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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Chemical Agents and Related Occupations. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100F.)

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Chemical Agents and Related Occupations.

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BENZO[a]PYRENE

Benzo[a]pyrene was considered by previous IARC Working Groups in 1972, 1983, and 2005 (IARC, 1973, 1983, 2010). Since that time new data have become available, which have been incorporated in this Monograph, and taken into consideration in the present evaluation.

1. Exposure Data

1.1. Identification of the agent

  • Chem. Abstr. Services Reg. No.: 50-32-8
  • Chem. Abstr. Name: Benzo[a]pyrene
  • IUPAC Systematic Name: Benzo[a]pyrene
  • Synonyms: BaP; benzo[def]chrysene; 3,4-benzopyrene*; 6,7-benzopyrene*; benz[a]pyrene; 3,4-benz[a]pyrene*; 3,4-benzpyrene*; 4,5-benzpyrene* (*alternative numbering conventions)

Image 978-9283201380-C014-F001.jpg

  • C20H12
  • Relative molecular mass: 252.31
  • Description: Yellowish plates, needles from benzene/methanol; crystals may be monoclinic or orthorhombic
  • Boiling-point: 310–312 °C at 10 mm Hg
  • Melting-point: 179–179.3 °C; 178.1 °C
  • Spectroscopy data: Ultraviolet/visual, infrared, fluorescence, mass and nuclear magnetic-resonance spectral data have been reported
  • Water solubility: 0.00162 mg/L at 25 °C; 0.0038 mg/L at 25 °C
  • log Kow (octanol–water): 6.35
  • Henry’s Law Constant: 0.034 Pa m3/mol at 20 °C

From IARC, (2010)

1.2. Occurrence and exposure

Benzo[a]pyrene and other polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants formed during incomplete combustion or pyrolysis of organic material. These substances are found in air, water, soils and sediments, generally at trace levels except near their sources. PAHs are present in some foods and in a few pharmaceutical products based on coal tar that are applied to the skin. Tobacco smoke contains high concentrations of PAHs (IARC, 2010).

1.2.1. Exposure of the general population

The general population can be exposed to benzo[a]pyrene through tobacco smoke, ambient air, water, soils, food and pharmaceutical products. Concentrations of benzo[a]pyrene in sidestream cigarette smoke have been reported to range from 52 to 95 ng/cigarette — more than three times the concentration in mainstream smoke. Major sources of PAHs in ambient air (both outdoors and indoors) include residential and commercial heating with wood, coal or other biomasses (oil and gas heating produce much lower quantities of PAH), other indoor sources such as cooking and tobacco smoke, and outdoor sources like motor-vehicle exhaust (especially from diesel engines), industrial emissions and forest fires. Average concentrations of individual PAHs in the ambient air in urban areas typically range from 1 to 30 ng/m3; however, concentrations up to several tens of nanograms per cubic metre have been reported in road tunnels, or in large cities that make extensive use of coal or other biomass as residential heating fuel. Estimates of PAH intake from food vary widely, ranging from a few nanograms to a few micrograms per person per day. Sources of PAHs in the diet include barbecued/grilled/broiled and smoke-cured meats; roasted, baked and fried foods (high-temperature processing); bread, cereals and grains (at least in part from gas/flame-drying of grains); and vegetables grown in contaminated soils, or in areas with surface contamination from atmospheric PAH fall-out (IARC, 2010).

1.2.2. Occupational exposure

Occupational exposure to PAHs occurs primarily through inhalation and via skin contact. Monitoring by means of ambient air-sampling or personal air-sampling at the workplace, to determine individual PAHs, sets of PAHs or surrogates (e.g. coal-tar pitch volatiles) has been used to characterize exposure via inhalation; more recently, biological monitoring methods have been applied to characterize the uptake of certain specific PAHs (e.g. benzo[a]pyrene) to be used as biomarkers of total exposure (IARC, 2010).

Industries where occupational exposure to benzo[a]pyrene has been measured and reported include: coal liquefaction, coal gasification, coke production and coke ovens, coal-tar distillation, roofing and paving (involving coal-tar pitch), wood impregnation/preservation with creosote, aluminium production (including anode manufacture), carbon-electrode manufacture, chimney sweeping, and power plants. Highest levels of exposure to PAHs are observed in aluminium production (Söderberg process) with values up to 100 μg/m3. Mid-range levels are observed in roofing and paving (e.g. 10−20 μg/m3) and the lowest concentrations (i.e. at or below 1μg/m3) are observed in coal liquefaction, coal-tar distillation, wood impregnation, chimney sweeping and power plants (IARC, 2010).

2. Cancer in Humans

No epidemiological data on benzo[a]pyrene alone were available to the Working Group.

