111

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)

1

2

3

4

7 6 5

8

9

10

11

12

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 

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.
IARC MONOGRAPHS – 100F

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.

112
Benzo[a]pyrene

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.

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 squamouscell 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).

113
IARC MONOGRAPHS – 100F

114 Table 3.1 Carcinogenicity studies of benzo[

a]pyrene in experimental animals

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Skin application

Mouse, Swiss ICR/Ha (F)52 wkVan Duuren et al. (1973)

0 (untreated), 0 (vehicle control), 5 μg/animal, 3 × /wk, 52 wk50/group

Skin T: 0/50, 0/50, 23/50 (46%; 13 P; 10 C) + NR (acetone)

Mouse, Swiss (F)38–65 wkCavalieri et al. (1977)

0 and 0.396 μmol [0.1 mg] per animal, twice/wk, 30 wk40/group

Skin T: 0% [0/29], 78.9% [30/38] (7 P, 7 K, 36 C, 1 malignant Schwannoma)

+ 99% (acetone)

Mouse, C57BL/6J (F)60 wkLevin et al. (1977)

Experiment 1 and 2: 0 (DMSO/acetone), 0.02 [5.28 μg], 0.1 [26.43 μg], 0.4 [105.75 μg] μmol/animal, once/2 wk, 60 wk (high dose given in two paintings, 30 min apart)Experiment 3: 0 (acetone/NH OH), 

4

0.025 [6.6 μg], 0.05 [13.21 μg], 0.1 [26.43 μg] μmol/animal, once/2 wk, 60 wk30/group

Skin T (mainly SCC):Experiment 1–0%, 0%, 38% (13 T), 100% (44 T)Experiment 2–0%, 4% (1 T), 50% (15 T), 100% (40 T)Experiment 3– 0%, 7% (2 T), 59% (20 T), 91% (24 T)

+ NR (DMSO/acetone (1:3) or 

acetone/NH OH (1 000:1))

4

Effective number of animals not clearly specifiedAt most, seven animals/group died prematurely without a skin tumour.

Mouse, NMRI (F)63–109 wkHabs et al. (1984)

0, 2, 4 μg/animal, twice/wk20/group

Skin T: 0/20, 9/20 (45%; 2 P, 7 C), 17/20 (85%; 17 C)

+ > 96% (acetone)

Mouse C3H/HeJ (M)99 wkWarshawsky & Barkley (1987)

0 (untreated), 0 (vehicle control) or 12.5 μg/animal, twice/wk

50/group

Skin T: 0/50, 0/50, 48/50 (96%; 47 C, 1 P) + 99.5% (acetone)

Mouse, Swiss (F)42 wkCavalieri et al. (1988a)

0, 0.1 [26.4 μg], 0.4 [105.7 μg] μmol/animal, twice/wk, 20 wk

30/group

Skin T incidence: 0/30, 26/29 (90%; SGA, 3 P, 23 SCC), 26/30 (90%; 2 P, 26 SCC)

+ Purified [NR] (acetone)
Benzo[

a]pyrene

115

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Mouse, C3H/fCum (M) Experiment 1: 15 mo Experiment 2: 18 mo Experiment 3: 18 moKouri et al. (1980)

Experiment 1: 0 (trioctanoin control), 0 (DMSO control), 0.9 μmol [0.23 mg] in trioctanoin or DMSO,

FibroS at injection site:Experiment 1–0/16, 0/20, 15/18 (83%), 12/19 (63%)

+ Pure (trioctanoin, DMSO)

Experiment 2: 0 (trioctanoin control), 0 (DMSO control), 0.9 μmol [0.23 mg] in trioctanoin or in DMSO,

Experiment 2–0/20, 0/18, 14/18 (78%), 7/19 (37%)

Experiment 3: 0 (trioctanoin/DMSO, 100:1), 0.9 μmol [0.23 mg] in trioctanoin/DMSO (100:1), 1 × 

20 or 40/group

Experiment 3–0/20, 36/40 (90%)

Mouse, NR (F)78 wkRippe & Pott (1989)

0, 10, 100 μg/animal, 1 × NR/group

S at injection site: 1/30 (3%), 13/30 (43%), 20/30 (67%)

+ NR (tricaprylin)

Mouse, Swiss (newborn) (M, F)75–200 dBalansky et al. (2007)

0 and 1.0 mg/animal, 1 × 12–15 M/group, 12–15 F/group

Lung A: M – 0/15, 9/12; F – 0/15, 11/12 P < 0.001 Pure (olive oil)

Rat, Wistar (F)~530 dPott et al. (1973a)

0, 33, 100, 300, 900, 2 700 μg/animal, 1 × 50/group

T (mainly fibroS) at injection site [incidence derived from dose–response curves]: 2/50 (~4%), 4/50 (~8%), 7/50 (~14%), 23/50 (~46%), 35/50 (~70%), 38/50 (~76%)

+ NR (tricaprylin)

Rat, NR (F)132 wkRippe & Pott (1989)

0 and 1 mg, 1 × NR/group

S at injection site: 0/24 (0%), 20/24 (83%) + NR (tricaprylin)

Rat, NR (F)132 wkRippe & Pott (1989)

0 and 15 mg, 1 × NR/group

S at injection site: 1/24 (4%), 19/24 (79%) + NR (DMSO)

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

116

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian, RB (randomly bred), BIO inbred strains designated as: 1.5, 4.22, 4.24, 7.88, 12.14, 15.16, 45.5, 54.7, 82.73, 86.93, 87.20 (M, F)53 wkHomburger et al. (1972)

500 μg/animal, 1 × 25 M/group, 25 F/group

FibroS at injection site:RB–M, 4/25 (16%); F, 6/23 (26%)1.5–M, 5/25 (20%); F, 4/23 (17%)4.22–M, 3/25 (12%); F, 8/25 (32%)4.24–M, not tested; F, 9/25 (36%)7.88–M, 13/25 (52%); F, 5/23 (23%)12.14–M, 3/25 (12%); F, 9/22 (41%)15.16–M, 9/25 (36%); F, 16/25 (64%)45.5–M, 12/25 (48%); F, 7/15 (47%)54.7:–M, 5/25 (20%); F, 5/25 (20%)82.73–M, 4/21 (19%); F, 4/24 (17%)

86.93–M, 9/25 (36%); F, 8/25 (32%)87.20–M, 16/25 (64%); F, 11/25 (42%)

+ NR (tricaprylin)

No subcutaneous T observed in historical controls

Oral administration

Mouse, A/J (F)260 dWeyand et al. (1995)

