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IARC Working Group on the Evaluation of Carcinogenic Risk 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).

References

  • Albert RE, Miller ML, Cody T, et al. Benzo[a]pyrene-induced skin damage and tumor promotion in the mouse. Carcinogenesis. 1991;12:1273–1280. [PubMed: 2070493] [CrossRef]
  • Anderson LM, Priest LJ, Deschner EE, Budinger JM. Carcinogenic effects of intracolonic benzo[a]pyrene in β-naphthoflavone-induced mice. Cancer Letters. 1983;20:117–123. [PubMed: 6321017] [CrossRef]
  • Andrews J, Halliday GM, Muller HK. A role for prostaglandins in the suppression of cutaneous cellular immunity and tumour development in benzo[a]pyrene- but not dimethylbenz(a)anthracene-treated mice. Clin Exp Immunol. 1991;85:9–13. [PMC free article: PMC1535727] [PubMed: 1906386]
  • Badary OA, Al-Shabanah OA, Nagi MN, et al. Inhibition of benzo[a]pyrene-induced forestomach carcinogenesis in mice by thymoquinone. European Journal of Cancer Prevention. 1999;8:435–440. [PubMed: 10548399] [CrossRef]
  • Balansky R, Ganchev G, Iltcheva M, et al. Potent carcinogenicity of cigarette smoke in mice exposed early in life. Carcinogenesis. 2007;28:2236–2243. [PubMed: 17522065] [CrossRef]
  • Balu N, Padgett WT, Nelson GB, et al. Benzo[a]pyrene-7,8-quinone-3′-mononucleotide adduct standards for 32P postlabeling analyses: detection of benzo[a]pyrene-7,8-quinone-calf thymus DNA adducts. Anal Biochem. 2006;355:213–223. [PubMed: 16797471] [CrossRef]
  • Banasiewicz M, Nelson G, Swank A, et al. Identification and quantitation of benzo[a]pyrene-derived DNA adducts formed at low adduction level in mice lung tissue. Anal Biochem. 2004;334:390–400. [PubMed: 15494147] [CrossRef]
  • Brauze D, Wielgosz SM, Pawlak AL, Baer-Dubowska W. Effect of the route of benzo[a]pyrene administration on sister chromatid exchange and DNA binding in bone marrow of mice differing with respect to cytochrome P450 1A1 induction. Toxicol Lett. 1997;91:211–217. [PubMed: 9217241] [CrossRef]
  • Briedé JJ, Godschalk RW, Emans MT, et al. In vitro and in vivo studies on oxygen free radical and DNA adduct formation in rat lung and liver during benzo[a]pyrene metabolism. Free Radic Res. 2004;38:995–1002. [PubMed: 15621718] [CrossRef]
  • Burchiel SW, Luster MI. Signalling by environmental polycyclic aromatic hydrocarbons in human lymphocytes. Clin Immunol. 2001;98:2–10. [PubMed: 11141320] [CrossRef]
  • Busby WF Jr, Stevens EK, Martin CN, et al. Comparative lung tumorigenicity of parent and mononitro-polynuclear aromatic hydrocarbons in the BLU:Ha newborn mouse assay. Toxicology and Applied Pharmacology. 1989;99:555–563. [PubMed: 2749740] [CrossRef]
  • Campling BG, el-Deiry WS. Clinical implications of p53 mutations in lung cancer. Methods Mol Med. 2003;75:53–77. [PubMed: 12407735]
  • Casale GP, Singhal M, Bhattacharya S, et al. Detection and quantification of depurinated benzo[a]pyrene-adducted DNA bases in the urine of cigarette smokers and women exposed to household coal smoke. Chem Res Toxicol. 2001;14:192–201. [PubMed: 11258968] [CrossRef]
  • Cavalieri E, Mailander P, Pelfrene A. 1977Carcinogenic activity of anthanthrene on mouse skin. Zeitschrift fur Krebsforschung 89113–118.PMID:14314010.1007/BF00308512. [PubMed: 143140] [CrossRef]
  • Cavalieri E, Rogan E, Cremonesi P, et al. Tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene in mouse skin and rat mammary gland. Journal of Cancer Research and Clinical Oncology. 1988;114:10–15. a. [PubMed: 3350835] [CrossRef]
  • Cavalieri E, Rogan E, Sinha D. 1988bCarcinogenicity of aromatic hydrocarbons directly applied to rat mammary gland. J. Cancer clin. Oncol 1143–9.PMID:3350839. [PubMed: 3350839]