3. Cancer in Experimental Animals

Benzo[a]pyrene was considered by three previous Working Groups (IARC, 1973, 1983, 2010).

In IARC Monograph Volume 3 (IARC, 1973) it was concluded that benzo[a]pyrene produced tumours in all species tested (mouse, rat, hamster, guinea-pig, rabbit, duck, newt, monkey) for which data were reported following exposure by many different routes (oral, dermal, inhalation, intratracheal, intrabronchial, subcutaneous, intraperitoneal, intravenous). Benzo[a]pyrene had both a local and a systemic carcinogenic effect, was an initiator of skin carcinogenesis in mice, and was carcinogenic in single-dose studies and following prenatal and transplacental exposures.

In IARC Monograph Volume 32 (IARC, 1983) no evaluation was made of studies of carcinogenicity in experimental animals published since 1972, but it was concluded that there is sufficient evidence for the carcinogenicity of benzo[a]pyrene in experimental animals.

Carcinogenicity studies with administration of benzo[a]pyrene by multiple route of exposure, reported after the initial evaluations, were subsequently reviewed in IARC Monograph Volume 92 (IARC, 2010) and are summarized below (Table 3.1). See Table 3.2 for an overview of malignant tumours induced in different animal species.

Table 3.1. Carcinogenicity studies of benzo[a]pyrene in experimental animals.

Table 3.1

Carcinogenicity studies of benzo[a]pyrene in experimental animals.

Table 3.2. Summary of reports of malignant tumours clearly induced in experimental animals by benzo[a]pyrene.

Table 3.2

Summary of reports of malignant tumours clearly induced in experimental animals by benzo[a]pyrene.

3.1. Skin application

In several studies in which benzo[a]pyrene was applied to the skin of different strains of mice, benign (squamous cell papillomas and keratoacanthomas) and malignant (mainly squamous-cell carcinomas) skin tumours were observed (Van Duuren et al., 1973; Cavalieri et al., 1977, 1988a; Levin et al., 1977; Habs et al., 1980, 1984; Warshawsky & Barkley, 1987; Albert et al., 1991; Andrews et al., 1991; Warshawsky et al., 1993). No skin-tumour development was seen in AhR−/− mice that lacked the aryl hydrocarbon receptor, whereas the heterozygous and wild-type mice developed squamous-cell carcinomas of the skin (Shimizu et al., 2000).

In a large number of initiation–promotion studies in mice, benzo[a]pyrene was active as an initiator (mainly of squamous-cell papillomas) when applied to the skin (IARC, 2010).

3.2. Subcutaneous injection

In subcutaneous injection studies of benzo[a]pyrene, malignant tumours (mainly fibrosarcomas) were observed at the injection site in mice (Kouri et al., 1980; Rippe & Pott, 1989) and rats (Pott et al., 1973a, b; Rippe & Pott, 1989). No fibrosarcomas were observed in AhR−/− mice that lacked the aryl hydrocarbon receptor, whereas the heterozygous and wild-type mice did develop these tumours (Shimizu et al., 2000).

In another study, male and female newborn Swiss mice that were given benzo[a]pyrene subcutaneously showed a significant increase in lung-adenoma incidence and multiplicity (Balansky et al., 2007).

A single study in 12 strains of hamsters resulted in sarcomas at the site of injection in both sexes of all 12 strains (Homburger et al., 1972).

3.3. Oral administration

After administration of benzo[a]pyrene by gavage or in the diet to mice of different strains (Sparnins et al., 1986; Estensen & Wattenberg, 1993; Weyand et al., 1995; Kroese et al., 1997; Culp et al., 1998; Hakura et al., 1998; Badary et al., 1999; Wijnhoven et al., 2000; Estensen et al., 2004), increased tumour responses were observed in lymphoid and haematopoeitic tissues and in several organs, including the lung, forestomach, liver, oesophagus and tongue.

Oral administration of benzo[a]pyrene to XPA–/– mice resulted in a significantly higher increase of lymphomas than that observed in similarly treated XPA+/– and XPA+/+ mice (de Vries et al., 1997). Benzo[a]pyrene given by gavage to XPA–/–/p53+/– double-transgenic mice induced tumours (mainly splenic lymphomas and forestomach tumours) much earlier and at higher incidences than in similarly treated single transgenic and wild-type counterparts. These cancer-prone XPA–/– or XPA–/–/p53+/– mice also developed a high incidence of tumours (mainly of the forestomach) when fed benzo[a]pyrene in the diet (van Oostrom et al., 1999; Hoogervorst et al., 2003).

Oral administration of benzo[a]pyrene by gavage to rats resulted in an increased incidence of mammary gland adenocarcinomas (el-Bayoumy et al., 1995).