0, 16, 98 ppm (total dose; 0, 11, 67 mg) in the diet30/group

Lung T: 4/21 (19%; 4 A; 0.19 ± 0.09 A/animal), 9/25 (36%*; 7 A, 2 AdC; 0.48 ± 0.14 T/animal), 14/27 (52%*; 14 A; 0.59 ± 0.12 A/animal)Forestomach T: (0%) 0/21, (5/25) (20%; 3 P, 2 C; 0.24 ± 0.11** T/animal), 27/27 (100%**; 13 P, 14 C; 4.22 ± 0.41**)

*P < 0.05

**P < 0.001

NR (gel diet)

Mouse B6C3F1 (F)2 yrCulp et al. (1998)

0 (acetone control diet), 5 ppm, 25 ppm, 100 ppm in the diet

48/group

Liver (A): 2/48 (4%), 7/48 (15%), 5/47 (11%), 0/45 (0%)Lung (A and/or C): 5/48 (10%), 0/48 (0%), 4/45 (9%), 0/48 (0%)

Forestomach (P and/or C): 1/48 (2%), 3/47 (6%), 36/46 (78% ), 46/47 (98%** **)

Oesophagus (P and/or C): 0/48 (0%), 0/48 (0%), 2/45 (4%), 27/46 (59%**)Tongue (P and/or C): 0/48 (0%), 0/48 (0%), 2/46 (4%), 23/48 (48%***)Larynx (P and/or C): 0/35 (0%), 0/35 (0%), 3/34 (9%), 5/38 (13%*)

*P < 0.014

**P < 0.0014

***P < 0.0003****P < 0.00001

98.5% (acetone)

Mouse, Swiss albino, inbred (F)27 wkBadary et al. (1999)

0 and 1 mg/animal by gavage, twice/wk, 4 wk

10/group

0, 10/10 (100%) (forestomach P; multiplicity, 7.11 ± 1.05)

+ Highest purity grade (corn 

oil)Drinking-water contained 0.005% ethanol

Table 3.1 (continued)
Benzo[

a]pyrene

117

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Mouse, CSB–/– or wildtype (CSP ±  or CSB+/+) 

(M, F)52 wkWijnhoven et al. 

(2000)

0 and 13 mg/kg bw by gavage, 3 × /wk, 13 wk6–18 M/group, 6–13 F/group

Wild-type: 5/27 (14 M, 13 F; 19%; 4 bronchioloalveolar A, 2 lymphoma), 17/29* (18 M, 11 F; 59%; 6 bronchiolo-alveolar A, 10 forestomach P, 2 forestomach SCC, 2 histiocytic S, 2 hepatocellular A, 1 intestinal AdC, 1 skin P)CSB–/–: 0/13 (6 M, 7 F), 7/12** (6 M, 6 F; 58%; 2 

bronchiolo-alveolar A, 2 uterine S, 1 forestomach SCC, 1 intestinal AdC, 1 skin histiocytic S)

*P = 0.0023 

**P = 0.0017

NR (soya oil)

Rat, Crl:CD(SD)BR (F)49 wkel-Bayoumy et al. 

(1995)

0 and 50 μmol/animal, once/wk, 8 wk by gavage30/group

Mammary T incidence: 11/30 [37%] [incidence not clearly specified] (8 desmoplastic A, 2 A, 1 AdC), 29/30 (96.7%; 8 fibroA**, 17 desmoplastic A*, 7 A, 22 AdC**)Numbers of mammary T: controls, 14 desmoplastic A, 2 A, 1 AdC; treated animals, 14 fibroA*, 35 desmoplastic A, 11 A, 56 AdC**

*P < 0.05

**P < 0.01

99% (trioctanoin)

Intraperitoneal injection

Mouse, B6C3F1; C3A/JF1 (M, F)90 wk or lifetimeVesselinovitch et al. (1975a, b)

0, 75, 150 μg in 10 μL/g bw, 1 × at 1, 15, 42 d of age

30–63/group, 96–100 controls/group

B6C3F1 mice (all ages combined):Liver T (A and hepatocellular C)–M, 1/98 (1%), 69/162 (43%), 81/165 (49%); F, 0/96 (0%), 7/147 (5%), 10/126 (8%)Lung T (A and AdC)–M, 7/98 (7%), 57/162 (35%), 73/165 (44%); F, 2/90 (2%), 53/147 (36%), 50/126 (40%)

Forestomach T (P and SCC)–

M, 0/98 (0%), 39/162 (24%), 64/165 (39%); F, 0/96 (0%), 22/147 (15%), 40/126 (32%)Lymphoreticular T (mainly reticulum-cell S)–M, 2/98 (2%), 104/314 (33%) (high- and low-dose groups combined); F, 2/96 (2%), 148/281 (53%) (high-and low-dose groups combined)

+ NR (trioctanoin)

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

118

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Vesselinovitch et al. (1975a, b)

Contd.

C3A/JF1 mice (all ages combined):Liver T (A and hepatocellular C)–M, 3/97 (3%), 30/148 (20%), 33/137 (24%); F, 0/100 (0%), 1.3% 2/126 (1.3%), 2/153 1.3%) Lung T (A and AdC)–

M, 49/97 (49%), 1 438/148 (93%), 125/137 (91%); F, 26/100 (26%), 115/126 (91%), 141/153 (92%)Forestomach T (P and SCC)–M, 0/97 (0%), 18/148 (12%), 42/137 (31%); F, 0/100 (0%), 18/126 (14%), 31/153 (20%)Lymphoreticular T (mainly reticulum-cell S)–M, 0/97 (0%), 26/285 (9%); F, 2/100 (2%), 50/278 (18%) (high- and low-dose groups combined)

+

Mouse, CD-1 (M, F)1 yrWislocki et al. (1986)

0 and 560 nmol [148 μg] (total dose; given as 1/7, 2/7, 4/7 on PND 0, 8, 15)37 M/group, 27 F/group

Liver T: M, 2/28 (7%; 2 A), 18/37* (49%; 11 A, 7 C*); F, no liver T foundLung T: M, 1/28 (4%; 1 A), 13/37** (35%; 13 A); F, 0/31, 13/27** (48%) (13 A)

Malignant lymphoma: M, 1/28 (4%), 2/37 (5%); F, 1/31 (3%), 4/27 (15%)

*P < 0.005

**P < 0.05

> 99% (DMSO)

Mouse, CD-1 (M, F)52 wkLavoie et al. (1987)

0 and 1.1 μmol [290 μg] (total dose; given as 1/6, 2/6, 4/6 on PND 1, 8, 15)17 M/group, 14–18 F/group