  • Cavalieri EL, Higginbotham S, RamaKrishna NVS, et al. Comparative dose–response tumorigenicity studies of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and two dibenzo[a,l]pyrene dihydrols in mouse skin and rat mammary gland. Carcinogenesis. 1991;12:1939–1944. [PubMed: 1934274] [CrossRef]
  • Cavalieri EL, Rogan EG. Central role of radical cations in metabolic activation of polycyclic aromatic hydrocarbons. Xenobiotica. 1995;25:677–688. [PubMed: 7483666] [CrossRef]
  • Chakravarti D, Venugopal D, Mailander PC, et al. The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin. Mutat Res. 2008;649:161–178. [PMC free article: PMC2254211] [PubMed: 17931959]
  • Chen JH, Chou FP, Lin HH, Wang CJ. Gaseous nitrogen oxide repressed benzo[a]pyrene-induced human lung fibroblast cell apoptosis via inhibiting JNK1 signals. Arch Toxicol. 2005;79:694–704. [PubMed: 16041517] [CrossRef]
  • Culp SJ, Gaylor DW, Sheldon WG, et al. A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay. Carcinogenesis. 1998;19:117–124. [PubMed: 9472702] [CrossRef]
  • Damiani LA, Yingling CM, Leng S, et al. Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Res. 2008;68:9005–9014. [PubMed: 18974146] [CrossRef]
  • de Vries A, van Oostrom CTM, Dortant PM, et al. Spontaneous liver tumors and benzo[a]pyrene-induced lymphomas in XPA-deficient mice. Molecular Carcinogenesis. 1997;19:46–53. [PubMed: 9180928] [CrossRef]
  • DeMarini DM, Landi S, Tian D, et al. Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions. Cancer Res. 2001;61:6679–6681. [PubMed: 11559534]
  • Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996;274:430–432. [PubMed: 8832894] [CrossRef]
  • Deutsch-Wenzel RP, Brune H, Grimmer G, et al. Experimental studies in rat lungs on the carcinogenicity and dose-response relationships of eight frequently occurring environmental polycyclic aromatic hydrocarbons. J Natl Cancer Inst. 1983;71:539–544. [PubMed: 6577228]
  • el-Bayoumy K, Chae Y-H, Upadhyaya P, et al. Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats. Carcinogenesis. 1995;16:431–434. [PubMed: 7859378] [CrossRef]
  • Eling T, Curtis J, Battista J, Marnett LJ. Oxidation of (+)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene by mouse keratinocytes: evidence for peroxyl radical- and monoxygenase-dependent metabolism. Carcinogenesis. 1986;7:1957–1963. [PubMed: 2430728] [CrossRef]
  • Estensen RD, Jordan MM, Wiedmann TS, et al. Effect of chemopreventive agents on separate stages of progression of benzo[alpha]pyrene induced lung tumors in A/J mice. Carcinogenesis. 2004;25:197–201. [PubMed: 14578161] [CrossRef]
  • Estensen RD, Wattenberg LW. Studies of chemopreventive effects of myo-inositol on benzo[a]pyrene-induced neoplasia of the lung and forestomach of female A/J mice. Carcinogenesis. 1993;14:1975–1977. [PubMed: 8403228] [CrossRef]
  • Farmer PB, Singh R. Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: the increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens. Mutat Res. 2008;659:68–76. [PubMed: 18468947] [CrossRef]
  • Feron VJ. Respiratory tract tumors in hamsters after intratracheal instillations of benzo(a)pyrene alone and with furfural. Cancer Res. 1972;32:28–36. [PubMed: 5007686]
  • Feron VJ, de Jong D, Emmelot P. Letter: Dose-response correlation for the induction of respiratory-tract tumours in Syrian golden hamsters by intratracheal instillations of benzo(a)pyrene. Eur J Cancer. 1973;9:387–390. [PubMed: 4746737] [CrossRef]
  • Feron VJ, Kruysse A. Effects of exposure to furfural vapour in hamsters simultaneously treated with benzo[alpha] pyrene or diethylnitrosamine. Toxicology. 1978;11:127–144. [PubMed: 715798] [CrossRef]
  • Feron VJ, van den Heuvel PD, Koëter HB, Beems RB. Significance of particle size of benzo(a)pyrene for the induction of respiratory tract tumours in hamsters. Int J Cancer. 1980;25:301–307. [PubMed: 7390654] [CrossRef]
