I would like to do my final project on benzo(a)pyrene, including it's history, carcinogenic effects, environmental impact, sources, and removal methods.

11/11/10 Possibly expand topic to all polycyclic aromatic hydrocarbons.

Assignment 2:

The article I am summarizing is Fifty years of benzo(a)pyrene, DAVID H. PHILLIPS*

Nature 303, 468 - 472 (09 June 1983); doi:10.1038/303468a0
here is a link to the pdf: http://www.nature.com/nature/journal/v303/n5917/pdf/303468a0.pdf
[Full Marks JCB]

  • In the ninteenth century, skin cancer was common among works in the parrafin refining, shale oil, and coal tar industries. Scientists in Tokyo were able to produce skin cancer in mice by repeatedly painting their ears with coal tar.
  • In the year 1922 E.L. Kennaway, a scientist at the Institute of Cancer research in London, was interested in characterizing the carcinogen in coal tar. After experimentation, he concluded that the carcinogen was a polycyclic aromatic hydrocarbon (PAH) and began experimentation to synthesize the carcinogens found in coal tar.
  • 1924-1926, more scientists joined Kennaway's efforts to synthesize the carcinogen using the Schroeter method, but were unable to able to match florescent bands of the synthetic material with that found in coal tar.
  • The group obtained PAH samples and found that synthetic benz(a)anthracene had similar florescent wavelengths to the carcinogens foudn in coal tar. The group found two more PAHs at intermediate wavelengths between benz(a)anthracene and coal tar. These compounds were able to produce tumors on mice, demonstrating the carcinogenic activity of a single compound.
  • The group progress with making and testing PAH compounds. In 1930 they were able to purify a coal tar carcinogen, a yellow crystalline material of melting point 116C, that showed a florescent band matching that found in their other experiments.
  • Hewett joined the group and was able to further purify the material into two pure compounds and determined them to be benzo(a)pyrene (BP) and benzo(e)pyrene. In April 1933 Cook, Hewett, and Hieger published a paper on their findings, with much ado to Kennaway who initiated their research efforts.
  • In 1939 all the scientist involved (Kennaway, Mayneord, Hewett, Hieger, and cook) won the first Anna Fuller Memorial prize for their accomplishments in cancer research.
Structure and activity
  • During the next decade hundred of PAH's were synthesized and tested for their cancer causing ability. Scientists found that putting methyl substituents into benz(a)anthracene increased potentecy of the carcinogen.
  • In 1935, benzo(a)pyrene was tested in human skin, after a short time of application it was concluded that long term application would be carcinogenic.
  • Scientists tried to correlate the k-region of PAH's (the 9,10 bond of the angular three-ringed phenanthrene unit) to biological activity using qualitative and quantum mechanical methods. Neither theory was correct.
  • It was unable to be proven that epoxide intermediates of PAHs were responsible for their activity. The widely held belief that carcinogenesis by PAHs is due to their physical intercalation into DNA was disproved in 1968.
  • The Millers proposed and tested the central idea for the mechanism of cancer induction by chemicals, which is that carcinogens become electrophilic reactants that react biologically by covalent interaction with macromolecules, the most important being DNA.
Covalent interactions
  • It took a while before the connection of metabolism, covalent bonding and biological activity of BP (and other PAHs) could be made.
  • It was progressively discovered that BP (and other PAHs) bound to protein in mouse skin, rat liver protein, DNA in mouse skin, and rat DNA only (not RNA or proteins), supporting the idea that DNA is the main target for carcinogenesis.
  • With the progression of metabolism studies in the 1960's, it became clear that PAHs could not covalently react on their own, and it was shown by Grover and Sims that BP and PAHs bound to DNA only in the presence of active metabolizing systems.