Liver T: M, 1/17 (6%; 1 H), 13/17* (76%; 9 hepatic A, 4 H); F, 0/18, 0/14 Lung A: M, 0/17, 14/17* (82%); F, 0/18, 9/14** (64%)

*P < 0.005

**[

P < 0.0005]

> 99% (DMSO)

Mouse, Swiss-Webster BLU: Ha(ICR) (M, F)26 wkBusby et al. (1989)

0 and 59.5 μg (total dose; given as 8.5, 17, 34 μg on PND 1, 8, 15)

NR/group

Lung T: M, 12/91 (13%; 12 A, 1 AdC; 0.15 ± 0.04 T/mouse), 13/28 (46%; 13 A; 0.71 ± 0.19 A/mouse); F, 7/101 (7%; 7 A; 0.08 ± 0.03 A/mouse), 18/27 (67%; 18 A, 1 AdC; 1.19 ± 0.21 T/mouse)

+ > 99% (DMSO)

statistics NR

Mouse, NR, newborn (M, F)30 wkRippe & Pott (1989)

0, 10, 100 μg/animal, 1 × NR/group

Lung T: 13% [5/38] (0.13 T/animal), 16% [5/31] (0.23 T/animal), 64% [21/33] (2.52 T/animal)

+ NR (saline solution + 1% 

gelatine + 0.4% Tween 20)Type of lung tumour NR; statistics NR

Mouse, A/J (F)260 dWeyand et al. (1995)

0 (untreated), 0 (vehicle control), 1.79 mg/animal, 1 × 29–30/group

Lung T: 7/30 (23%; 7 A; 0.27 ± 0.12 A/animal), 11/30 (37%; 11 A; 0.43 ± 0.11 A/animal), 29/29* (100%; 27 A, 2 AdC; 15.8 ± 1.28** T/animal); forestomach T: 0/30 (0%), 0/30 (0%), 24/29** (83%; 15 P, 9 C; 1.83 ± 0.25** T/animal)

*P < 0.05

**P < 0.001

NR (tricaprylin)

Table 3.1 (continued)
Benzo[a]pyrene

119

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Mouse, B6C3F1, infant 

(M, F)26 wk, 39 wk, 52 wkRodriguez et al. (1997)

0 (untreated), 0 (vehicle controls), 125, 250, 375 μg/7 g bw, 1 × > 30 M/group, > 30 F/group

Liver T (M):At wk 26: 0/41, 0/58, 0/29, 0/25, 3/34 (9%; multiplicity, 1.0); at wk 39: 0/34, 0/59, 6/26 (23%; multiplicity, 1.0), 13/34 (38%; multiplicity, 1.9), 15/23 (65%; multiplicity, 1.9); at wk 52: 4/64 (6%; multiplicity, 1.0), 3/63 (5%; multiplicity, 1.0), 13/29 (45%; multiplicity, 1.8), 14/27 (52%; multiplicity, 2.2), 19/24 (79%; multiplicity, 2.5)No liver T in F

+ NR (corn oil)

No forestomach tumours

Mouse, CD-1 (M)12 moVon Tungeln et al. (1999)

0, 100, 400 nmol [26, 111 μg]/animal (total dose; given as 1/7, 2/7, 4/7 on PND 1, 8, 15)

24/group

Liver T: 3/20 (15%; 1 A, 2 C; 1.7 T/liver section), 5/21 (24%; 4 A, 1 C; 1.5 T/liver section), 9/20 (45%; 7 A*, 2 C; > 2.3 T/liver section)

Lung T: 4/20 (20%; 4 A; 1.0 T/lung section), 1/21 (5%; 1 A; 1.0 T/lung section), 9/20 (45%; 7 A, 2 C; 1.9 T/lung section)

*P = 0.0234 > 99% (DMSO)

Rat, Wistar (F)~112 wkRoller et al. (1992)

0 and 5 mg/animal, 1 × 

NR/group

Abdominal mesothelioma and S: 3/41 (7.3%), 33/37 (89.2%)

+ NR (3:1 mixture of 

tricaprylin/ beeswax)Limited reporting

Rat, Wistar (F)~116 wkRoller et al. (1992)

5 mg/animal, 1 × NR/group

Abdominal mesothelioma and S: 19/38 (50%); historical controls, 11/369 (3%)

+ NR (saline solution)

No control; limited reporting of tumour data

Inhalation

Hamster, Syrian golden (M)LifetimeThyssen et al. (1981)

0, 2.2, 9.5, 46.5 mg/m3, 4.5 h/d, 7 d/wk, 10 wk; thereafter 3 h/d, 7 d/wk (total average doses: 0, 29, 127, 383 mg/animal)

24/group (+ animals added during the study)

Respiratory tract T:(polyps, P, SCC)–0/27, 0/27, 34.6% [9/26; 3 nasal, 8 laryngeal, 1 tracheal], 52% [13/25; 1 nasal, 13 laryngeal, 3 tracheal; no bronchogenic T]Upper digestive tract T:(polyps, P, SCC)–0/27, 0/27, 26.9% [6/26; 6 pharyngeal, 1 forestomach], 56% [14/25; 14 pharyngeal, 2 oesophageal, 1 forestomach]

+ NR (0.1% saline solution); 

particle size, > 99% diameter 0.2–0.5 μm, > 80% diameter 0.2–0.3 μmSurvival decreased for high dose-exposed animals (59 wk) vs other groups (96 wk).

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

120

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Intrapulmonary injection

Rat, OM (F)64 (high-dose group)–133 wk (untreated controls)Deutsch-Wenzel et al. 

(1983)

0 (untreated), 0 (vehicle control), 0.1, 0.3, 1.0 mg/animal, 1 × 35/group

Lung T: [0/35] (0%), [0/35] (0%), [10/35] (28.6%) (4 epidermoid C; 6 pleomorphic S), [23/35] (65.7%) (21 epidermoid C; 2 pleomorphic S), [33/35] (94.3%) (33 epidermoid C)

+ 99.1% (1:1 mixture of beeswax 

and trioctanoin)

Rats, F344/NSlc (M)104 wkIwagawa et al. (1989)

0, 0.03, 0.1, 0.3, 1.0 mg/animal, 1 × NR/group

Lung T: 0/40, 1/29 (3%; 1 undifferentiated T), 7/30 (23%; 6 SCC, 1 undifferentiated T), 22/29 (76%; 20 SCC, 2 undifferentiated T), 9/13 (69%; 9 SCC)

+ NR (1:1 mixture of beeswax/

tricaprylin)

Rat, Osborne-Mendel (F)134 wk (low-dose group)–140 wk (vehicle controls)Wenzel-Hartung et al. 