  • Flesher JW, Horn J, Lehner AF. 6-sulfooxymethylbenzo[a]pyrene is an ultimate electrophilic and carcinogenic form of the intermediary metabolite 6-hydroxymethylbenzo[a]pyrene. Biochem Biophys Res Commun. 1997;234:554–558. [PubMed: 9175750] [CrossRef]
  • Flesher JW, Stansbury KH, Sydnor KL. S-Adenosyl-L-methionine is a carbon donor in the conversion of benzo[alpha]pyrene to 6-hydroxymethylbenzo[alpha]pyrene by rat liver S-9. Cancer Lett. 1982;16:91–94. [PubMed: 6288234] [CrossRef]
  • Godleski JJ, Melnicoff MJ, Sadri S, Garbeil P. Effects of inhaled ammonium sulfate on benzo[a]pyrene carcinogenesis. J Toxicol Environ Health. 1984;14:225–238. [PubMed: 6502734] [CrossRef]
  • Godschalk RW, Moonen EJ, Schilderman PA, et al. Exposure-route-dependent DNA adduct formation by polycyclic aromatic hydrocarbons. Carcinogenesis. 2000;21:87–92. [PubMed: 10607738] [CrossRef]
  • Gyorffy E, Anna L, Kovács K, et al. Correlation between biomarkers of human exposure to genotoxins with focus on carcinogen-DNA adducts. Mutagenesis. 2008;23:1–18. [PubMed: 17989146] [CrossRef]
  • Habs M, Jahn SAA, Schmähl D. Carcinogenic activity of condensate from coloquint seeds (Citrullus colocynthis) after chronic epicutaneous administration to mice. J Cancer Res Clin Oncol. 1984;108:154–156. [PubMed: 6746706] [CrossRef]
  • Habs M, Schmähl D, Misfeld J. Local carcinogenicity os some environmentally relevant polycyclic aromatic hydrocarbons after lifelong topical application to mouse skin. Arch Geschwulstforsch. 1980;50:266–274. [PubMed: 7436704]
  • Hainaut P, Pfeifer GP. Patterns of p53 G–>T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis. 2001;22:367–374. [PubMed: 11238174] [CrossRef]
  • Hakura A, Tsutsui Y, Sonoda J, et al. Comparison between in vivo mutagenicity and carcinogenicity in multiple organs by benzo[a]pyrene in the lacZ transgenic mouse (Muta Mouse). Mutat Res. 1998;398:123–130. [PubMed: 9626972]
  • Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91:1194–1210. [PubMed: 10413421] [CrossRef]
  • Heinrich U, Pott F, Mohr U, et al. Lung tumours in rats and mice after inhalation of PAH-rich emissions. Exp Pathol. 1986;29:29–34. a. [PubMed: 3699126]
  • Henry MC, Port CD, Bates RR, Kaufman DG. Respiratory tract tumors in hamsters induced by benzo(a)pyrene. Cancer Res. 1973;33:1585–1592. [PubMed: 4721222]
  • Homburger F, Hsueh S-S, Kerr CS, Russfield AB. Inherited susceptibility of inbred strains of Syrian hamsters to induction of subcutaneous sarcomas and mammary and gastrointestinal carcinomas by subcutaneous and gastric administration of polynuclear hydrocarbons. Cancer Res. 1972;32:360–366. [PubMed: 5058191]
  • Hoogervorst EM, de Vries A, Beems RB, et al. Combined oral benzo[a]pyrene and inhalatory ozone exposure have no effect on lung tumor development in DNA repair-deficient Xpa mice. Carcinogenesis. 2003;24:613–619. [PubMed: 12663525] [CrossRef]
  • Horikawa K, Sera N, Otofuji T, et al. Pulmonary carcinogenicity of 3,9- and 3,7-dinitrofluoranthene, 3-nitrofluoranthene and benzo[a]pyrene in F344 rats. Carcinogenesis. 1991;12:1003–1007. [PubMed: 2044179] [CrossRef]
  • IARC. Certain polycyclic aromatic hydrocarbons and heterocyclic compounds. IARC Monogr Eval Carcinog Risk Chem Man. 1973;3:1–271.
  • IARC. Polynuclear aromatic compounds, Part 1, chemical, environmental and experimental data. IARC Monogr Eval Carcinog Risk Chem Hum. 1983;32:1–453. [PubMed: 6586639]
  • IARC. Polynuclear aromatic compounds, Part 3, industrial exposures in aluminium production, coal gasification, coke production, and iron and steel founding. IARC Monogr Eval Carcinog Risk Chem Hum. 1984;34:1–219.
  • IARC. Polynuclear aromatic compounds, Part 4, bitumens, coal-tars and derived products, shale-oils and soots. IARC Monogr Eval Carcinog Risk Chem Hum. 1985;35:1–247. [PubMed: 2991123]
  • IARC. Tobacco smoking. IARC Monogr Eval Carcinog Risk Chem Hum. 1986;38:1–421.