  • The biological significance of this metabolite activity was not established until 1973 when it was shown that carcinogens are mutagenic to bacteria in the presence of the same metabolizing systems that can catalyse covalent bonging to macromolecules. B.N. Ames tested this in strains of bacteria using BP and other PAHs, which developed into the Ames test which is now used to screen chemical for carcinogenic activity. The focus then shifted to identification of involved metabolites.
K-region epoxides
  • In 1968 Jerina at al provided conclusive evidence of epoxide formation of PAHs.PAHs (BP) form epoxides at the K-region of the molecule, which alludes to the idea that epoxides are the active form of PAHs.
  • Epoxides were found to react with nucleic acids and prtein in the absence of a metabolizing system, but further experimentation showed weaker carcingensis that parents PAHs. It was concluded by Baird et al. that K-region epoxides were not responsible for covalent modification of DNA and PAH's biological activity. Hmm... Now what?
Activation via diol-epoxides
  • The involvement of other unidentified epoxides in covalent bonding to DNA was still a possibility, however, this would not be a simple epoxide because experimental digests of DNA treated with epoxides were more polar than what would be expected after treatment with a simple epoxide.
  • Crocker's laboratory in 1973 gathered data that the metabolite, trans-BP-7,8-dihydrodiol, would be an intermediate in pathway leading to the binding of BP to DNA.
  • More data hinted that epoxides were In 1974, Sims presented data that suggested trans-BP-7,8 was the proximate carcinogen and 7,8-diol-9,10-epoxide was the ultimate carcinogen of BP.
  • The next 5 years were spent determining and verifying the pathway of BP interactiong with DNA. (the pathway is shown in the link below)
  • The pathway is stereoselective, which is indicated by the increases activity of (-)-trans-7,8-BP-dihydrodiol in comparison to its enantiomer.
  • The chemical reactivity of of the syn configuration and anti configuration of trans-7,8-BP-dihydrodiol show that syn-diol-epoxide will open up to form electrophilic carbonium ion more easily than the anti-diol-epoxide.
  • Mutagenicity studies indicate that syn-isomers are more potent mutagens in S.typhimurium less potent in mammilian cell lines.
  • The (+)-anti-isomer and the (-)-syn-isomer are more mutafenic than their respective enantiomers. All the isomers show less activity than BP when applied topically to mouse skin.
  • Physiochemical studies indicate that BP-diol-epoxides react mostly with guanine residues. Adducts formed in tissues or cells treated with BP are derivied predominantly from the (+)-anti-diol-epoxide.
  • How the mutagenic or carcinogenetic event is caused is not surely known. A minor product of BP diol-epoxide DNA interaction may be responsible, the 35 degree angle between bound diol-epoxide forms a grove that hold the carcinogen, such a conformation would cause minimal distortion of the double helix.
  • Inversion of the guanine in the DNA could cause mutation by mispairing the neucleotide with another guanine. Several binding conformations occur, some may result in a permanently altered phenotype.
  • The C-10 position of BP is adjecent to the "bay region" (the angel between the benzo rings fused in nonlinear arrangement. bordered by the 10- and 11- positions), this may lead to a more readily formed carbonium ion, leading to greater reactivity.
  • BP-7,8-diol-9,10-epoxides are probably poor substrates for epoxide hydrolase and thus are not readily detoxified, although there may be other factors that influence this.
The risk to humans
  • BP is a standard to which new systems can be evaluated, such as assays of tissues and cells ability to metabolize BP. HPLC can be used to assay complex mixtures of metabolites,
  • Exposure to PAHs, environemntal pollutants, is unavoidable, s they are combusted by different sources into air. They can cause caner, but some people may be more susceptible than others.More data is needed to draw more conclusions on the rish of BP and other PAHs to humans.
  • Addendum:
    • PAHs have been studied in the treatment of cancer, some studies showed tumor regression after treatment with BP in advanced cases or the inhibition of malignancy after treatment with 3-methylcholanthrene.