3.4. Intraperitoneal injection

In a series of studies in newborn and adult mice, intraperitoneal injection of benzo[a]pyrene increased the incidence of liver (adenomas and carcinomas) and lung (adenomas and adenocarcinomas) tumours and, occasionally, forestomach (squamous cell papillomas and carcinomas) and lymphoreticular tumours (Vesselinovitch et al., 1975a, b; Wislocki et al., 1986; Lavoie et al., 1987; Busby et al., 1989; Rippe & Pott, 1989; Mass et al., 1993; Nesnow et al., 1995; Ross et al., 1995; Weyand et al., 1995; Rodriguez et al., 1997; Von Tungeln et al., 1999).

In one study in rats with a single intraperitoneal injection of benzo[a]pyrene, a high incidence of abdominal mesotheliomas and sarcomas was observed (Roller et al., 1992).

3.5. Inhalation

In a lifetime inhalation study (Thyssen et al., 1981) in male hamsters, benzo[a]pyrene induced dose-related increases in the incidence of papillomas and squamous-cell carcinomas in both the upper respiratory tract (nose, larynx and trachea) and the upper digestive tract (pharynx, oesophagus and forestomach).

3.6. Intrapulmonary injection

Dose-related increases in the incidence of malignant lung tumours (mainly epidermoid and squamous-cell carcinomas and a few pleomorphic sarcomas) were found after injection of benzo[a]pyrene into the lung of rats (Deutsch-Wenzel et al., 1983; Iwagawa et al., 1989; Wenzel-Hartung et al., 1990; Horikawa et al., 1991).

3.7. Intratracheal administration

Intratracheal administration of benzo[a]pyrene alone or mixed with particulates and suspended in saline with or without suspendents resulted in benign and malignant respiratory tumours in mice (Heinrich et al., 1986a), rats (Pott et al., 1987; Steinhoff et al., 1991) and in numerous studies in hamsters (IARC, 2010). This treatment also induced forestomach tumours in hamsters (Saffiotti et al., 1972; Sellakumar et al., 1973; Smith et al., 1975a, b, Stenbäck & Rowland, 1979). Larger benzo[a]pyrene particles were generally more effective than smaller ones.

Mice that lack the nucleotide excision-repair gene XPA (XPA–/– mice) showed a stronger lung-tumour response after intratracheal instillation of benzo[a]pyrene than did their similarly treated XPA+/+ and XPA+/– counterparts (Ide et al., 2000).

3.8. Buccal pouch application

Repeated application of benzo[a]pyrene to the buccal pouch mucosa of male hamsters resulted in a high incidence of forestomach papillomas (Solt et al., 1987).

3.9. Subcutaneous tracheal grafts transplantation

In one study conducted in rats transplanted with subcutaneous rat tracheal grafts exposed to beeswax pellets containing various amounts of benzo[a]pyrene, a high incidence of squamous-cell carcinomas was reported (Nettesheim et al., 1977).

3.10. Intramammilary administration

In three studies in rats, benign and malignant mammary gland tumours developed after intrammilary injection of benzo[a]pyrene (Cavalieri et al., 1988a, b, 1991).

3.11. Intracolonic instillation

In three experiments in mice, intracolonic instillation of benzo[a]pyrene induced lymphomas and a variety of benign and malignant tumours in various organs including the forestomach (Toth, 1980; Anderson et al., 1983).

3.12. Intravaginal application

Intravaginal application of benzo[a]pyrene in mice produced invasive cervical carcinoma; no such tumours were seen in controls (Näslund et al., 1987).

3.13. Intrafetal injection

In one study in male and female Swiss mice, intrafetal injection of benzo[a]pyrene produced lung adenomas (Rossi et al., 1983).

4. Other Relevant Data

Benzo[a]pyrene is a carcinogen that induces tumours in many animal species. Some of the examples relevant for this review are: lung tumours in mice, rats, and hamsters; skin tumours in mice; liver tumours in mice; forestomach tumours in mice and hamsters; and mammary gland tumours in rats (Osborne & Crosby, 1987; IARC, 2010). In humans, occupational exposures to benzo[a]pyrene-containing mixtures have been associated with a series of cancers: coke production: lung; coal gasification: lung, bladder; paving and roofing: lung; coal tar distillation: skin; soots: lung, oesophagus, haematolymphatic system, skin; aluminum smelting: lung, bladder; tobacco smoking: lung, lip, oral cavity, pharynx, oesophagus, larynx, bladder (IARC, 1984, 1985, 1986, 2010).

Studies on the mechanisms of action of benzo[a]pyrene have been reviewed (Xue & Warshawsky, 2005; IARC, 2010).