  • IARC. Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. IARC Monogr Eval Carcinog Risks Hum. 2010;92:1–853. [PMC free article: PMC4781319] [PubMed: 21141735]
  • Ide F, Iida N, Nakatsuru Y, et al. Mice deficient in the nucleotide excision repair gene XPA have elevated sensitivity to benzo[a]pyrene induction of lung tumors. Carcinogenesis. 2000;21:1263–1265. [PubMed: 10837020] [CrossRef]
  • Iwagawa M, Maeda T, Izumi K, et al. Comparative dose-response study on the pulmonary carcinogenicity of 1,6-dinitropyrene and benzo[a]pyrene in F344 rats. Carcinogenesis. 1989;10:1285–1290. [PubMed: 2736719] [CrossRef]
  • Jeffrey AM, Weinstein IB, Jennette KW, et al. Structures of benzo(a)pyrene–nucleic acid adducts formed in human and bovine bronchial explants. Nature. 1977;269:348–350. [PubMed: 904688] [CrossRef]
  • Jiao S, Liu B, Gao A, et al. Benzo(a)pyrene-caused increased G1-S transition requires the activation of c-Jun through p53-dependent PI-3K/Akt/ERK pathway in human embryo lung fibroblasts. Toxicol Lett. 2008;178:167–175. [PMC free article: PMC3759236] [PubMed: 18448277] [CrossRef]
  • Joseph P, Jaiswal AK. NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones. Br J Cancer. 1998;77:709–719. [PMC free article: PMC2149967] [PubMed: 9514048]
  • Kalina I, Brezáni P, Gajdosová D, et al. Cytogenetic monitoring in coke oven workers. Mutat Res. 1998;417:9–17. [PubMed: 9729241]
  • Ketkar M, Green U, Schneider P, Mohr U. Investigations on the carcinogenic burden by air pollution in man. Intratracheal instillation studies with benzo[a]pyrene in a mixture of Tris buffer and saline in Syrian golden hamsters. Cancer Lett. 1979;6:279–284. [PubMed: 436122] [CrossRef]
  • Ketkar M, Reznik G, Misfeld J, Mohr U. Investigations on the carcinogenic burden by air pollution in man. The effect of a single dose of benzo(a)pyrene in Syrian golden hamsters. Cancer Lett. 1977;3:231–235. [CrossRef]
  • Ketkar M, Reznik G, Schneider P, Mohr U. Investigations on the carcinogenic burden by air pollution in man. Intratracheal instillation studies with benzo(a)pyrene in bovine serum albumin in Syrian hamsters. Cancer Lett. 1978;4:235–239. [PubMed: 647664] [CrossRef]
  • Kliesch U, Roupova I, Adler ID. Induction of chromosome damage in mouse bone marrow by benzo[a]pyrene. Mutat Res. 1982;102:265–273. [PubMed: 7144782] [CrossRef]
  • Kobayashi N. Production of respiratory tract tumors in hamsters by benzo(a)pyrene. Gann. 1975;66:311–315. [PubMed: 1181231]
  • Kouri RE, Wood AW, Levin W, et al. Carcinogenicity of benzo[a]pyrene and thirteen of its derivatives in C3H/fCum mice. J Natl Cancer Inst. 1980;64:617–623. [PubMed: 6766516]
  • Kroese ED, Dortant PM, van Steeg H, et al. Use of E μ-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA. Carcinogenesis. 1997;18:975–980. [PubMed: 9163683] [CrossRef]
  • Kruysse A, Feron VJ. 1976Repeated exposure to cyclopentenone vapour: long-term study in Syrian golden hamsters Zentralbl Bakteriol[Orig.B] 1635–6448–457. .PMID:1020535. [PubMed: 1020535]
  • Lavoie EJ, Braley J, Rice JE, Rivenson A. Tumorigenic activity of non-alternant polynuclear aromatic hydrocarbons in newborn mice. Cancer Letters. 1987;34:15–20. [PubMed: 3802065] [CrossRef]
  • Levin W, Wood AW, Wislocki PG, et al. 1977Carcinogenicity of benzo ring derivatives of benzo[a]pyrene on mouse skin. Cancer Research 373357–3361.PMID:884679. [PubMed: 884679]
  • Mangal D, Vudathala D, Park JH, et al. Analysis of 7,8-dihydro-8-oxo-2′-deoxyguanosine in cellular DNA during oxidative stress. Chem Res Toxicol. 2009;22:788–797. [PMC free article: PMC2684441] [PubMed: 19309085] [CrossRef]
