At seven weeks, females given 1.0 mg of benzo[a]pyrene (B[a]P) showed a statistically significant reduction in comparison to controls. In female A/J mice, benzo[a]pyrene-induced lung cancer was dose-dependent. When females treated with 0.25, 0.50, and 1.0 mg of benzo[a]pyrene were compared to the control group, the incidence of hyperplasia was considerably higher. Compared to controls, the incidence of adenomas was considerably greater in females given 1.0 mg of benzo[a]pyrene. Compared to controls, females given 0.50 or 1.0 mg of benzo[a]pyrene exhibited a much higher diversity of growths. In comparison to the control group, the group receiving 1.0 mg treatment had a significantly higher diversity of adenomas. In female A/J mice, benzo[a]pyrene dose-dependently elevates the incidence of hyperplasia and adenoma [1]. When compared to the control, benzo[a]pyrene caused an average of 9.38±1.75 tumors and an average tumor burden of 19.53±3.81 mm3 (P<0.05). Treatment with benzo[a]pyrene considerably (P<0.05) decreased the levels of cAMP in tumors that were next to lung tissue. When benzo[a]pyrene is administered, the PDE4D gene's expression level likewise rises [2].

Absorption, Distribution and Excretion
... Readily absorbed from the intestinal tract and tend to localize primarily in body fat and fatty tissues such as breast. Disappearance of Benzo(a)Pyrene from blood and liver of rats following single IV injection is very rapid, having a half-life in blood of less than 5 min and a half-life in liver of 10 min. In ... blood and liver ... initial rapid elimination phase is followed by slower disappearance phase, lasting 6 hr or more ... A rapid equilibrium is established between BaP in blood and that in liver and ... the cmpd fast disappearance from blood is due to ... metabolism and distribution in tissues.
BaP crosses the placenta in mice & rats ... .
(14)C metabolites were secreted into bile of rats within 7 min of iv dose of (14)C-benzo[a]pyrene. Pretreatment of animals with this carcinogen ... enhanced biliary secretion of (14)C.
Male rats cannulated in the bile duct received iv injections of radiolabeled benzo[a]pyrene (BaP) noncovalently bound to the very-low-density, low-density, or high-density lipoproteins in equimolar amounts. Cumulative biliary excretions of BaP complexed with rat lipoproteins were 39.6, 24.6, and 21.2% for very-low density, low-density, and high-density lipoprotein, respectively. Values for excretion of BaP complexed with rat or human lipoproteins were comparable. Excretion increased as the degree of BaP hydroxylation increased. The excretion of BaP bound to very-low-density, low-density, or high-density lipoproteins in Aroclor-induced rats was not greater than the control. Hence, 60-80% of injected BaP and 50-60% of injected BaP metabolites were not excreted immediately in control or induced animals. Thus BaP may represent a carcinogen pool that is slowly excreted.
For more Absorption, Distribution and Excretion (Complete) data for Benzo(a)pyrene (16 total), please visit the HSDB record page.

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Metabolism / Metabolites
/It was/ demonstrated that macrophages were the primary cell type in a splenic leukocyte preparation capable of metabolizing /benzo[a]pyrene/ BaP to 7,8-dihydroxy-9,10-epoxy-benzo[a]pyrene (BPDE), the reactive metabolite proposed to be the ultimate carcinogenic and immunotoxic form of BaP.
Human liver microsomal fractions from 13 different individuals were characterized ... . Pronounced interindividual differences in the composition of microsomal proteins in the mol wt range of 49,000-60,000 were found. Most of the variations among profiles of microsomal proteins are interindividual differences in the composition of isoenzymes of cytochrome P450. Large variations among the human liver microsomal samples were seen in benzo[a]pyrene metabolism. The results indicate the presence of 7-8 different forms of cytochrome P450 in human liver microsomes and interindividual variations seen in drug metabolism may at least in part be explained by variations in the distribution of these isoenzymes.
Colonic biopsy specimens from patients with ulcerative colitis and normal subjects were studied for the ability to metabolize benzo[a]pyrene. Approx 73% of 30 colonic biopsy specimens from 7 ulcerative colitis patients could metabolize benzo[a]pyrene to oxidized products, with an average production of 11.6 nmol/mg biopsy protein. In contrast, 39% of 23 biopsy specimens from 5 normal persons showed an average metabolic activity, 2.79 nmol. Benzo[a]pyrene oxidation activity in colonic tissue from colitis patients was, on the average, fourfold greater than that in normal subjects. This study suggest that the colonic mucosa of patients with ulcerative colitis has a greater ability than that of normal subjects to oxidize such chemicals possibly to electrophiles with higher mutagenic potential.
Benzo[a]pyrene is metabolized to approximately 20 primary and secondary oxidized metabolites and to a variety of conjugates. Several metabolites can induce mutations, transform cells and/or bind to cellular macromolecules; however only a 7,8-diol-9,10-epoxide is presently considered to be an ultimate carcinogenic metabolite.
For more Metabolism/Metabolites (Complete) data for Benzo(a)pyrene (24 total), please visit the HSDB record page.
Benzo[a]pyrene has known human metabolites that include Benzo[a]pyrene-7,8-epoxide, Benzo[a]pyrene-4,5-epoxide, 9-Hydroxybenzo[a]pyrene, 1-Hydroxybenzo[a]pyrene, and 3-Hydroxybenzo[a]pyrene.
PAH metabolism occurs in all tissues, usually by cytochrome P-450 and its associated enzymes. PAHs are metabolized into reactive intermediates, which include epoxide intermediates, dihydrodiols, phenols, quinones, and their various combinations. The phenols, quinones, and dihydrodiols can all be conjugated to glucuronides and sulfate esters; the quinones also form glutathione conjugates. (L10)