4.1. Metabolism

Benzo[a]pyrene is metabolized by both phase-I and phase-II enzymes to form a series of arene oxides, dihydrodiols, phenols, and quinones and their polar conjugates with glutathione, sulfate, and glucuronide (Osborne & Crosby, 1987). Benzo[a]pyrene-7,8-diol is a key metabolite that is formed by the action of epoxide hydrolase on benzo[a]pyrene-7,8-epoxide. This dihydrodiol can be further metabolized by cytochrome P450s (CYPs) to a series of benzo[a]pyrene-7,8-diol-9,10-epoxides, which form one class of ultimate carcinogenic metabolites of benzo[a]pyrene. Both CYPs and peroxidases (e.g. prostaglandin-H synthase) can oxidize benzo[a]pyrene. The major cytochrome P450s involved in the formation of diols and diolepoxides are CYP1A1, CYP1A2 and CYP1B1 (Eling et al., 1986; Shimada, 2006). Cytochrome P450s are inducible by benzo[a]pyrene and other PAHs through binding to the aryl hydrocarbon-receptor (AhR) nuclear complex, leading to changes in gene transcription of CYPs and phase-II enzymes. Mice lacking the AhR receptor are refractory to benzo[a]pyrene-induced tumorigenesis (Shimizu et al., 2000). Both CYPs and peroxidases can form radical cations by one-electron oxidation. These cations comprise another class of ultimate carcinogenic metabolites (Cavalieri & Rogan, 1995). Some polymorphisms in human CYPs and phase-II enzymes (glutathione S-transferases, uridine 5′-diphosphate glucuronosyltransferases and sulfotransferases modulate susceptibility to cancer (Shimada, 2006). In another metabolic pathway, benzo[a]pyrene-7,8-dihydrodiol is oxidized to benzo[a]pyrene-7,8-quinone by enzymes of the aldo-keto reductase (AKR1) family. Among these, gene polymorphisms that influence susceptibility have been identified. NAD(P)H: quinone oxidoreductase-1 (NQO1) catalyses the reduction of benzo[a]pyrene quinones to hydroquinones, which may be re-oxidized and generate reactive oxygen species. Polymorphisms in this gene have also been described (Penning & Drury, 2007; IARC, 2010).

The current understanding of mechanisms underlying benzo[a]pyrene-induced carcinogenesis in experimental animals is almost solely based on two complementary pathways: those of the diolepoxides and the radical cations. Each provides a different explanation for the effects observed in experimental animals in specific tissues.

4.2. Diolepoxide mechanism

The diolepoxide mechanism for benzo[a]pyrene features a sequence of metabolic transformations: benzo[a]pyrene → benzo[a]pyrene-7,8-oxide (by CYP1A1 and CYP1B1) → benzo[a]pyrene-7,8-diol (by epoxide hydrolase) → benzo[a]pyrene-7,8-diol-9,10-epoxides (by CYP1A1 and CYP1B1) (Xue & Warshawsky, 2005). Each class of metabolic intermediate has been shown to be genotoxic and carcinogenic (Osborne & Crosby, 1987). The stereochemistry of the metabolic transformation of benzo[a]pyrene to diols and diolepoxides is an important component of this mechanism of action. Due to the creation of chiral carbons during the metabolic conversions, many of the metabolic intermediates of benzo[a]pyrene have multiple streochemical forms (enantiomeric and diastereomeric). As the metabolism proceeds the complexity of the stereochemical forms increases, eventually leading to four benzo[a]pyrene-7,8-diol-9,10-epoxides [(+)- and (-)-anti, (+)- and (-)-syn]. Diolepoxides react with DNA, mainly with the purines, deoxyguanosine and deoxyadenosine, and each diolepoxide can form both cis and trans adducts thus giving a total of 16 possible benzo[a]pyrene-7,8-diol-9,10-epoxide DNA adducts. However, in most cases far fewer DNA adducts are actually observed. The most ubiquitous benzo[a]pyrene adduct detected in isolated mammalian DNA after metabolic conversion in metabolically competent mammalian cells in culture, or in mammals, is the N2-deoxyguanosine adduct, (+)-N2-10S-(7R,8S,9R-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene)-yl)-2'-deoxyguanosine (BPDE-deoxyguanosine), derived from 7R,8S-dihydroxy-9R,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-benzo[a]pyrene-7,8-diol-9,10-epoxide, or BPDE). This adduct was first fully identified after isolation from benzo[a]pyrene-treated human and bovine bronchial explants (Jeffrey et al., 1977). This diolepoxide is considered to be an ultimate, DNA-reactive, metabolite of benzo[a]pyrene (Osborne & Crosby, 1987). The anti-benzo[a]pyrene-7,8-diol-9,10-epoxide can form both stable and unstable (so-called ‘depurinating’) adducts with DNA, mediated by electrophilic carbonium ions (Chakravarti et al., 2008). In vivo, anti-benzo[a]pyrene-7,8-diol-9,10-oxide produces stable adducts that were formed primarily with guanines in many species and organs (IARC, 2010).

