a]PDE
contributed equally to B[a]P metabolism in the preferentially forms DNA adducts in hot spots on
presence and absence of TCDD (Lu et al., 2011). the p53 tumour suppressor gene, which is one of
The rate of absorption of PAHs from the the most mutated genes in human lung cancer.
tracheobronchial epithelium after inhalation These hot spots correspond to the same codons
exposure is determined by their high lipophilicity that are mutated in tumours obtained from
(Gerde et al., 1993). For lipophilic carcinogens humans with lung cancer. The dominant muta-
such as B[a]P, the delayed absorption in the tion observed was again a G → T transversion,
airway mucosa is a result of slow passage through consistent with DNA adduct formation on deox-
the airway epithelium, yielding a very high dose yguanosine (Denissenko et al., 1996; Hainaut
to these target cells. Because of the long retention and Pfeifer, 2001).
time, the metabolic activation can be consider- In a separate in vitro study, the mutagenic
able even at low enzyme activities (Bond et al., potency of (±)-anti-B[a]PDE and B[a]P-7,8-dione
1988). (AKR product) were compared in a yeast-re-
porter gene assay for p53 mutation. It was found
that B[a]P-7,8-dione was 80-fold more mutagenic
Modes of action than the diol-epoxide provided it was permitted
Carcinogenic PAHs are generally positive in to redox cycle (Yu et al., 2002). In these exper-
short-term tests for mutagenicity (Table 7.4), for iments there was a linear correlation between
example the bacterial Salmonella mutagenicity (±)-anti-B[a]PDE mutagenicity and the forma-
(Ames) assay and the HPRT-mammalian cell tion of (+)-anti-B[a]PDE-N2-dGuo adducts, and
mutagenicity assay, provided a metabolic acti- a linear correlation between B[a]P-7,8-dione
vation system is present (Malaveille et al., 1977; mutagenicity and the formation of 8-oxo-dGuo
MacLeod et al., 1988; Chen et al., 1990; Wei et al., adducts (Park et al., 2008a). In addition,
1993). In the Ames assay, a rat liver S9 activa- B[a]P-78-dione gave predominately G → T trans-
tion system is used; in the HPRT assay, recom- versions, consistent with the base mispairing of
binant P4501A1 and P4501B1 are co-expressed. 8-oxo-dGuo with adenine. The position of the
The mutagenic species has been identified by point mutations within p53 was quite random
comparing the mutagenic potency of different until there was biological selection for domi-
PAH metabolites, which demonstrates that of nance, and then the spectrum of mutations was
the known metabolites the diol-epoxides are the similar to that seen in lung cancer (Park et al.,
most potent mutagens (Malaveille et al., 1977). 2008b). These data suggest that B[a]P-7,8-dione
Treatment of a plasmid containing K-Ras with formed by AKRs has the potential to contribute
the (+)-anti-B[a]PDE followed by transfection to the carcinogenic mode of action of B[a]P.
into NIH3T3 cells led to cell transformation with Planar PAHs can induce their own metabo-
increased foci in soft agar. Rescue of the plasmid lism. Compounds such as B[a]P can bind to the
showed that there were single point mutations of AhR (Nebert and Jensen, 1979; Nebert et al.,

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 Air pollution and cancer

Table 7.4 Genotoxicity of individual PAHs that are carcinogenic in experimental animals after
inhalation or intratracheal instillation

Compound Results
Anthanthrene Positive, limited database
Benzo[b]fluoranthene Positive
Benzo[j]fluoranthene Positive
Benzo[k]fluoranthene Positive
Benzo[a]pyrene Positive
Chrysene Positive
Dibenz[a,h]anthracene Positive
Dibenzo[a,i]pyrene Positive
Indeno[1,2,3-cd]pyrene Positive
Naphthalene Negative for gene mutations, positive for clastogenicity in vitro
Source: WHO (1998); reproduced with permission from the publisher.