(1990)

0 (untreated), 0 (vehicle control), 30, 100, 300 μg/animal, 1 × 

35/group

Lung T: [0/35] (0%), [0/35] (0%), [3/35] (8.6%; 3 SCC), [11/35] (31.4%; 11 SCC), [27/35] (77.1%; 27 SCC).

+ 99.6% (beeswax/trioctanoin 

mixture of varying composition)SCC predominantly keratinized

Rat, F344/DuCrj (M)100 wkHorikawa et al. (1991)

0, 50, 100, 200 μg/animal, 1 × 9–10/group

Lung T: 0/19, 0/10, 3/10 (30%; 2 SCC, 1 AdSC), 4/9 (44.4%; 3 SCC, 1 undifferentiated T)

+ NR (1:1 mixture of beeswax/

tricaprylin)

Intratracheal administration

Rat, Wistar-WU/Kisslegg (F)124–126 wkPott et al. (1987)

0 and 1 mg/animal, once/wk, 20 wkNR/group

Lung T: 0/40, 7/36 (19%; 1 A, 5 SCC, 1 mixed AdC/SCC)

+ NR (0.9% saline solution)

Rat, Sprague-Dawley (M, F)Controls, 131 wk; treated animals, 112 wkSteinhoff et al. (1991)

0 and 0 (physiological saline), 7 mg/kg bw/instillation (physiological saline with Tween 60), once/2 wk, 44 wk20 or 50/group

M: 0/50, 0/50, 19/20 (95%; 19 malignant lung T)

F: 0/50, 0/50, 19/20 (95%; 18 malignant, 1 benign lung T)

+ NR (physiological saline 

solution with or without Tween 60)Limited histology

Table 3.1 (continued)
Benzo[a]pyrene

121

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (M, F)78 wkFeron (1972)

0 (only for M), 1 mg/animal, once/wk, 36 wk35/group

Respiratory tract T/adenomatoid lesions:

M–6/27 (22%; 1 tracheal P, 5 pulmonary adenomatoid lesion), 19/29 (66%; 1 tracheal P, 17 SCC, 26 pulmonary adenomatoid lesion, 5 A, 1 AdC, 1 SCC)F–22/27 (81%; 1 laryngeal SCC, 16 tracheal SCC, 2 bronchial A, 1 AdC, 21 pulmonary adenomatoid lesion, 8 A, 1 AdC)

+ > 99% (0.9% saline solution)

No female controls; Statistics NR

Hamster, Syrian golden (M)78 wkFeron et al. (1973)

0, 0.0625, 0.125, 0.25, 0.5, 1.0 mg/animal, once/wk, 52 wk30/group

Respiratory tract T:0/29, 3/30 (10%; 3 tracheal P, 1 pulmonary A), 4/30 (13%; 1 tracheal P, 4 pulmonary A), 9/30 (30%; 5 tracheal P, 7 pulmonary A), 25/29 (86%; 2 tracheal polyp, 9 P, 5 SCC, 1 AdSC, 1 fibroS, 2 bronchial polyp, 1 P, 2 SCC, 1 AdSC), 26/28 (93%; 6 tracheal P, 11 SCC, 1 AdSC, 1 bronchial polyp, 2 P, 4 SCC, 2 AdSC, 4 AdC, 1 anaplastic C, 16 pulmonary A, 4 SCC, 3 AdSC, 1 AdC, 2 anaplastic C)

+ NR (0.9% saline solution)

Hamster, Syrian golden (M, F)M, 67–88 wk; F, 60–88 wkHenry et al. (1973)

0, 13.3–15.5 mg/animal, once/wk, 8 wk50/group, 25 controls/group

Respiratory tract T:

Controls–1 tracheal polyp, 6 pulmonary bronchiolar adenomatoid lesions/47 animalsTreated animals–

26/65 (40%; 1 nasal polyp; 6 laryngeal polyps, 1 P, 1 A, 1 AdC, 7 tracheal polyps, 1 AdC, 1 SCC, 1 fibroS, 2 bronchial AdC, 13 pulmonary bronchiolar adenomatoid lesion, 3 A, 5 AdC, 1 SCC, 2 anaplastic C, 1 mixed C, 1 myelogenous leukaemia, 1 neurofibroS)

T at other sites:Controls–1 renal ATreated animals–3 blast-cell leukaemia, 2 adrenocortical A, 1 renal AdC, 1 oesophageal fibroS, 1 haemangioma

+ NR (0.5% gelatine in 0.9% 

saline solution)Tumour data for M and F combined; statistics NR

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

122

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (M, F)60 wkKobayashi (1975)

0 and 1 mg/animal, once/wk, 30 wk20–32 M/group, 20–28 F/group

Respiratory tract T:M–0/20, 11/26 (42.3%; 1 laryngeal polyp, 1 tracheal polyp, 1 P, 1 bronchial SCC, 9 lung A, 7 AdC, 3 SCC, 1 anaplastic C, 2 AdSC)F–0/20, 14/26 (53.8%; 1 laryngeal P, 2 tracheal polyps, 1 bronchial SCC, 10 lung A, 3 AdC, 1 SCC)

+ NR (0.9% saline)

Hamster, Syrian golden (M, F)78 wkKruysse & Feron (1976)

0 (untreated), 0 (vehicle controls), 1 mg/animal, once/2 wk, 52 wk17 or 40/group

Respiratory tract T:M–0/40, 0/40, 13/14 (93%; 2 laryngeal P, 1 SCC, 4 tracheal P, 3 SCC, 1 anaplastic C, 1 S, 1 bronchial SCC, 1 AdC, 5 pulmonary A, 1 AdC)

F–0/40, 0/40, 7/12 (58%; 2 tracheal P, 3 SCC, 1 bronchial P, 5 pulmonary A)

+ > 99% (saline solution)

Hamster, Syrian golden (M)100 wkSellakumar et al. 