Final Project

  1. Fifty years of benzo(a)pyrene, DAVID H. PHILLIPS*Nature 303, 468 - 472 (09 June 1983); doi:10.1038/303468a0 pdf: http://www.nature.com/nature/journal/v303/n5917/pdf/303468a0.pdf

  2. Carcinogenic substances and their fluorescence spectra BMJ 1930; 1 : 1044 doi: 10.1136/bmj.1.3622.1044 (Published 7 June 1930) Pdf:http://www.bmj.com/content/1/3622/1044.full.pdf+html
  3. The formation of polyaromatic hydrocarbons, fullerenes and soot in combustion: pyrolytic mechanisms and the industrial and environmental connection.
    Gas Phase Reactions in Organic Synthesis (1997), 143-194. Publisher: (Gordon&Breach, Amsterdam, Neth) CODEN:66INAR Google Book:
  4. Biodegradation of toxic and environmental pollutants.
    Current opinion in biotechnology (1991), 2, (3), 429-35. ISSN:0958-1669. pdf:
  5. The critical DNA damage by benzo[a]pyrene in lung tissues of smokers and approaches to preventing its formation.
    Toxicology Letters (2010), 198, (1), 63-68. Publisher: (Elsevier Ireland Ltd., ) CODEN:TOLED5 ISSN:0378-4274. pdf:
  6. Noncovalent Interactions of a Benzo[a]pyrene Diol Epoxide with DNA Base Pairs: Insight into the Formation of Adducts of (+)-BaP DE-2 with DNAJ.
  7. Forrest, Martin (2009). Food Contact Materials - Rubbers, Silicones, Coatings and Inks. (pp: 116). Smithers Rapra Technology. Online version available at: http://knovel.com/web/portal/browse/display?_EXT_KNOVEL_DISPLAY_bookid=2608&VerticalID=0
  8. Preliminary Feasibility Study of Benzo(a)Pyrene Oxidative Degradation by Fenton Treatment
  9. "Persistent Bioaccumulative and Toxic (PBT) Chemical Program - Benzo(a)pyrene." US Environmental Protection Agency. Web. 29 Nov. 2010. <http://www.epa.gov/pbt/pubs/benzo.htm>.
  10. Polycyclic Aromatic Hydrocarbons – Occurrence in foods, dietary exposure and health effects pdf: http://ec.europa.eu/food/fs/sc/scf/out154_en.pdf
  11. FAQ- Delaware Health and social services, Department of Public Health - Benzo(a)Pyrene pdf: http://www.dhss.delaware.gov/dhss/dph/files/benzopyrenefaq.pdf
  12. Toxicity of Polycyclic Aromatic Hydrocarbons (PAHs) What Are Polycyclic Aromatic Hydrocarbons (PAHs) http://www.atsdr.cdc.gov/csem/pah/pah.html
  13. 106. The isolation of a cancer-producing hydrocarbon from coal tar. Parts I, II, and III
    J. W. Cook, C. L. Hewett and I. Hieger, J. Chem. Soc., 1933, 395
    DOI: 10.1039/JR9330000395
  14. Title: Immunotoxicity of polyaromatic hydrocarbons Author: Ladics, Gregory link: http://illiad.library.drexel.edu:8000/224387.pdf
  15. A screen for benzo(a)pyrene in fis samples from crude oil polluted environments pdf:http://www.scipub.org/fulltext/ajes/ajes42145-150.pdf
  16. http://www.sciencedirect.com.ezproxy2.library.drexel.edu/science?_ob=MImg&_imagekey=B6V3W-40SFGYV-B-3W&_cdi=5741&_user=95578&_pii=S0360128500000095&_origin=search&_coverDate=08/31/2000&_sk=999739995&view=c&wchp=dGLbVzW-zSkzk&md5=5d119772dd5a629cb2504e14936cd19a&ie=/sdarticle.pdf [Do you need help to convert this to a proper DOI? JCB]
  17. http://www.worldlingo.com/ma/enwiki/en/Incineration
  18. Benzo-a-Pyrene: Environmental Partitioning and Human Exposure http://tih.sagepub.com.ezproxy2.library.drexel.edu/content/7/3/141.abstract
  19. Basic Information about Benzo(a)pyrene in Drinking Water http://water.epa.gov/drink/contaminants/basicinformation/benzo-a-pyrene.cfm
  20. Analysis of DNA and protein adducts of benzo[a]pyrene in human tissues using structure-specific methods pdf:http://www.sciencedirect.com.ezproxy2.library.drexel.edu/science?_ob=MImg&_imagekey=B6T2G-4778GY4-1-4&_cdi=4918&_user=95578&_pii=S1383574202000686&_origin=search&_coverDate=01/31/2003&_sk=994569998&view=c&wchp=dGLzVtz-zSkWA&md5=a0fbf51b7dcfbe9e77b4e32d17263d84&ie=/sdarticle.pdf
  21. Polycyclic aromatic hydrocarbon-DNA adducts in humans: relevance as biomarkers for exposure and cancer risk pdf:http://www.sciencedirect.com.ezproxy2.library.drexel.edu/science?_ob=MImg&_imagekey=B6T2C-3X4W734-22-3&_cdi=4915&_user=95578&_pii=S0027510798000657&_origin=search&_coverDate=05/25/1998&_sk=995999998&view=c&wchp=dGLzVlz-zSkzS&md5=42ab6577da373184b3390cb6f446f404&ie=/sdarticle.pdf
  22. Biodegradation aspects of Polycyclic Aromatic Hydrocarbons (PAHs): A review pdf:http://www.sciencedirect.com.ezproxy2.library.drexel.edu/science?_ob=MImg&_imagekey=B6TGF-4W15KWY-D-C&_cdi=5253&_user=95578&_pii=S0304389409005494&_origin=search&_coverDate=09/30/2009&_sk=998309998&view=c&wchp=dGLbVlW-zSkWA&md5=8109588e5e8c21cf21c90fa3e697f668&ie=/sdarticle.pdf
  23. doi:10.1021/es00051a002
  24. doi:10.1016/j.jhazmat.2006.01.006 carpet-dyign fenton treatment


Intro of Poly Aromatic Hydrocarbons
7, 10 (page 11 has good data on BaP)

Discovery of Benzo(a)Pyrene
  • fluorescence analysis: 2

Sources and production of Benzo(a)Pyrene

Mechanism of Carcinogenesis- reactivity with DNA

Environmental Impact- Bioaccumlation

Removal methods

Assignment 1: 5 properties


I Melting Point:
  1. -38 C
  2. -38.30 C
  3. -38.21 C
  4. -38.3 C
  5. -38 C

II Density at 20 C:
  1. 1.066
  2. 1.0644
  3. 1.06485
  4. 1.0581
  5. 1.0649

III Boiling Point at 760mm:
  1. 84.12 C
  2. 84.4 C
  3. 84.0 C
  4. 84 C
  5. 84 C

IV Index of Refraction:
  1. 1.529
  2. 1.5280
  3. 1.5287
  4. 1.5287
  5. 1.527-1.529

V Flash Point:
  1. -1 C
  2. -9 C
  3. -9 C
  4. -9 C
  5. -1 C