Mice treated with benzo[a]pyrene had anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-N2-deoxyguanosine adducts in their lung tissue, while the lung tumours induced by benzo[a]pyrene had G→T and G→A mutations in the Ki-Ras gene at codon 12 (Mass et al., 1993). In mice treated with benzo[a]pyrene the major stable DNA adduct in the epidermis was the anti-benzo[a]pyrene-7,8-diol-9,10-oxide-deoxyguanosine adduct (Melendez-Colon et al., 1999). Skin tumours from benzo[a]pyrene-treated mice or in preneoplastic skin from benzo[a]pyrene-treated mice had G→T mutations in codon 13 and A→T mutations in codon 61 of the Ha-Ras gene (Chakravarti et al., 2008).

Benzo[a]pyrene-induced skin tumours harboured G→T transversion mutations in the Tp53 tumour-suppressor gene (Ruggeri et al., 1993). The anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adducts occurred at guanine positions in codons 157, 248, and 273 of the TP53 gene in anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-treated human HeLa cells. The same positions are the major mutational hotspots found in human lung cancers (Denissenko et al., 1996).

4.3. Radical-cation mechanism

The radical-cation mechanism for benzo[a]pyrene has been studied exclusively in connection with mouse-skin tumorigenesis (Cavalieri & Rogan, 1995). One-electron oxidation of benzo[a]pyrene by CYPs or peroxidases creates a radical cation localized on carbon 6, as a consequence of the ionization potential and geometric configuration. In mouse skin, this radical cation gives rise to the formation of covalent adducts with guanine (at the C8 carbon and N7 nitrogen) and adenine (at the N7 nitrogen). These adducts are unstable and are thought to generate apurinic sites in mouse skin. However, only low levels of apurinic sites were measured in the epidermis of mice treated with benzo[a]pyrene (Melendez-Colon et al., 1999) and no studies to date have shown an increase in the number of apurinic sites in lung tissues treated with benzo[a]pyrene. In two in vivo studies, rats treated intraperitoneally with benzo[a]pyrene were shown to excrete 7-(benzo[a]pyrene-6-yl)-N7-guanine in faeces and urine, while the same adduct was detected in lung tissue of mice treated intraperitoneally with benzo[a]pyrene (Rogan et al., 1990; Banasiewicz et al., 2004). Skin papillomas obtained from mice treated topically with benzo[a]pyrene showed mutations (at guanine and/or adenine) at codons 12, 13 and 61 in the Ha-Ras oncogene (Wei et al., 1999). Similar studies in preneoplastic skin from benzo[a]pyrene-treated mice showed Ha-Ras mutations at codons 13 and 61 (Chakravarti et al., 2008). The anti-benzo[a]pyrene-7,8-diol-9,10-epoxide can also form depurinating DNA adducts at guanine and adenine (at the N7 nitrogen). The distribution and chemical nature of the depurinating adducts (from both radical-cation and diolepoxide intermediates) in mouse skin and the distribution and chemical nature of the specific benzo[a]pyrene-induced mutations in mouse-skin papillomas have been reported (Chakravarti et al., 2008).

4.4. Other activation mechanisms of benzo[a]pyrene

4.4.1 Meso-region mechanism

The mechanism of meso-region biomethylation and benzylic oxidation features biomethylation of benzo[a]pyrene to 6-methylbenzo[a]pyrene, with S-adenosylmethione as the carbon donor (Flesher et al., 1982). This process has been shown to occur in vitro, and in vivo in rat liver (Stansbury et al., 1994). 6-Methylbenzo[a]pyrene is further metabolized by CYPs to 6-hydroxymethylbenzo[a]pyrene (Flesher et al., 1997) and then conjugated to sulfate by 3′-phosphoadenosine-5′-phosphosulfate sulfotransferase to 6-[(sulfooxy)methyl]-benzo[a]pyrene. This reactive sulfate ester forms DNA adducts in vivo (Stansbury et al., 1994). These benzo[a]pyrene-DNA adducts have only been measured in rat liver (Surh et al., 1989), which is not a target for benzo[a]pyrene-induced carcinogenesis. There is no evidence to date that this mechanism operates in lung.