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Biological Half-Life
... /In mice/ hydrocarbon/deoxyribonucleoside adduct showed approx parallel dose-response curves. The half-life of the BaP/deoxyribonucleoside adducts and the total radioactivity bound to the DNA were 4.5 and 5.5 days ...
(14)C-Benzo[a]pyrene (1 mg/kg) was metabolized and excreted very slowly after intracardial administration to lobsters. The half-life for disappearance of radiolabel was approximately 2 mo, and most of the radioactivity was stored in the hepatopancreas. Similar studies in the spiny lobster demonstrated that metab and excretion were considerably faster in this species (half-life approximately 1 wk in the summer and approximately 2 wk in the winter).
... mussels were exposed to [(3)H]-BaP or [(14)C]-BaP either injected or via the surrounding water, and the tissue distribution of radiolabeled compound was studied. The half-life of BaP was 15-17 days and unaffected by the food concentration.
Disappearance of Benzo(a)Pyrene from blood and liver of rats following single iv injection is very rapid, having a half-life in blood of less than 5 min and a half-life in liver of 10 min.

Toxicity Summary
IDENTIFICATION AND USE: Benzo[a]pyrene (BaP) is a five-ring polycyclic aromatic hydrocarbon (PAH). Benzo[a]pyrene (along with other PAHs) is released into the atmosphere as a component of smoke from forest fires, industrial processes, vehicle exhaust, cigarettes, and through the burning of fuel (such as wood, coal, and petroleum products). HUMAN EXPOSURE AND TOXICITY: Epidemiology studies involving exposure to PAH mixtures have reported associations between internal biomarkers of exposure to benzo[a]pyrene (benzo[a]pyrene diol epoxide-DNA adducts) and adverse birth outcomes (including reduced birth weight, postnatal body weight, and head circumference), neurobehavioral effects, and decreased fertility. In addition, there is strong evidence of carcinogenicity in occupations involving exposure to PAH mixtures containing benzo[a]pyrene, such as aluminum production, chimney sweeping, coal gasification, coal-tar distillation, coke production, iron and steel founding, and paving and roofing with coal tar pitch. An increasing number of occupational studies demonstrate a positive exposure-response relationship with cumulative BaP exposure and lung cancer. BaP was mutagenic in human MCL-5 cells. Accumulation of BaP in blood plasma of coking workers played a major role in the formation of lymphocyte micronucleus. The characteristics of chromosomal aberrations induced in vitro by activated benzo[a]pyrene diol epoxide (BPDE) in lymphocyte cultures of 172 normal individuals ages 19-95 years were described. The BPDE-induced chromosomal aberrations were predominantly single chromatid breaks, with few isochromatid breaks or exchange figures. 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 tumorsuppressor gene in human lung tumors, and in corresponding genes in mouse-lung tumors. ANIMAL STUDIES: Animal studies demonstrate that exposure to benzo[a]pyrene is associated with developmental (including developmental neurotoxicity), reproductive, and immunological effects. Studies in multiple animal species demonstrate that benzo[a]pyrene is carcinogenic at multiple tumor sites (alimentary tract, liver, kidney, respiratory tract, pharynx, and skin) by all routes of exposure. BaP is primarily metabolized to diol epoxides, which react principally at N2-dG in DNA. BaP-N2-dG adducts have been shown to induce a variety of mutations, notably G-->T, G-->A, G-->C and -1 frameshifts. Oral exposure to BaP causes spermatogonial stem cell mutations in mice. ECOTOXICITY STUDIES: Thirty-four ducks were given single intratracheal dose of 50-200 mg benzo(a)pyrene. Survival rate was poor. One duck developed a lung carcinoma, and two had bronchial squamous metaplasia. Histological and skeletal examinations were performed on rainbow trout alevins reared in 0.00, 0.08, 0.21, 0.39, 1.48, 2.40, or 2.99 ng/mL aqueous benzo[a]pyrene (BaP). Nuclear pycnosis and karyorrhexis were most common in neuroectodermal and mesodermal derivatives and in liver of BaP-treated alevins. Microphthalmia was noted in 17% of the test fish and was frequently associated with a patent optic fissure. Depressed mitotic rates in the retina and brain, but not liver, were seen in alevins reared in 0.21 to 1.48 ng/mL aqueous BaP. Test alevins had a significantly higher incidence of skeletal malformations in the skull and vertebral column and abnormalities of vertebral arcualia often corresponded to areas of kyphoscoliotic flexures. In the purple sea urchin (Strongylocentrotus purpuratus) teratogenic effect were related to embryonic cytotoxicity and genotoxicity as evidenced by the presence of aberrant chromosome arrangements during mitosis. Developmental abnormalities were observed in gastrulae treated with initial benzo(a)pyrene concentrations of 1-50 ng/mL.
The ability of PAH's to bind to blood proteins such as albumin allows them to be transported throughout the body. Many PAH's induce the expression of cytochrome P450 enzymes, especially CYP1A1, CYP1A2, and CYP1B1, by binding to the aryl hydrocarbon receptor or glycine N-methyltransferase protein. These enzymes metabolize PAH's into their toxic intermediates. The reactive metabolites of PAHs (epoxide intermediates, dihydrodiols, phenols, quinones, and their various combinations) covalently bind to DNA and other cellular macromolecules, initiating mutagenesis and carcinogenesis. The main carcinogenic metabolite of benzo(a)pyrene is the diol-epoxide trans-9,10-epoxy-7,8-dihydrodiol. (L10, L23, A27, A32)