  • Marczynski B, Rihs HP, Rossbach B, et al. Analysis of 8-oxo-7,8-dihydro-2′-deoxyguanosine and DNA strand breaks in white blood cells of occupationally exposed workers: comparison with ambient monitoring, urinary metabolites and enzyme polymorphisms. Carcinogenesis. 2002;23:273–281. [PubMed: 11872632] [CrossRef]
  • Mass MJ, Jeffers AJ, Ross JA, et al. Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice. Molecular Carcinogenesis. 1993;8:186–192. [PubMed: 8216737] [CrossRef]
  • Matullo G, Dunning AM, Guarrera S, et al. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study. Carcinogenesis. 2006;27:997–1007. [PubMed: 16308313] [CrossRef]
  • McCoull KD, Rindgen D, Blair IA, Penning TM. Synthesis and characterization of polycyclic aromatic hydrocarbon o-quinone depurinating N7-guanine adducts. Chem Res Toxicol. 1999;12:237–246. [PubMed: 10077486] [CrossRef]
  • Melendez-Colon VJ, Luch A, Seidel A, Baird WM. Cancer initiation by polycyclic aromatic hydrocarbons results from formation of stable DNA adducts rather than apurinic sites. Carcinogenesis. 1999;20:1885–1891. [PubMed: 10506100] [CrossRef]
  • Näslund I, Rubio CA, Auer GU. 1987Nuclear DNA changes during pathogenesis of squamous cell carcinoma of the cervix in 3,4-benzopyrene-treated mice. Analytical and Quantitative Cytology 9411–418.PMID: 3675800. [PubMed: 3675800]
  • Nebert DW, Roe AL, Dieter MZ, et al. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol. 2000;59:65–85. [PubMed: 10605936] [CrossRef]
  • Nesnow S, Davis C, Nelson GB, et al. Comparison of the genotoxic activities of the K-region dihydrodiol of benzo[a]pyrene with benzo[a]pyrene in mammalian cells: morphological cell transformation; DNA damage; and stable covalent DNA adducts. Mutat Res. 2002;521:91–102. [PubMed: 12438007]
  • Nesnow S, Ross JA, Stoner GD, Mass MJ. Mechanistic linkage between DNA adducts, mutations in oncogenes and tumorigenesis of carcinogenic environmental polycyclic aromatic hydrocarbons in strain A/J mice. Toxicology. 1995;105:403–413. [PubMed: 8571376] [CrossRef]
  • Nettesheim P, Griesemer RA, Martin DH, Caton JE Jr. 1977Induction of preneoplastic and neoplastic lesions in grafted rat tracheas continuously exposed to benzo[a]pyrene. Cancer Research 371271–1278.PMID: 856459. [PubMed: 856459]
  • Oguri T, Singh SV, Nemoto K, Lazo JS. The carcinogen (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene induces Cdc25B expression in human bronchial and lung cancer cells. Cancer Res. 2003;63:771–775. [PubMed: 12591724]
  • Osborne MR, Crosby NT (1987). Benzopyrenes. Cambridge Monographs on Cancer Research. Cambridge, England: Cambridge University Press .
  • Pal K, Grover PL, Sims P. The induction of sister-chromatid exchanges in Chinese hamster ovary cells by some epoxides and phenolic derivatives of benzo[a]pyrene. Mutat Res. 1980;78:193–199. [PubMed: 7393246] [CrossRef]
  • Park JH, Mangal D, Tacka KA, et al. Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans-dihydrodiol activation in human lung A549 cells. Proc Natl Acad Sci U S A. 2008;105:6846–6851. [PMC free article: PMC2383938] [PubMed: 18474869] [CrossRef]
  • Pavanello S, Pulliero A, Saia BO, Clonfero E. Determinants of anti-benzo[a]pyrene diol epoxide-DNA adduct formation in lymphomonocytes of the general population. Mutat Res. 2006;611:54–63. [PubMed: 16978913]
  • Penning TM, Burczynski ME, Hung CF, et al. Dihydrodiol dehydrogenases and polycyclic aromatic hydrocarbon activation: generation of reactive and redox active o-quinones. Chem Res Toxicol. 1999;12:1–18. [PubMed: 9894013] [CrossRef]
  • Penning TM, Drury JE. Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms. Arch Biochem Biophys. 2007;464:241–250. [PMC free article: PMC2025677] [PubMed: 17537398] [CrossRef]
  • Pfeifer GP, Denissenko MF, Olivier M, et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002;21:7435–7451. [PubMed: 12379884] [CrossRef]