4.4.2 Mechanism via formation of ortho-quinone/ reactive oxygen species

This mechanism features enzymatic oxidation of benzo[a]pyrene-7,8-diol to the ortho-quinone, benzo[a]pyrene-7,8-quinone, by aldo-keto reductases (Mangal et al., 2009). Benzo[a]pyrene-7,8-quinone can react with DNA to yield both stable and depurinating DNA adducts in vitro (McCoull et al., 1999; Balu et al., 2006) and can also undergo repetitive redox cycling which generates reactive oxygen species that damage DNA (Penning et al., 1999). In human A549 lung-tumour cells benzo[a]pyrene-7,8-quinone increased the formation of 8-oxo-deoxyguanosine and DNA strand-breaks (Park et al., 2008; Mangal et al., 2009). In a yeast reporter-assay, benzo[a]pyrene-7,8-quinone (in the presence of redox cycling) induced 8-oxo-deoxyguanosine formation and G→T transversions in the Tp53 tumour-suppressor gene. The mutational spectra induced in the yeast reporter-assay closely matched those seen in DNA from human lung tumours (Shen et al., 2006). Benzo[a]pyrene-7,8-quinone inhibited the activity of protein kinase C in MCF-7 cell lysates suggesting an ability to alter cell signalling (Yu et al., 2002). Rats treated with benzo[a]pyrene showed increased urinary concentrations of 8-oxo-deoxyguanosine, but lower levels in liver and lung tissues. This suggested that reactive oxygen species are generated during the CYP-dependent metabolism of benzo[a]pyrene, but induction of DNA-repair mechanisms may reduce these levels in target tissues (Briedé et al., 2004). To date this mechanism has been studied only in in-vitro systems.

It is noted that formation of reactive oxygen species is not limited to the redox cycling of the ortho-quinone of benzo[a]pyrene (benzo[a]pyrene-7,8-quinone). There are several other sources of benzo[a]pyrene-induced reactive oxygen species. In vivo, both mice and rats metabolize benzo[a]pyrene to benzo[a]pyrene-1,6-quinone, benzo[a]pyrene-3,6-quinone and benzo[a]pyrene-6,12-quinone and these quinones enter into redox cycling and induce mutations (Osborne & Crosby, 1987; Joseph & Jaiswal, 1998). Many of the reactive intermediates of benzo[a]pyrene (oxides, diol-epoxides, radical cations) and quinone-generated reactive oxygen species can disrupt the balance of cellular oxidants and anti-oxidants by reducing the anti-oxidant levels thus leading to an imbalance and an excess of reactive oxygen species.

4.4.3. Aryl hydrocarbon-receptor mechanism

The AhR regulates the transcription of a series of genes including Cyp1A1, Cyp1A2, Nqo1, Aldh3a1 (encoding aldehyde dehydrogenase 3A1), UGT1a6 (uridine 5′-diphosphate-glucuronosyl transferase), and Gsta1 (glutathione S-transferase A1). All these genes are activated by AhR-ligands, including benzo[a]pyrene, via the AhR-mediated aromatic hydrocarbon response element. The AhR plays a role in the response to oxidative stress in cell-cycle regulation and apoptosis. In addition, the CYP1A1/1A2-mediated metabolism generates oxidative stress (Nebert et al., 2000). Mitochondrial hydrogen-peroxide production was induced by an AhR-ligand in wild-type mice but not in AhR−/− knockout mice (Senft et al., 2002). These mice were shown to be refractory to benzo[a]pyrene-induced carcinogenicity (Shimizu et al., 2000). Benzo[a]pyrene induced oxidative stress in mouse lung (Rajendran et al., 2008).

4.4.4. Immunosuppression mechanism

Benzo[a]pyrene induces immunosupression in adult mice by altering the cell-mediated responses (Wojdani & Alfred, 1984). Immune development in offspring is also altered following in utero exposure to benzo[a]pyrene (Urso & Gengozian, 1984). It is postulated that PAHs, including benzo[a]pyrene, act principally through their AhR-mediated CYP-derived metabolites (diolepoxides, quinones) to activate oxidative and electrophilic signalling pathways in lymphoid and nonlymphoid cells, including myeloid cells, epithelial cells, and other cell types. Furthermore, there is evidence that PAHs suppress immunity by p53-dependent pathways, by modulating signalling pathways in lymphocytes via non-genotoxic mechanisms, and by oxidative stress (Burchiel & Luster, 2001).

4.4.5. Epigenetic mechanisms

Benzo[a]pyrene and/or its metabolites have been shown to increase cell proliferation in several human cell lines, including terminally differentiated human bronchial squamous epithelial cells and in lung-cancer cells where increased expression of the Cdc25B gene (cell-division cycle 25B) was observed, along with reduced phosphorylation of Cdk1 (cyclin-dependent kinase 1) (Oguri et al., 2003). Treatment with benzo[a]pyrene increased the number of human embryo lung-fibroblasts in the G1–S transition via the activation of c-Jun, through the p53-dependent PI-3K/Akt/ERK (phosphatidylinositol-3-kinase/protein kinase β/extracellular signal-regulated kinase) pathway (Jiao et al., 2008).