(1976)

0 (untreated), 3 mg/animal, once/wk, 10 wk48/group

Respiratory tract T:0/48, 7/48 (15%; 2 laryngeal P, 4 tracheal P, 1 lung A)T at other sites:

6/48 (13%; 3 forestomach P, 2 lymphoma, 1 anaplastic C), 26/48 (54%; 21 forestomach P, 1 skin melanoma, 1 liver haemangioma, 1 adrenocorticoA, 3 adrenocorticoC)

+ > 99% (0.9% saline solution)

Hamster, Syrian golden (M, F)Experiment 1: up to 89 wk for M and 70 wk for FExperiment 2: up to 83 wk for M and 68 wk for FKetkar et al. (1977)

Experiment 1:

0, 4, 8, 16 mg in 0.9% saline solution/animal, 1 × 30/group

Respiratory tract T:Experiment 1–M 0/24, 3/30 (10%; 1 laryngeal P, 1 tracheal P, 1 lung S), 5/28 (18%; 1 laryngeal SCC, 1 tracheal P, 4 lung S), 4/27 (15%; 3 tracheal P, 1 lung A, 1 S)F 0/28, 3/29 (10%; 1 tracheal P, 2 lung A), 1/30 (3%; 1 lung A), 3/28 (13%; 1 laryngeal P, 2 lung A)

+ 97% (0.9% saline solution or 

Tris buffer)

Experiment 2:0, 4, 8, 16 mg in Tris buffer/

animal, 1 × 

30/group

Experiment 2–

M 0/27, 5/24 (21%; 1 tracheal P, 5 lung A), 13/25 (52%; 1 laryngeal P, 7 tracheal P, 4 lung A, 3 AdC), 8/27 (30%; 2 laryngeal P, 1 SCC, 3 tracheal P, 3 lung A)F 0/27, 3/27 (11%; 2 tracheal P, 1 lung AdC), 2/29 (7%; 2 tracheal P), 8/29 (28%; 1 laryngeal P, 4 tracheal P, 5 lung A)

+

Table 3.1 (continued)
Benzo[a]pyrene

123

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (M, F)81 wkFeron & Kruysse (1978)

0 (untreated), 0 (vehicle controls), 0.35, 0.7 mg/animal, once/wk, 52 wk15 or 30/group

Respiratory tract T:M–0/30 (untreated and vehicle controls combined), 4/29 (14%; 2 tracheal P, 1 bronchial P, 2 pulmonary A), 19/30 (63%; 1 laryngeal P, 5 tracheal P, 1 SCC, 1 anaplastic C, 1 S, 2 bronchial P, 1 AdC, 11 pulmonary A, 2 AdC, 1 SCC, 1 anaplastic C)F–0/28 (untreated and vehicle controls combined), 3/27 (11%; 1 laryngeal P, 1 bronchial P, 1 pulmonary A), 7/24 (29%; 1 tracheal P, 2 SCC, 1 bronchial AdC, 5 pulmonary A)

+ > 99% (0.9% saline solution)

Statistics NR

Hamster, Syrian golden (M, F)Average survival up to 41 wk for M and 35 wk for FKetkar et al. (1978)

0, 0.1, 0.33, 1.0 mg/animal, once/wk30/group

Respiratory tract T:

M–0/29, 5/26 (19%; 5 bronchiogenic A), 7/29 (24%; 5 tracheal P, 2 bronchiogenic A), 6/27 (22%; 5 tracheal P, 2 bronchiogenic A)F–0/30, 12/30 (40%; 1 tracheal P, 1 SCC, 10 bronchiogenic A), 10/28 (36%; 7 tracheal P, 5 bronchiogenic A, 1 SCC), 6/30 (20%; 3 tracheal P, 3 bronchiogenic A, 3 SCC)

+ 97% (10% bovine serum 

albumin)Average survival time much lower in the high-dose group than in the other groups

Hamster, Syrian golden (M, F)Lifetime, up to 90 wkStenbäck & Rowland (1978)

0, 3 mg large particles, 3 mg small particles/animal, once/wk, 18 wk48 (M + F)/group

Respiratory tract T (M + F combined): 0/46, 31/47 (66%; 5 laryngeal P, 12 tracheal P, 20 SCC, 2 unspecified T, 2 bronchial P, 9 SCC, 3 A, 2 anaplastic C), 5/46 (11%; 1 laryngeal P, 1 SCC, 4 tracheal P)

+ 99.4% (0.9% saline solution);

particle size by weight: large-98% < 30 μm, 90% < 20 μm, 36% < 10 μm, 10% < 5 μm; small-98% < 10 μm, 79% < 5 μm, 5% < 1 μm

Hamster, Syrian golden (M)Average survival up to 88 wkKetkar et al. (1979)

0 (untreated), 0 (vehicle controls), 0.125, 0.25, 0.5, 1.0 mg/animal, once/wk30/group

Respiratory tract T:

0/29, 0/28, 9/29 (31%; 2 laryngeal polyps/P, 1 tracheal P, 1 SCC, 2 lung A, 2 SCC, 5 AdC), 24/29 (83%; 1 nasal SCC, 2 laryngeal polyps/P, 4 tracheal P, 9 SCC, 5 lung A, 5 SCC, 11 AdC), 19/29 (66%; 1 laryngeal P, 2 SCC, 5 tracheal P, 11 SCC, 7 lung SCC, 2 AdC), 9/29 (31%; 1 laryngeal P, 1 SCC, 1 tracheal P, 5 SCC, 1 lung A, 4 SCC)

P < 0.001, all treated groups

97% (Tris buffer + 0.9% saline solution); particle size: majority < 10 μm but particles up to 80 μm also presentAverage survival in two highest-dose groups much lower than that in the other groups due to many early deaths from pulmonary lesions other than tumours

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

124

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (M, F)105 wkFeron et al. (1980)

0 (untreated), 0 (gelatine in 0.9% saline), 0.5, 1.0 mg fine particles, 0.5, 1.0 mg coarse particles, 1.0 mg wide-range particles/animal, once/wk, 52 wk30–35/group

Respiratory tract T:M–0/29, 2/34 (6%; 2 laryngeal P), 7/34 (21%; 1 laryngeal P, 6 tracheal P, 1 lung A), 6/31 (19%; 2 laryngeal P, 1 tracheal P, 1 S,1 pulmonary A), 13/31 (42%; 2 laryngeal P, 3 tracheal P, 9 pulmonary A), 25/34 (74%; 2 laryngeal P, 9 tracheal P, 4 SCC, 2 S, 1 pulmonary A, 1 AdC), 23/34 (68%; 2 laryngeal P, 1 SCC, 6 tracheal P, 2 SCC, 1 bronchial P, 1 SCC, 13 pulmonary A, 2 AdC, 2 anaplastic C)F–0/28, 2/33 (6%; 1 tracheal P, 1 pulmonary A), 2/34 (6%; 1 bronchial P, 1 A), 5/32 (16%; 1 laryngeal P, 2 tracheal P, 3 pulmonary A), 9/32 (28%; 2 laryngeal P, 5 tracheal P, 6 pulmonary A), 19/32 (31%; 4 tracheal P, 1 SCC, 1 S, 1 bronchial P, 7 pulmonary A, 1 AdC), 11/34 (34%; 1 laryngeal P, 3 tracheal P, 2 bronchial P, 7 pulmonary A, 1 AdC)