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Toxicity Data
LD50: 250 mg/kg (Intraperitoneal, Mouse) (L138)

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Interactions
The results of both the Salmonella/microsome mutagenicity assay and HPLC analysis were used to evaluate the interactions of binary mixtures of benzo[a]pyrene and several different polychlorinated aromatic hydrocarbons. Binary mixtures of either 2-nitro-3,7,8-trichlorodibenzo-p-dioxin or pentachlorophenol with benzo[a]pyrene produced synergism, whereas strictly additive effects were observed with mixtures of octa- or heptachlorodibenzo-p-dioxin and benzo[a]pyrene. ... HPLC analysis of the mixtures indicated that preincubation of benzo[a]pyrene with 2-nitro-3,7,8-trichlorodibenzo-p-dioxin increased the quantity of benzo[a]pyrene-7,8-dihydrodiol, and 9,10-dihydrodiol metabolites detected. The data suggest that nonmutagenic components of a complex mixture may alter the metabolism of promixate mutagens. Thus, in the present study, 2-nitro-3,7,8-trichlorodibenzo-p-dioxin appears to have inhibited the detoxication of benzo[a]pyrene metabolites.
Investigators/ have recently found that transition metals, such as nickel and chromium, and oxidative stress induced lipid peroxidation metabolites such as aldehydes can greatly inhibit nucleotide excision repair (NER) and enhance carcinogen-induced mutations. Because particulate matter(PM) is rich in metal and aldehyde content and can induce oxidative stress, /the authors/ tested the effect of PM on DNA repair capacity in cultured human lung cells using in vitro DNA repair synthesis and host cell reactivation assays. PM greatly inhibits NER for ultraviolet (UV) light and benzo[a]pyrene diol epoxide (BPDE) induced DNA damage in human lung cells. /The authors/ further demonstrated that PM exposure can significantly increase both spontaneous and UV-induced mutagenesis. These results together suggest that the carcinogenicity of PM may act through its combined effect on suppression of DNA repair and enhancement of DNA replication errors. /Benzo(a)pyrene diol epoxide/
In this study we investigated effects of titanium dioxide nanoparticles (TiO2NP) on the blue mussel (Mytilus edulis) and determined their influence on the bioavailability and toxicity of benzo(a)pyrene (B(a)P), a carcinogenic polyaromatic hydrocarbon (PAH). Blue mussels were exposed to either TiO2NP (0.2 and 2.0 mg/L) or B(a)P (20 ug/L) and to the respective combinations of these two compounds. Aqueous contaminant concentrations, the uptake of Ti and B(a)P into mussel soft tissue, effects on oxidative stress and chromosomal damage were analyzed. The uncoated TiO2NP agglomerated rapidly in the seawater. The presence of TiO2NP significantly reduced the bioavailability of B(a)P, shown by lowered B(a)P concentrations in exposure tanks and in mussel tissue. The activities of antioxidant enzyme superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were impacted by the various exposure regimes, indicating oxidative stress in the contaminant exposure groups. While SOD activity was increased only in the 0.2TiO2NP exposure group, CAT activity was enhanced in both combined exposure groups. The GPx activity was increased only in the groups exposed to the two single compounds. In hemocytes, increased chromosomal damage was detected in mussels exposed to the single compounds, which was further increased after exposure to the combination of compounds. In this study we show that the presence of TiO2NP in the exposure system reduced B(a)P uptake in blue mussels. However, since most biomarker responses did not decrease despite of the lower B(a)P uptake in combined exposures, the results suggest that TiO2NP can act as additional stressor, or potentially alters B(a)P toxicity by activation.
Groups of 20 female Fischer 344 rats (aged unspecified) received implants of beeswax pellets containing either 1 mg benzo(a)pyrene, 0.5 mg benzo(a)pyrene, 1 mg benzo(e)pyrene (purity unspecified), 0.5 mg benzo(a)pyrene + 1 mg benzo(e)pyrene, or 1 mg benzo(a)pyrene + 1 mg benzo(e)pyrene in tracheas from isogenic donors transplanted subcutaneously in the retroscapular region (two tracheas/animal). All surviving animals were killed 28 months after the start of exposure. Benzo(e)pyrene did not induce tumors in tracheal explants, while 1 mg benzo(a)pyrene induced carcinomas in 65% of the grafts. Benzo(e)pyrene appeared to reduce the incidence of carcinomas from 65% (benzo(a)pyrene alone) to 40% (benzo(a)pyrene plus benzo(e)pyrene). However, the incidence of sarcoma in tracheal and peritracheal explants was enhanced two- to three-fold by benzo(e)pyrene given with benzo(a)pyrene compared with benzo(a)pyrene alone.
For more Interactions (Complete) data for Benzo(a)pyrene (76 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse ip about 250 mg/kg