Benzo[a]pyrene and/or its metabolites also affect apoptosis. Benzo[a]pyrene induced apoptosis in human MRC-5 lung fibroblasts via the JNK1/FasL (c-Jun N-terminal kinase 1/Fas Ligand) and JNK1/p53 signalling pathways (Chen et al., 2005). Apoptosis induced by anti-benzo[a]pyrene-7,8-diol-9,10-epoxide in H460 human lung-cancer cells was associated with induction of Bak (BCL2-antagonist/killer) and with activation of caspase, but it was independent of Bcl-2 (Xiao et al., 2007).

Altered DNA methylation has been reported to be associated with exposure to benzo[a]pyrene and/or its metabolites. After treatment of immortalized bronchial epithelial cells with anti-benzo[a]pyrene-7,8-diol-9,10-epoxide, the concentration of cytosine-DNA methyltransferase-1 was increased and was associated with hypermethylation of the promoters of 5–10 genes, including members of the cadherin gene-family (Damiani et al., 2008).

4.5. Human exposure to PAH-rich mixtures

4.5.1. Biomarkers of exposure and effect

Molecular-epidemiological studies of cancer associated with occupational and environmental exposures to PAH have provided biomarkers that may be used to estimate internal exposure as well as to inform about molecular mechanisms that may be relevant to cancer causation, particularly in defining the early events in the carcinogenesis process. Biomarkers can be detected in the target organ, in surrogate tissues, or in tumours. These can be categorized into biomarkers of exposure, which are generally specific to the PAH of concern (e.g. DNA or protein adducts), biomarkers of effect (e.g. genotoxic and cytogenetic effects, 8-oxo-deoxyguanosine, sister chromatid exchange (SCE), micronuclei, chromosomal aberrations, mutations in oncogenes, tumour-suppressor genes, or indicator genes), and biomarkers of susceptibility (DNA-repair enzymes, e.g. XPA, XPC – xeroderma pigmentosum complementation groups A and C), bioactivation enzymes (e.g. CYPs), detoxification enzymes (e.g. GSTs), and mutagenic metabolites in urine (Kalina et al., 1998; Pilger et al., 2000; Simioli et al., 2004; Raimondi et al., 2005; Vineis & Husgafvel-Pursiainen, 2005; Matullo et al., 2006; Farmer & Singh, 2008; Gyorffy et al., 2008). Although biomarkers of effect and susceptibility are generally not unique to any specific PAH exposure, several these biomarkers may provide insight into the mechanism of carcinogenesis induced in humans by PAHs or PAH-rich exposures.

4.5.2. Exposure to benzo[a]pyrene and relationship with specific biomarkers

Biomarkers of exposure to complex mixtures that contain benzo[a]pyrene have been studied in populations exposed in industrial settings: coke production, coal-tar distillation, the aluminium industry, roofing and paving with coal-tar pitch, coal gasification, chimney sweeping, and iron and steel founding. Most if not all of these biomarkers are genotoxic markers. Populations of patients who undergo coal-tar therapy and groups exposed to combustion emissions, and tobacco smokers have also been evaluated. Studies on biomarkers of exposure are dominated by those focusing on the anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adduct, the most commonly studied PAH-DNA adduct because of the availability of specific analytical methods and standards (Gyorffy et al., 2008). In one study the depurinating adducts resulting from radical-cation formation, viz. 7-(benzo[a]pyrene-6-yl)guanine and 7-(benzo[a]pyrene-6-yl)adenine were found in the urine of women exposed to coal smoke (Casale et al., 2001). Concomitantly, several biomarkers of effect have also been evaluated in these studies: chromosomal aberrations, sister chromatid exchange (Kalina et al., 1998), DNA damage (measured by the comet assay) and 8-oxo-deoxyguanosine formation (Marczynski et al., 2002). It is important to note that these genotoxic effects observed in humans in relation to exposure to benzo[a]pyrene-containing mixtures have also been observed in experimental studies where benzo[a]pyrene or anti-benzo[a]pyrene-7,8-diol-9,10-epoxide has been shown to induce sister chromatid exchange (Pal et al., 1980; Brauze et al., 1997), chromosomal aberrations, micronuclei (Kliesch et al., 1982), DNA damage (Nesnow et al., 2002), and 8-oxo-deoxyguanosine (Thaiparambil et al., 2007). Tobacco smoke, dietary habits and indoor ambient air are also important sources of exposure to benzo[a]pyrene, which has been implicated as one of the components of tobacco smoke related to the induction of lung cancer in smokers (Watanabe et al., 2009). In a large study of 585 smokers and nonsmokers, smoking and diet were highly correlated with anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adduct levels (Pavanello et al., 2006). Several studies have demonstrated moderately increased levels of 8-oxo-deoxyguanosine from lungs, sperm, and leukocytes of smokers. Increased urinary excretion of 8-oxo-deoxyguanosine has also been reported (Hecht, 1999). In rats exposed to benzo[a]pyrene via oral, intratracheal and dermal routes, anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adducts were formed in white blood cells independently of the exposure route and their numbers correlated with those found in lung DNA, suggesting that anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA-adduct levels in white blood cells may be used as a surrogate for pulmonary anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adducts (Godschalk et al., 2000).