+ NR; particles size by weight: 

fine, 77% < 5.2 μm, 60% < 3.9 μm; coarse, 77% < 42 μm, 3% < 16 μm; wide-range, 72% < 30 μm, 19% < 10 μm (gelatine in 0.9% saline solution)Statistics NR

Hamster, Syrian golden (M)129 wkGodleski et al. (1984)

0 and 5 mg/animal, once/wk, 15 wk80/group

Malignant T: 4/80 (5%; 1 multicentric undifferentiated lung C, 3 lymphoma), 25/80* (31%; 9 SCC, 2 undifferentiated C of the respiratory tract, 5 lymphoma, 1 SCC, 2 AdC of the gastrointestinal tract, 2 soft-tissue T, 1 hepatoma, 2 mouth SCC, 1 skin C)

*P < 0.001 > 99% (0.5% gelatine in 0.9% 

saline solution)

Intratracheal administration of combinations of benzo[a]pyrene and ‘particles/fibres’

Rat, Sprague-Dawley (M, F)Up to 130 wkSteinhoff et al. (1991)

0, (untreated), 0 (physiological saline), 10–40 mg/kg bw Bayferrox 130 (96.2% cubic α-Fe

O2 3), 

10–40 mg/kg bw Bayferrox 920 (86.1% fibrous α-FeOOH), 7 mg/kg bw, 7 mg/kg bw + 10–40 mg/kg bw Bayferrox 130, 7 mg/kg bw + 10–40 mg/kg bw Bayferrox 920, ~once/2 wk, 44–~130 wk20 or 50/group

Lung T:M–0/50, 0/50, 0/50, 0/50, 19 malignant T in 20 animals, 21 malignant and 1 benign T in 20 animals, 17 malignant and 1 benign T in 20 animalsF–0/50, 0/50, 0/50, 1 malignant and 1 benign T in 50 animals, 18 malignant and 1 benign T in 20 animals, 16 malignant T in 20 animals, 17 malignant and 2 benign T in 20 animals

+ NR (physiological saline 

solution with or without Tween 60);Bayferrox 130,Bayferrox 920Limited histology

Table 3.1 (continued)
Benzo[

a]pyrene

125

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (M, F)Lifetime (up to 140 wk)Saffiotti et al. (1972)

Experiment 10, 50 mg ferric oxide, 5 mg + 45 mg ferric oxide, 12.5 mg + 37.5 mg ferric oxide/ animal, 1 × Experiment 2(2 groups/dose level)

5 mg + 5 mg ferric oxide,

10 mg + 10 mg ferric oxide, 15 mg + 15 mg ferric oxide, once/wk, 15 wk23–110 M/group, 18–107 F/group

Experiment 1:Respiratory tract T–M 0/45, 0/101, 3/92 (3%; 1 tracheal polyp, 1 P, 1 bronchial A), 3/27 (11%; 1 bronchial A, 1 bronchogenic SCC, 1 anaplastic C)F 0/44, 0/89, 4/97 (4%; 1 tracheal polyp, 1 P, 1 bronchiolar A, 1 AdC), 6/33 (18%; 1 bronchial P, 1 A, 2 bronchogenic SCC, 1 anaplastic C, 2 bronchiolar A)

Forestomach P–M 5/45 (11%; 6 T), 5/101 (5%; 5 T), 15/92 (16%; 35 T), 8/27 (30%; 16 T)F 2/44 (5%; 2 T), 2/89 (2%; 3 T), 5/97 (5%; 5 T), 4/33 (12%; 6 T)

+ NR (0.9% saline solution); 

ferric oxide

Experiment 2:Respiratory tract T (M + F combined)–7/50 (14%; 2 tracheal P, 1 SCC, 1 bronchial P, 1 A, 2 SCC, 1 anaplastic C, 1 pulmonary SCC),8/58 (14%; 2 tracheal polyps, 1 bronchial polyp, 2 SCC, 2 AdC, 2 pulmonary A, 2 AdC), 17/61 (28%; 2 tracheal polyps, 2 P, 5 SCC, 5 bronchial SCC, 1 pulmonary A, 1 SCC, 1 AdC, 1 anaplastic C), 25/60 (42%; 4 tracheal polyps, 3 P, 3 SCC, 4 anaplastic C, 1 bronchial P, 1 SCC, 2 anaplastic C, 4 AdC, 1 A, 2 pulmonary SCC, 2 anaplastic C, 6 A), 25/39 (64%; 1 tracheal P, 10 SCC, 1 anaplastic C, 3 bronchial P, 7 SCC, 11 anaplastic C, 2 AdC, 2 pulmonary SCC, 2 A), 35/55 (64%; 2 laryngeal SCC, 11 tracheal P, 1 polyp, 12 SCC, 1 carcinoS, 2 fibroS, 16 bronchial SCC, 10 anaplastic C, 6 AdC, 3 A, 2 pulmonary A)

+

Forestomach T–M 8/22 (36%; 13 P, 1 SCC), 

6/28 (21%; 9 P), 11/34 (32%; 28 P, 1 SCC), 11/30 (37%; 18 P), 5/22 (23%; 10 P), 1/28 (4%; 1 P)

F 9/28 (32%; 14 P), 6/30 (20%; 9 P), 5/27 (19%; 20 P), 8/30 (27%; 10 P, 1 SCC), 5/17 (29%; 11 P), 3/27 (11%; 3 P)

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

126

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (F)Presumably lifetimePott et al. (1973b)

340 μg in tricaprylin, 340 μg in Tween 60/saline solution, 340 μg in Tween 60/saline solution + 850 μg atmospheric dust/animal, 45 × within a period of 6.5 mo (total dose, ~15 mg; dust, 38 mg)

48/group

Respiratory tract T (benign and malignant T of the larynx, trachea or bronchi):

2/48 (4%), 14/48 (29%), 16/48 (33%)

+ NR (tricaprylin, Tween 60/

saline solution); atmospheric dust from Bochum, Germany (particle size < 5 μm)

Hamster, Syrian (M, F)100 wkSellakumar et al. 