1993, 2004). This leads to nuclear localization of genes involved in growth as well as biotransfor-
the liganded AhR, where it can act as a transcrip- mation and differentiation (Nebert et al., 1993).
tion factor by binding to the xenobiotic response Studies also indicate the ability of both PAHs and
element to induce the CYP1A1 and CYP1B1 genes their metabolites to activate kinases involved in
(Denison et al., 1988a, 1988b, 1989), which will survival signalling, thus giving DNA-damaged
result in enhanced monoxygenation of the parent cells a survival advantage (Burdick et al., 2003).
PAH. PAH metabolism leads to the produc- At higher concentrations some PAHs induce
tion of electrophiles (e.g. quinones), which can apoptosis (Solhaug et al., 2004). In addition,
activate the Nrf2-Keap 1 system. Nrf2 acts as a PAHs show inhibitory effects on gap junctional
transcription factor and binds to the antioxidant intercellular communication (Upham et al.,
response element to induce γGCS, NQO1 and 1996; Weis et al., 1998).
AKR1C1–AKR1C3, and AKR1B10 (Burczynski
et al., 1999; Jin and Penning 2007; Penning and
Drury, 2007). Importantly, AKR1C1–AKR1C3
Carcinogenicity studies in animals
are involved in the metabolic activation of PAH Most investigations of PAH carcinogenesis
trans-dihydrodiols to the electrophilic and redox by the respiratory route are intratracheal instil-
active PAH o-quinones, which could further lation studies (WHO, 1998). In all, 10 PAHs have
exacerbate PAH activation via induction of been found to be carcinogenic in experimental
AKRs. The PAH o-quinones produced by this animals after inhalation or intratracheal instil-
pathway are also ligands for the AhR (Burczynski lation (WHO, 1998; NTP, 2000) (Table 7.5).
and Penning, 2000). Thus, both the parent PAH Only B[a]P and naphthalene have been studied
and their downstream metabolites can lead to by the inhalation route. In one inhalation study
the metabolic activation of PAHs in ambient air. in hamsters, groups of 24 males were exposed to
PAHs may, in addition to initiating carcino- B[a]P condensed onto sodium chloride particles
genesis via a genotoxic mechanism, exert promo- at concentrations of 2.2, 9.5, and 46.5 mg/m3 for
tional effects through various modes of action. 4.5 hours per day, 7 days per week for the first
Certain PAHs induce inflammatory processes 10 weeks, then for 3 hours per day for 2 years.
(Casale et al., 1997). The binding of PAHs to the Exposure was by nose breathing only. There were
AhR also leads to transcriptional upregulation of no tumours in the controls or in the low-exposure

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IARC SCIENTIFIC PUBLICATION – 161