4.5.3. Relationship of biomarkers to human cancer

Mutations in TP53 are common in lung cancers from smokers and less common in nonsmokers. These mutations are G→T transversions with hotspots in codons 157, 248 and 273 (Hainaut & Pfeifer, 2001; Pfeifer et al., 2002) and they are associated with anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adducts. The active metabolite anti-benzo[a]pyrene-7,8-diol-9,10-oxide causes a unique spectrum of TP53 mutations distinct from those found in cancers that are not associated with smoking (Campling & el-Deiry, 2003). Similar G→T mutations have been reported in lung tumours from nonsmoking Chinese women whose tumours were associated with exposure to PAHs from smoke generated by burning smoky coal in unventilated homes. The mutations were clustered at the CpG rich codons 153–158 of the TP53 gene, and at codons 249 and 273. The mutation spectrum was fully consistent with exposure to PAHs (DeMarini et al., 2001).

4.6. Synthesis

Benzo[a]pyrene is metabolically activated to a series of reactive intermediates by CYP450 and related enzymes under control of the aryl-hydrocarbon receptor. There is strong evidence that the benzo[a]pyrene diolepoxide mechanism operates in mouse-lung tumorigenesis, while there is also strong evidence that both the radical-cation and the diolepoxide mechanisms are involved in mouse-skin carcinogenesis. The meso-region mechanism has been studied only in rat liver, while the mechanism that involves the formation of ortho-quinone/reactive oxygen species has only been studied in vitro, although reactive oxygen species can be formed in vivo by other benzo[a]pyrene-mediated mechanisms. All these pathways reflect genotoxic mechanisms, as they involve alterations to DNA. Benzo[a]pyrene is pleotropic and has the ability to affect many cell- and organ-based systems. Therefore, there are probably many modes of carcinogenic action operating to different extents in vivo. These include mechanisms that involve AhR, oxidative stress, immunotoxicity and epigenetic events.

Based on the best available, consistent and strong experimental and human mechanistic evidence it is concluded that benzo[a]pyrene contributes to the genotoxic and carcinogenic effects resulting from occupational exposure to complex PAH mixtures that contain benzo[a]pyrene. The most commonly encountered – and most widely studied – mechanistically relevant DNA lesion is the anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adduct. The formation of this adduct is consistent with anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-associated genotoxic effects in surrogate tissues and with the mutation pattern in the TP53 gene in lung tumours from humans exposed to PAH mixtures that contain benzo[a]pyrene. The fact that those PAH mixtures and benzo[a]pyrene itself induce genotoxic effects like sister chromatid exchange, chromosomal aberrations, micronuclei, DNA damage (comet assay) and 8-oxo-deoxyguanosine, supports the notion that benzo[a]pyrene contributes to human cancer.

5. Evaluation

There is sufficient evidence for the carcinogenicity of benzo[a]pyrene in experimental animals.

[No epidemiological data on benzo[a]pyrene alone were available to the Working Group.]

The genotoxic mechanism of action of benzo[a]pyrene involves metabolism to highly reactive species that form covalent adducts to DNA. These anti-benzo[a]pyrene-7,8-diol-9,10-oxide-DNA adducts induce mutations in the K-RAS oncogene and the TP53 tumour-suppressor gene in human lung tumours, and in corresponding genes in mouse-lung tumours. Exposure to benzo[a]pyrene and benzo[a]pyrene-containing complex mixtures also induce other genotoxic effects, including sister chromatid exchange, micronuclei, DNA damage and 8-oxo-deoxyguanosine, all of which can contribute to the carcinogenic effects of benzo[a]pyrene and benzo[a]pyrene-containing complex mixtures in exposed humans.

Benzo[a]pyrene is carcinogenic to humans (Group 1).

In making the overall evaluation, the Working Group took the following into consideration:

The strong and extensive experimental evidence for the carcinogenicity of benzo[a]pyrene in many animal species, supported by the consistent and coherent mechanistic evidence from experimental and human studies provide biological plausibility to support the overall classification of benzo[a]pyrene as a human carcinogen (Group 1).

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