[1]. Dosimetry for lung tumorigenesis induced by urethane, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo[a]pyrene (B[a]P) in A/JJmsSlc mice. J Toxicol Pathol. 2017 Jul; 30(3): 209–216.

[2]. Roflumilast treatment inhibits lung carcinogenesis in benzo(a)pyrene-induced murine lung cancer model. Eur J Pharmacol. 2017 Oct 5;812:189-.

[3]. Pharmacokinetics of low doses of benzo [a] pyrene in the rat. Food and chemical toxicology, 1988, 26(1): 45-51.

[4]. Capsaicin inhibits benzo(a)pyrene-induced lung carcinogenesis in an in vivo mouse model. Inflamm Res. 2012 Nov;61(11):1169-75.

[5]. Benzo(a)pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention. Pharmacol Rep. 2015 Oct;67(5):996-1009.

Therapeutic Uses
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Benzo(a)pyrene is included in the database.
/EXPL THER/ A 1% soln of benzo[a]pyrene in benzene was applied daily to protected and unprotected surfaces of skin of 26 patients suffering from pemphigus vulgaris, mycosis fungoides, prokeratosis, xeroderma pigmentosum, basal cell cancer, squamous cell cancer, lupus erythematosis, psoriasis, syphilis in various stages, or ringworm. The period of application did not exceed 4 mo, and diam of treated area was 2 cm. A progressive series of alterations developed in normal skin (chronically): erythema, pigmentation, desquamation, formation of verrucae, /clinically not true verrucae/ and infiltration. The manifestations regressed completely within 2 to 3 mo of cessation of treatment. Clinically, perceptible erythema occurred in only 2 patients with basal cell cancer. Pigmentation, which occurred in all patients, consisted of an increase in melanin in basal cell layer of epidermis and was more evident in exposed skin (eg, hand, face). It developed more readily in skin of senile individuals than in younger patients. Rarely, small masses of pigment granules were found in the more superficial layers. Desquamation was proportional in extent to erythema of the 1st stage. The formation of verrucae was the most constant manifestation caused by treatment. The skin of patient with xeroderma pigmentosum did not react differently ... from that of other patients.

C20H12

252.3093

252.093

50-32-8

2336

Light yellow to yellow solid powder

1.3±0.1 g/cm3

495.0±0.0 °C at 760 mmHg

177-180°C

228.6±13.7 °C

0.0±0.6 mmHg at 25°C

1.887

6.4

0

0

0

20

372

0

FMMWHPNWAFZXNH-UHFFFAOYSA-N

InChI=1S/C20H12/c1-2-7-17-15(4-1)12-16-9-8-13-5-3-6-14-10-11-18(17)20(16)19(13)14/h1-12H

benzo[a]pyrene

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 25 mg/mL (~99.08 mM)

Solubility in Formulation 1: ≥ 1.67 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 1.67 mg/mL (6.62 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 5 mg/mL (19.82 mM) in 1% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication (<50°C).
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)