group. In the other two groups, exposure-related Kapitulnik et al., 1978). Similarly, in the A/J
tumours were found in the nasal cavity, larynx, mouse lung model of B[a]P-induced carcino-
trachea, pharynx, oesophagus, and forestomach, genesis, anti-B[a]PDE-DNA adducts were early
but not in the lung (Thyssen et al., 1981). RIVM lesions that could be detected in the initiation
(1989) cites two other inhalation studies with phase (Nesnow et al., 1998).
B[a]P not found in the open literature: one in Carcinogenesis experiments with mixtures
mice (Knizhnikow et al., 1982; see RIVM, 1989) containing PAHs have also been reported.
and one in rats with co-exposure with sulfur Heinrich et al. (1994) exposed groups of 72 female
dioxide (Laskin et al., 1970; see RIVM, 1989). Wistar rats to a coal tar/pitch aerosol containing
In both studies malignant lung tumours were either 20 or 46 μg/m3 B[a]P for 17 hours per day,
observed. 5 days per week, for 10 or 20 months, followed
In recent bioassay inhalation studies with by a clear air period of up to 20 or 10 months,
naphthalene, Fischer 344/N rats developed respectively. The cumulative doses of inhaled
neuroblastomas of the nasal olfactory epithelium B[a]P of the four exposure groups were 71, 143,
after being exposed in inhalation chambers to 0, 158, and 321 mg B[a]P/m3 hours, and the corre-
10, 30, or 60 ppm (80, 52, 157, or 314 mg/m3) for sponding lung tumour rates were 4.2%, 33.3%,
6 hours per day, on 5 days per week, for 105 weeks 38.9%, and 97.2%, respectively, whereas there
(NTP, 2000). The observed rates in males were were no tumours in the control group. In similar
0/49, 0/49, 4/48, and 3/48, respectively, and in experiments in which rats were exposed to coal
females 0/49, 2/49, 3/49, and 12/49, respectively. tar/pitch vapour condensed on the surface of fine
In addition, adenomas of the nasal respiratory carbon black particles, the resulting lung tumour
epithelium were observed in 0/49, 06/49, 8/48, rate was about twice as high.
and 15/48 males and in 0/49, 0/49, 4/49, and 2/49 Pott and Heinrich (1990) have also performed
females, respectively. In the study with B6C3F1 a lifelong inhalation study with rats exposed to
mice subjected to whole-body exposure of 0, 10, diesel exhaust. In this study, tumour rates similar
or 30 ppm (0, 52, or 157 mg/m3) naphthalene in to those in the study with pitch pyrolysis vapours
inhalation chambers for 6 hours per day, 5 days were induced, although the PAH content (meas-
per week, for 104 weeks, a statistically signifi- ured as B[a]P) was 100–1000 times lower. This
cant increase in the incidence of bronchioloal- result indicates that diesel exhaust contains
veolar adenomas in high-dose female mice was other potent carcinogenic or tumour-promoting
observed (NTP, 2000). Increased incidences of compounds besides unsubstituted PAHs.
bronchioloalveolar adenomas and carcinomas Numerous carcinogenicity studies have been
were observed in the male mice, but the increases performed using dermal application and subcu-
were not statistically significant. taneous and intramuscular injection (for over-
PAHs and their metabolites will also view, see WHO, 1998). An oral gavage study with
cause lung cancer in animals when adminis- B[a]P revealed tumour development in the liver,
tered by other routes. Classically, the newborn forestomach, auditory canal, oral cavity, skin,
mouse model of lung cancer was used to rank and intestines in both sexes of rats, and addi-
the tumorigenicity of different B[a]P metab- tionally the kidney in males and the mammary
olites, given that the developing lung is more gland and oesophagus in females (RIVM, 2001).
susceptible to carcinogen exposure. Studies However, no lung tumours were observed
such as these showed that the (+)-anti-B[a]PDE after this route of administration. In a feeding
was the most potent lung tumorigen of the study of B[a]P in mice, tumours in the tongue,
known B[a]P metabolites (Buening et al., 1978;

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Table 7.5 Carcinogenicity of individual PAHs in experimental animals after inhalation or

intratracheal instillation

Compound Carcinogenicity Species No. of studies with positive,

(weight of evidence) negative, and questionable
results
+ – ±
Anthanthrene Positive Mouse 1
Anthracene Negative Rat 1
Benzo[b]fluoranthene Positive Rat 1 1
Hamster
Benzo[j]fluoranthene Positive Rat 1
Benzo[k]fluoranthene Positive Rat 1
Benzo[g,h,i]perylene Negative Rat 1
Benzo[a]pyrene Positive Mouse 1 1 1
Rat 9
Hamster 11
Benzo[e]pyrene Negative Rat 1
Chrysene Positive Rat 1
Dibenz[a,h]anthracene Positive Rat 1 1
Hamster 1
Dibenzo[a,i]pyrene Positive Hamster 2
Indeno[1,2,3-cd]pyrene Positive Rat 1
Naphthalene Positive Mouse 1 2
Rat
Phenanthrene Negative Rat 1
Pyrene Negative Hamster 1
Source: WHO (1998); reproduced with permission from the publisher; IARC (2002).

oesophagus, forestomach, and larynx, but not Ambient air exposures

lung, were observed (Culp et al., 1998).
Few studies have addressed the impact of
exposure to PAHs in ambient air on human
Carcinogenicity studies in humans cancer. Studies using other exposure indicators
(PM or NO2) have shown associations between
Occupational exposures air pollution and lung cancer; however, no PAH
A review and meta-analysis on the associa- exposure information was available (Pope et al.,
tion between occupational exposure to PAHs and 2002; Hoek et al., 2002; Nafstad et al., 2003). An
lung cancer development in 39 cohorts found an analysis of the United States data on lung cancer,
average relative risk of 1.20 per 100 μg/m3 years PM exposure, and older PAH and metal air
cumulative B[a]P (Armstrong et al., 2004). For concentration data, supports the plausibility that
some occupations relative risks were consider- known chemical carcinogens may be responsible
ably higher, but confidence intervals were very for the lung cancer attributed to PM2.5 exposure
wide. For exposures in coke ovens, gas works, in the American Cancer Society study (Harrison
and aluminium industries, the risk is equivalent et al., 2004). A study by Cordier et al. (2004)
to a relative risk of 1.06 for a working lifetime of found an increased risk of childhood brain cancer
40 years at 1 μg/m3. associated with PAH exposure. Both paternal