(1973)

0 (untreated), 3 mg + 3 mg ferric oxide, 3 mg + 6 mg ferric oxide, 3 mg + 9 mg ferric oxide, once/2 wk, 20 wk36/group, 193 controls/group

Respiratory tract T (M + F combined):

0/193, 26/67 (39%; 3 laryngeal polyp, 3 P, 3 SCC, 7 tracheal polyp, 6 P, 2 SCC, 2 bronchial polyp, 5 SCC, 9 AdC, 1 anaplasic C, 7 lung A, 1 AdC), 28/64 (44%; 1 laryngeal polyp, 3 P, 6 SCC, 3 tracheal polyp, 9 P, 3 SCC, 3 bronchial polyp, 1 P, 4 SCC, 3 AdC, 1 anaplastic C, 7 lung A, 4 AdC), 26/66 (39%; 3 laryngeal polyp, 6 SCC, 6 tracheal polyp, 11 P, 1 SCC, 1 bronchial polyp, 1 P, 4 SCC, 4 AdC, 2 anaplastic C, 6 lung A, 6 AdC) 

Forestomach T:M–0/193 (M + F), 17/32 (53%; 37 P), 10/31 (32%; 16 P, 1 SCC), 6/35 (17%; 15 P)F–0/193 (M + F), 10/35 (29%; 30 P), 12/33 (36%; 25 P), 15/31 (48%; 33 P)

+ NR (0.9% saline solution);

ferric oxide

Hamster, Syrian golden (M, F)Lifetime (up to 120 wk)Stenbäck et al. (1975)

0 (untreated), 2 mg + 1 mg magnesium oxide/animal, once/wk, 20 wk, 3 mg + 3 mg ferric oxide/animal, once/wk, 15 wk48 or 90/group

Respiratory tract tumours (M + F combined): 0/89, 32/45 [71%] (11 laryngeal P, 3 SCC, 1 tracheal polyp, 20 P, 5 SCC, 1 AdC, 1 bronchial P, 3 A, 8 AdC, 9 SCC, 1 AdSC), 31/44 (70%; 10 laryngeal P, 4 SCC, 8 tracheal P, 12 SCC, 2 anaplastic C, 2 bronchial P, 4 A, 2 AdC, 17 SCC, 3 anaplastic C)

+ NR (0.2% saline solution); 

ferric oxide, magnesium oxide

Table 3.1 (continued)
Benzo[a]pyrene

127

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Hamster, Syrian golden (M, F)Lifetime (up to 100 wk)Stenbäck & Rowland (1979)

0 (untreated), 0 (saline), 0 (gelatine in saline), 3 mg silicon dioxide in saline, 1.5 mg manganese dioxide in saline, 3 mg in saline, 3 mg in gelatine/saline, 3 mg + 3 mg silicon dioxide in saline, 1.5 mg + 1.5 mg manganese dioxide in saline/animal, once/wk, 20 wk 50/group

All T (M + F combined): 2/100 (2%; 2 lymphoma), 1/48 (2%; 2 forestomach P), 2/45 (4%; 2 lymphoma), 0/48 (0%), 2/48 (4%; 1 forestomach P, 1 lymphoma), 18/46 (39%; 1 laryngeal P, 1 SCC, 4 tracheal P, 15 forestomach P), 11/47 (23%; 2 tracheal P, 1 SCC, 3 bronchial SCC, 1 splenic haemangioma, 1 adrenal cortical A, 1 lymphoma, 2 forestomach SCC), 25/48 (52%; 1 laryngeal SCC, 8 tracheal P, 2 SCC, 3 bronchial SCC, 6 lung A, 3 AdC, 10 forestomach P, 1 thyroid A, 1 uterine fibroma, 1 A, 1 lymphoma), 20/48 (42%; 1 laryngeal P, 3 tracheal P, 1 SCC, 1 bronchial SCC, 24 forestomach P, 1 ovarian fibroma, 1 thyroid A, 2 forestomach SCC, 1 squamous-cell fibroma)

+ > 99% (saline, 0.5% gelatine 

in saline); manganese dioxide, silicon dioxide

Hamster, Syrian golden (M, F)82 wkReynders et al. (1985)

0 and 8 mg + 6 mg ferric oxide/animal, once/wk, 6 wk

35/group

Respiratory tract T:M–0/32, 12/24 (50%; 15 T: 3 laryngeal P, 1 tracheal P, 1 SCC, 2 bronchial polyp, 2 SCC, 1AdC, 3 pulmonary SCC, 1 AdSC, 1 AdC)

F–0/35, 9/26 (35%; 12 T: 1 laryngeal P, 5 tracheal P, 2 bronchial polyp, 2 pulmonary SCC, 1 AdSC, 1 AdC)

+ NR (0.9% saline solution); 

ferric oxide

Buccal pouch

Hamster, Syrian golden (M)Up to 40–44 wk with interim kills after 5, 20, and 24–32 wkSolt et al. (1987)

Painting of both buccal pouch with 0, 20 mM solution/animal, twice/wk, 20 wk28/group, 20 controls/group

Forestomach P: 0/6, 8/10* (after 40–44 wk)Buccal pouch SCC: 0/6, 1/10 (after 40–44 wk)

*[

P < 0.01] NR (paraffin oil)

Intramammary or intramamillary administration

Rat, Sprague-Dawley (F)20 wkCavalieri et al. (1988a)

0 and 0 (untreated contralateral mammary gland), 4 [1 mg], 16 μmol [4.2 mg] (5th right 

mammary gland), 1 × 20/group

Mammary gland T: [0/20] (0%), [0/20] (0%), [10/20] (50%; 6 AdC, 4 fibroS), [16/20] (80%; 8 AdC, 2 fibroA, 10 fibroS)

+ > 99% (no vehicle)

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

128

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Rat, Sprague-Dawley (F)45 wkCavalieri et al. (1988a, 

b)

0 and 4 μmol [1 mg]/mammary gland (2nd, 3rd, 4th and 5th mammary gland on both sides injected), 1 × 20/group

Epithelial mammary T: [3/20] (15%; 3 fibroA), [14/20] (70%; 13 AdC, 3 fibroA); multiplicity: controls, 3/3 [1]; treated rats: AdC, 18/13 [1.4]; fibroA, 4/3 [1.3]Mesenchymal (mammary) T: [0/20] (0%), [11/20] (55%; 11 fibroS; multiplicity, 20/11 [1.8])Skin T: [0/20] (0%), [9/20] (45%; 9 SCC; multiplicity, 11/9 [1.2])

+ > 99% (trioctanoin)

Rat, Sprague-Dawley (F)24 wkCavalieri et al. (1991)

0, 0.25 [66 μg], 1 μmol [264 μg]/mammary gland (the 2nd, 3rd, 4th and 5th on both sides), 1 × 20/group

Epithelial mammary gland T: 1/18 (6%; 1 fibroA), 1/20 (5%; 1 AdC), 0/20 (0%)