  • Pilger A, Germadnik D, Schaffer A, et al. 8-Hydroxydeoxyguanosine in leukocyte DNA and urine of quartz-exposed workers and patients with silicosis. Int Arch Occup Environ Health. 2000;73:305–310. [PubMed: 10963413] [CrossRef]
  • Pott F, Brockhaus A, Huth F. Zbl. Bakt. Hyg. Abt. Orig. B. 1973;157:34–43. a[Tests on the production of tumours in animal experiments with polycyclic aromatic hydrocarbons.] [in German] [PubMed: 4734048]
  • Pott F, Tomingas R, Reiffer FJ. Experimental studies on the carcinogenicity and the retention of benzo[a]pyrene in application region after intratracheal and subcutaneous injection. Zbl. Bakt. Hyg. I.Abt. Orig. B. 1973;158:97–108. b. [PubMed: 4779177]
  • Pott F, Ziem U, Reiffer F-J, et al. Carcinogenicity studies on fibres, metal compounds, and some other dusts in rats. Exp Pathol. 1987;32:129–152. [PubMed: 3436395]
  • Raimondi S, Boffetta P, Anttila S, et al. Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res. 2005;592:45–57. [PubMed: 16009381]
  • Rajendran P, Ekambaram G, Sakthisekaran D. Cytoprotective effect of mangiferin on benzo(a)pyrene-induced lung carcinogenesis in swiss albino mice. Basic Clin Pharmacol Toxicol. 2008;103:137–142. [PubMed: 18816296] [CrossRef]
  • Reynders JB, Immel HR, Scherrenberg PM, et al. Respiratory tract tumors in hamsters after severe focal injury to the trachea and intratracheal instillation of benzo[a]pyrene. Cancer Lett. 1985;29:93–99. [PubMed: 4063958] [CrossRef]
  • Rippe RM, Pott D (1989). Kanzerogenitätsuntersuchungen von Nitro-PAH (Nitroarenen) im Hinblick auf ihre Bedeutung für die krebserzeugende Wirkung von Dieselmotorabgas. In: Gesellschaft zur Förderung der Lufthygiene und Silikoseforschung. Düsseldorf: Stefan W. Albers, pp. 65–89.
  • Rodriguez LV, Dunsford HA, Steinberg M, et al. Carcinogenicity of benzo[a]pyrene and manufactured gas plant residues in infant mice. Carcinogenesis. 1997;18:127–135. [PubMed: 9054599] [CrossRef]
  • Rogan EG, RamaKrishna NVS, Higginbotham S, et al. Identification and quantitation of 7-(benzo[a]pyren-6-yl)guanine in the urine and feces of rats treated with benzo[a]pyrene. Chem Res Toxicol. 1990;3:441–444. [PubMed: 2133095] [CrossRef]
  • Roller M, Kamino K, Rosenbruch M (1992). Carcinogenicity testing of bladder carcinogens and other organic compounds by the intraperitoneal and intravesicular route. In: Environmental Hygiene III. Seemayer NH, Hadnagy W, editors. Berlin: Springer-Verlag, pp. 95–98.
  • Ross JA, Nelson GB, Wilson KH, et al. Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels. Cancer Res. 1995;55:1039–1044. [PubMed: 7866986]
  • Rossi L, Barbieri O, Sanguineti M, et al. Carcinogenic activity of benzo[a]pyrene and some of its synthetic derivatives by direct injection into the mouse fetus. Carcinogenesis. 1983;4:153–156. [PubMed: 6297822] [CrossRef]
  • Ruggeri B, DiRado M, Zhang SY, et al. Benzo[a]pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. Proc Natl Acad Sci U S A. 1993;90:1013–1017. [PMC free article: PMC45801] [PubMed: 8430068] [CrossRef]
  • Saffiotti U, Montesano R, Sellakumar AR, et al. Respiratory tract carcinogenesis in hamsters induced by different numbers of administrations of benzo[a]pyrene and ferric oxide. Cancer Res. 1972;32:1073–1081. [PubMed: 4336025]
  • Sellakumar A, Stenbäck F, Rowland J. Effects of different dusts on respiratory carcinogenesis in hamsters induced by benzo (a) pyrene and diethylnitrosamine. Eur J Cancer. 1976;12:313–319. [PubMed: 954792] [CrossRef]
  • Sellakumar AR, Montesano R, Saffiotti U, Kaufman DG. Hamster respiratory carcinogenesis induced by benzo[a]pyrene and different dose levels of ferric oxide. J Natl Cancer Inst. 1973;50:507–510. [PubMed: 4702121]
  • Senft AP, Dalton TP, Nebert DW, et al. Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radic Biol Med. 2002;33:1268–1278. [PubMed: 12398935] [CrossRef]