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IARC SCIENTIFIC PUBLICATION – 161

preconception occupational PAH exposure and the highest risk of lung cancer (odds ratio [OR],
paternal smoking were associated with increased 4.14; 95% CI, 1.60–10.74) (Wenzlaff et al., 2005a).
risks for childhood brain tumours. In the same study cohort, variants in GSTM1,
GSTT1, and GSTP1 were examined to determine
whether there was an association of the genotype
Human susceptibility with lung cancer incidence in never-smokers.
PAHs are metabolically activated by phase I Individuals who had been exposed to household
P450 isozymes (CYP1A1, CYP1B1) in combina- environmental tobacco smoke for > 20 years, and
tion with epoxide hydrolase (EPHX) and phase who were carriers of either the GSTM1 null allele
I AKR isozymes (AKR1A1, AKR1C1-AKR1C4) or the GSTP1 Val allele, were at a 4-fold increased
and are detoxified by phase II enzymes including risk of developing lung cancer (OR, 4.56; 95%
GSTs, UTGs, SULTs, and COMT. In addition, CI, 1.21–17.21) (Wenzlaff et al., 2005b). In a lung
bulky covalent diol-epoxide DNA adducts can be cancer case–control study in China, women
repaired by nucleotide excision repair proteins who were never-smokers were found to be at a
(XPD [helicase], XPA, and XPC [damage recogni- significant increased risk of adenocarcinoma if
tion]), and oxidative DNA lesions can be repaired they were carriers of the variants in the nucleo-
by base excision repair enzymes (hOGG1 and tide excision repair variant XRCC1 399 Gln/Gln
APE). Each of these genes is highly polymorphic versus the Arg/Arg genotype (OR, 14.12; 95% CI,
in the human population. (A complete list of 2.14–92.95). The OR of lung adenocarcinoma
these variants is available at the NCBI database: for the XRCC1 399Gln allele with exposure to
http://www.ncbi.nlm.nih.gov/.) Many of these cooking oil smoke was 6.29 (95% CI, 1.99–19.85)
variants are non-synonymous single-nucleotide (Li et al., 2005). DNA integrity was investigated
polymorphisms (nSNPs) that can affect enzyme in 50 bus drivers, 20 garage men, and 50 controls
activity. Combinations of these nSNPs rather in the Czech Republic and associated with vari-
than an individual SNP may affect human genetic ants in the base excision repair gene hOGG1.
susceptibility to PAH emissions in ambient air. Carriers of at least one variant (Cys allele) had
In a study of Prague policemen occupationally a higher degree of DNA damage (Bagryantseva
exposed to polluted air, B[a]P-like DNA adducts et al., 2010). To date, no molecular epidemiolog-
were detected and found to be positively asso- ical study has been performed whereby combina-
ciated with SNPs in XPD and GSTM1 (Binková tions of polymorphic variants in phase I, phase
et al., 2007). In another lung cancer case–control II, and DNA repair genes have been pooled.
study, exposure to environmental tobacco smoke However, based on the studies described, carriers
and polymorphisms in CYP1B1 Leu(432)Val was of variants in all three classes of genes might be at
significantly associated with lung cancer suscep- higher risk of developing lung cancer from emis-
tibility, with an odds ratio for at least one allele sions of PAHs in ambient air.
of 2.87 (95% confidence interval [CI], 1.63–5.07)
(Wenzlaff et al., 2005a). Combinations of the Conclusions
polymorphism in this phase I enzyme gene
along with those selected from either phase II PAHs generated from the incomplete
enzyme genes (GSTM1 null, GSTP1 Ile(105)Val) combustion of organic material are ubiquitous
or NADPH-quinone oxidoreductase (NQO1) contaminants in urban air. There are numerous
C(609)T) were also evaluated. Here the combi- unsubstituted PAHs (pyrogenic) and substi-
nation of the CYP1B1 Leu(432)Val allele and tuted PAHs (petrogenic). The pyrogenic PAHs
the NQO1 C(609)T allele was associated with may occur in the gas phase, particulate phase,

88
 Air pollution and cancer

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