Mesenchymal (mammary) T: 0/18 (0%), 6/20 (30%; 6 fibroS; multiplicity, 7/6), 8/20 (40%; 8 fibroS; multiplicity, 10/8)Skin T: 0/18 (0%), 0/20 (0%), 1/20 (5%; 1 SCC)

+ > 99% (trioctanoin)

Statistics NR

Intracolonic instillation

Mouse, Swiss albino (M, F)120 wkToth (1980)

0, 200, 2000 μg/g bw (total doses); control and high-dose group, 10 × /wk instillations of 0 and 200 μg, respectively; low-dose group, 1 instillation 50/group/sex

Malignant lymphoma:M–0/50, 6/50* (12%; 1 histiocytic, 4 lymphocytic, 1 mixed), 7/50** (14%; 2 histiocytic, 3 lymphocytic, 2 mixed) F–11/49 (22%; 5 histiocytic, 6 lymphocytic), 21/50*** (42%; 5 histiocytic, 16 lymphocytic), 18/49 (36%; 6 histiocytic, 8 lymphocytic, 4 mixed)Oesophagus T:M–no tumourF–0/49, 0/50, 5/49 (10%)Forestomach T:M–0/50, 2/50 (4%; 2 P), 10/50  (20%; 9 P, 1 SCC)F–1/49 (2%; 1 SCC), 5/10 (20%; 3 P, 2 SCC), 11/49** ** (22%; 9 P, 2 SCC)

*P < 0.04

**P < 0.02

***P < 0.053

 P < 0.006** ***P < 0.0001

98% (olive oil)Anal and skin tumours probably due to release of benzo[a]pyrene through the anal orifice

Table 3.1 (continued)
Benzo[

a]pyrene

129

Species, strain (sex)DurationReference

Dosing regimenAnimals/group at start

Incidence of tumours Result or 

significance

Purity (vehicle)Comments

Toth (1980)Contd.

Anal T :M–0/50, 0/50, 7/50** (14%; 4 P, 3 SCC)F–0/49, 1/50 (2%; 1 P), 6/49* (12%; 1 P, 4 SCC, 1 K)Skin T :M–1/50 (2%; 1 K), 0/50, 13/50***** (26%; 5 P, 7 SCC, 1 K)

F–0/49, 2/50 (4%; 2 SCC), 11/49**** (22%; 4 P, 5 SCC, 2 K)

Mouse, C57Bl/6 (F)18 moAnderson et al. (1983)

0 (untreated, olive oil or β-naphthoflavone in olive oil), 1 mg/animal (in olive oil), once/wk, 14 wk45–60/group

Forestomach P: 7/34 (21%; multiplicity, 1.1 ± 0.4), 17/18* (94%; multiplicity, 3.2 ± 2.3*)Peritoneal S: 0/40, 5/32*Lymphoma: 1/40 (2.5%), 9/32* (28%)

*P < 0.05 99% (olive oil, enzyme 

inducer β-naphthoflavone)No colon tumours found

Intravaginal application

Mouse, C57B1 (F)5 moNäslund et al. (1987)

Cotton swab soaked in acetone (controls) or 1% solution of benzo[a]pyrene in acetone, twice/wk10 or 76/group

0/10, 17/76 (22%; invasive cervical C) + NR (acetone)

Intrafetal injection

Mouse, Swiss (M, F)12 wkRossi et al. (1983)

0, 0.4, 4.0, 9.9, 19.8 nmol [0, 0.1, 1, 2.6, 5.2 μg]/animal, 1 × 

43–56/group

Lung A (M + F combined):0/37, 1/39 (3%), 10/42 (25%), 10/38 (26%), 12/31 (39%)

+ > 99%

(trioctanoin-acetone mixture (1:1))

A, adenoma; AdC, adenocarcinoma; AdSC, adenosquamous carcinoma; bw, body weight; C, carcinoma; d, day or days; DMSO, dimethyl sulfoxide; F, female; H, hepatoma; K, keratocanthoma; M, male; min, minute or minutes; mo, month or months; NH OH, ammonium hydroxide; NR, not reported; P, papilloma; PND, postnatal day; S, sarcoma; SCC, 4

squamous-cell carcinoma; SGA, sebaceous gland adenoma; T, tumour; vs, versus; wk, week or weeks; yr, year or years

Table 3.1 (continued)
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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 (DeutschWenzel et al., 1983; Iwagawa et al., 1989; WenzelHartung 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 lungtumour response after intratracheal instillation 

of benzo[a]pyrene than did their similarly treated 

XPA+/+ and XPA+/– counterparts (Ide et al., 2000).

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Table 3.2 Summary of reports of malignant tumours clearly induced in experimental animals by 

benzo[a]pyrene

Organ 

site/ 

species

Lung Trachea Larynx Forestomach Liver Lymphoid 

tissue 

(lymphoma)

Sarcoma 

(injection 

site)

Skin Mammary 

gland

Mouse x x x x x x

Rat x x x

Hamster x x x x x
Benzo[a]pyrene

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 squamouscell 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-diol9,10-epoxides, which form one class of ultimate 

carcinogenic metabolites of benzo[a]pyrene. 

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IARC MONOGRAPHS – 100F

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]pyrene7,8-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 stereo-chemical 

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]pyrene7,8-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, 

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Benzo[a]pyrene

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, antibenzo[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-epoxideN2

-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]pyrenetreated 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-epoxidetreated 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 (MelendezColon 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-diol9,10-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 radicalcation 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]

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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 orthoquinone/ 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]pyrene7,8-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]pyrene1,6-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 antioxidant 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′-diphosphateglucuronosyl 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 

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Benzo[a]pyrene

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), 

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IARC MONOGRAPHS – 100F

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]pyrene7,8-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 radicalcation 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 antibenzo[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-oxodeoxyguanosine 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-DNAadduct levels in white blood cells may be used as 

a surrogate for pulmonary anti-benzo[a]pyrene7,8-diol-9,10-oxide-DNA adducts (Godschalk 

et al., 2000).

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Benzo[a]pyrene

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-diol9,10-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 arylhydrocarbon 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-diol9,10-oxide-DNA adduct. The formation of this 

adduct is consistent with anti-benzo[a]pyrene7,8-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-diol9,10-oxide-DNA adducts induce mutations in 

the K-RAS oncogene and the TP53 tumoursuppressor gene in human lung tumours, and 

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IARC MONOGRAPHS – 100F

in corresponding genes in mouse-lung tumours. 

Exposure to benzo[a]pyrene and benzo[a]pyrenecontaining complex mixtures also induce other 

genotoxic effects, including sister chromatid 

exchange, micronuclei, DNA damage and 8-oxodeoxyguanosine, 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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