  • Shen YM, Troxel AB, Vedantam S, et al. Comparison of p53 mutations induced by PAH o-quinones with those caused by anti-benzo[a]pyrene diol epoxide in vitro: role of reactive oxygen and biological selection. Chem Res Toxicol. 2006;19:1441–1450. [PMC free article: PMC2366885] [PubMed: 17112231] [CrossRef]
  • Shimada T. Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug Metab Pharmacokinet. 2006;21:257–276. [PubMed: 16946553] [CrossRef]
  • Shimizu Y, Nakatsuru Y, Ichinose M, et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:779–782. [PMC free article: PMC15407] [PubMed: 10639156] [CrossRef]
  • Simioli P, Lupi S, Gregorio P, et al. Non-smoking coke oven workers show an occupational PAH exposure-related increase in urinary mutagens. Mutat Res. 2004;562:103–110. [PubMed: 15279833]
  • Smith DM, Rogers AE, Herndon BJ, Newberne PM. Vitamin A (retinyl acetate) and benzo[a]pyrene-induced carcinogenesis in hamsters fed a commercial diet. Cancer Res. 1975;35:11–16. a. [PubMed: 162856]
  • Smith DM, Rogers AE, Newberne PM. Vitamin A and benzo[a]pyrene carcinogenesis in the respiratory tract of hamsters fed a semisynthetic diet. Cancer Res. 1975;35:1485–1488. b. [PubMed: 1131819]
  • Solt DB, Polverini PJ, Calderon L. Carcinogenic response of hamster buccal pouch epithelium to 4 polycyclic aromatic hydrocarbons. Journal of Oral Pathology. 1987;16:294–302. [PubMed: 2445943] [CrossRef]
  • Sparnins VL, Mott AW, Barany G, Wattenberg LW. Effects of allyl methyl trisulfide on glutathione S-transferase activity and BP-induced neoplasia in the mouse. Nutrition and Cancer. 1986;8:211–215. [PubMed: 3737423] [CrossRef]
  • Stansbury KH, Flesher JW, Gupta RC. Mechanism of aralkyl-DNA adduct formation from benzo[a]pyrene in vivo. Chem Res Toxicol. 1994;7:254–259. [PubMed: 8199315] [CrossRef]
  • Steinhoff D, Mohr U, Hahnemann S. Carcinogenesis studies with iron oxides. Exp Pathol. 1991;43:189–194. [PubMed: 1797572]
  • Stenbäck F, Rowland J. Role of particle size in the formation of respiratory tract tumors induced by benzo(a)pyrene. Eur J Cancer. 1978;14:321–326. [PubMed: 656185] [CrossRef]
  • Stenbäck F, Rowland J. Experimental respiratory carcinogenesis in hamsters: environmental, physicochemical and biological aspects. Oncology. 1979;36:63–71. [PubMed: 223099] [CrossRef]
  • Stenbäck F, Sellakumar A, Shubik P. Magnesium oxide as carrier dust in benzo(a)pyrene-induced lung carcino-genesis in Syrian hamsters. J Natl Cancer Inst. 1975;54:861–867. [PubMed: 1127716]
  • Surh YJ, Liem A, Miller EC, Miller JA. Metabolic activation of the carcinogen 6-hydroxymethylbenzo[a]pyrene: formation of an electrophilic sulfuric acid ester and benzylic DNA adducts in rat liver in vivo and in reactions in vitro. Carcinogenesis. 1989;10:1519–1528. [PubMed: 2752526] [CrossRef]
  • Thaiparambil JT, Vadhanam MV, Srinivasan C, et al. Time-dependent formation of 8-oxo-deoxyguanosine in the lungs of mice exposed to cigarette smoke. Chem Res Toxicol. 2007;20:1737–1740. [PubMed: 18031018] [CrossRef]
  • Thyssen J, Althoff J, Kimmerle G, Mohr U. Inhalation studies with benzo[a]pyrene in Syrian golden hamsters. J Natl Cancer Inst. 1981;66:575–577. [PubMed: 6937711]
  • Toth B. Tumorigenesis by benzo[a]pyrene administered intracolonically. Oncology. 1980;37:77–82. [PubMed: 7360483] [CrossRef]
  • Urso P, Gengozian N. Subnormal expression of cell-mediated and humoral immune responses in progeny disposed toward a high incidence of tumors after in utero exposure to benzo[a]pyrene. J Toxicol Environ Health. 1984;14:569–584. [PubMed: 6239929] [CrossRef]
  • Van Duuren BL, Katz C, Goldschmidt BM. Cocarcinogenic agents in tobacco carcinogenesis. J Natl Cancer Inst. 1973;51:703–705. [PubMed: 4765384]
  • van Oostrom CT, Boeve M, van Den Berg J, et al. Effect of heterozygous loss of p53 on benzo[a]pyrene-induced mutations and tumors in DNA repair-deficient XPA mice. Environ Mol Mutagen. 1999;34:124–130. [PubMed: 10529736] [CrossRef]
  • Vesselinovitch SD, Kyriazis AP, Mihailovich N, Rao KVN. Factors influencing augmentation and/or acceleration of lymphoreticular tumors in mice by benzo[a]pyrene treatment. Cancer Res. 1975;35:1963–1969. a. [PubMed: 1097103]
  • Vesselinovitch SD, Kyriazis AP, Mihailovich N, Rao KVN. Conditions modifying development of tumors in mice at various sites by benzo[a]pyrene. Cancer Res. 1975;35:2948–2953. b. [PubMed: 1182688]
  • Vineis P, Husgafvel-Pursiainen K. Air pollution and cancer: biomarker studies in human populations. Carcinogenesis. 2005;26:1846–1855. [PubMed: 16123121] [CrossRef]
  • Von Tungeln LS, Xia Q, Herreno-Saenz D, et al. Tumorigenicity of nitropolycyclic aromatic hydrocarbons in the neonatal B6C3F1 mouse bioassay and characterization of ras mutations in liver tumors from treated mice. Cancer Letters. 1999;146:1–7. [PubMed: 10656603] [CrossRef]
  • Warshawsky D, Barkley W. Comparative carcinogenic potencies of 7H-dibenzo[c,g]carbazole, dibenz[a,j]acridine and benzo[a]pyrene in mouse skin. Cancer Letters. 1987;37:337–344. [PubMed: 3677065] [CrossRef]
  • Warshawsky D, Barkley W, Bingham E. Factors affecting carcinogenic potential of mixtures. Fundamental and Applied Toxicology. 1993;20:376–382. [PubMed: 8504912] [CrossRef]
  • Watanabe KH, Djordjevic MV, Stellman SD, et al. Incremental lifetime cancer risks computed for benzo[a]pyrene and two tobacco-specific N-nitrosamines in mainstream cigarette smoke compared with lung cancer risks derived from epidemiologic data. Regul Toxicol Pharmacol. 2009;55:123–133. [PMC free article: PMC2789685] [PubMed: 19540296]
  • Wei SJ, Chang RL, Merkler KA, et al. Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene. Carcinogenesis. 1999;20:1689–1696. [PubMed: 10469612] [CrossRef]
  • Wenzel-Hartung R, Brune H, Grimmer G, et al. Evaluation of the carcinogenic potency of 4 environmental polycyclic aromatic compounds following intrapulmonary application in rats. Exp Pathol. 1990;40:221–227. [PubMed: 1711479]
  • Weyand EH, Chen Y-C, Wu Y, et al. Differences in the tumorigenic activity of a pure hydrocarbon and a complex mixture following ingestion: benzo[a]pyrene vs manufactured gas plant residue. Chemical Research in Toxicology. 1995;8:949–954. [PubMed: 8555410] [CrossRef]
  • Wijnhoven SWP, Kool HJM, van Oostrom CTM, et al. The relationship between benzo[a]pyrene-induced mutagenesis and carcinogenesis in repair-deficient Cockayne syndrome group B mice. Cancer Res. 2000;60:5681–5687. [PubMed: 11059760]
  • Wislocki PG, Bagan ES, Lu AY, et al. Tumorigenicity of nitrated derivatives of pyrene, benz[a]anthracene, chrysene and benzo[a]pyrene in the newborn mouse assay. Carcinogenesis. 1986;7:1317–1322. [PubMed: 3731386] [CrossRef]
  • Wojdani A, Alfred LJ. Alterations in cell-mediated immune functions induced in mouse splenic lymphocytes by polycyclic aromatic hydrocarbons. Cancer Res. 1984;44:942–945. [PubMed: 6420057]
  • Xiao H, Rawal M, Hahm ER, Singh SV. Benzo[a]pyrene-7,8-diol-9,10-epoxide causes caspase-mediated apoptosis in H460 human lung cancer cell line. Cell Cycle. 2007;6:2826–2834. [PubMed: 17986867]
  • Xue W, Warshawsky D. Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol Appl Pharmacol. 2005;206:73–93. [PubMed: 15963346] [CrossRef]
  • Yu D, Kazanietz MG, Harvey RG, Penning TM. Polycyclic aromatic hydrocarbon o-quinones inhibit the activity of the catalytic fragment of protein kinase C. Biochemistry. 2002;41:11888–11894. [PubMed: 12269833] [CrossRef]
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