Benzo(c)fluorene

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The correct title of this article is Benzo[c]fluorene. The substitution of any brackets is due to technical restrictions.
Benzo[c]fluorene
Benzocfluorene.svg
Benzocfluorene 3D structure.png
Names
Preferred IUPAC name
7H-Benzo[c]fluorene
Other names
Tetracyclo[8.7.0.02,7.012,17]heptadeca-1,3,5,7,9,12,14,16-octaene[ citation needed ]
Identifiers
ChEBI
ChemSpider
ECHA InfoCard 100.005.372 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 205-908-2
KEGG
PubChem CID
UNII
Properties
C17H12
Molar mass 216.283 g·mol−1
Density 1.185 g/cm3
Melting point 125–127 °C (257–261 °F; 398–400 K) predicted
Boiling point 398 °C (748 °F; 671 K) predicted
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Benzo[c]fluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. [1] The mutagenicity of benzo[c]fluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. [2] According to the KEGG it is a group 3 carcinogen (not classifiable as to its carcinogenicity to humans). [3] Other names for benzo[c]fluorene are 7H-benzo[c]fluorene, 3,4-benzofluorene, and NSC 89264. [4] [5]

Contents

Structure and reactivity

The structure of benzo[c]fluorene is depicted in the infobox on the right. It is an aromatic fluorene-derived molecule with an extra benzene ring. This benzene ring is attached to carbon 3 and 4 of the fluorene-derived molecule. The 3D structure of benzo[c]fluorene is depicted in the infobox on the right as well. It is mostly flat, because it consists of 3 aromatic rings. Only the 2 hydrogen atoms on the 5 ring are oriented into the 3D plane.

Synthesis

An example of a DNA adduct (at center), in this case the metabolite of benzo[a]pyrene, another PAH. Benzopyrene DNA adduct 1JDG.png
An example of a DNA adduct (at center), in this case the metabolite of benzo[a]pyrene, another PAH.

Benzo[c]fluorene occurs naturally in tar, but can also be manually synthesized in a four step process, which is depicted in the picture below. The starting product is 1-indanone (1). This is brominated in a substitution reaction to 3-bromoindanone (2) using the reagent N-bromosuccinimide. This substance is dehydrobrominated to 2H-inden-1-one (3) using the reagent triethylamine. Benzo[c]fluorenone-9 (4) is generated by self-condensation of 2H-inden-1-one, when heated. The final step is reduction of this compound with hydrazine hydrate, generating benzo[c]fluorene (5). [7]

Synthesis of benzo[c]fluorene Benzocfluorene synthesis.png
Synthesis of benzo[c]fluorene

Metabolism

In general PAH carcinogenesis involves activation by the enzyme P-450 to diol epoxide metabolites with an epoxide ring in the bay or fjord region. These diol epoxide metabolites are reactive and capable of forming DNA adducts (see the adjacent image). While benzo[c]fluorene does not have a bay or fjord region it does undergo a similar transformation with a pseudo-bay region that reacts instead. The type of cytochrome P 450 involved is thought to be CYP1A1. [8]

The biotransformation is depicted in the image below. First benzo[c]fluorene (1) is transformed into trans-3,4-dihydrodiol (2). This substance is transformed by CYP1A1 into the highly carcinogenic metabolites anti-diolepoxide (3) and syn-diolepoxide (4). [2]

Metabolism of benzo[c]fluorene Benzocfluorene metabolism.png
Metabolism of benzo[c]fluorene

ADME of benzo[c]fluorene and PAHs in general

Absorption

Benzo[c]fluorene and PAHs in general are mostly absorbed via ingestion, inhalation, and dermal contact. Also, depending on the vehicle (transport medium) in which the PAHs are located, the percentages of absorption can differ. Ingestion of benzo[c]fluorene makes it a very potent lung tumorigen [9] In particular, benzo[c]fluorene is better absorbed in the lungs. [10]

Distribution

Once it is absorbed, benzo[c]fluorene enters the lymph, circulates in the blood and is metabolized. The distribution of PAHs depends on their lipophilicity and probably benzo[c]fluorene can easily cross the cell membrane, because of this lipophilicity. This has been proven for similar substances like fluorene and fluoranthene, but has yet to be investigated for benzo[c]fluorene. [11]

Metabolism and excretion

Benzo[c]fluorene is mainly metabolized by the CYP enzymes in the liver. There is also evidence that a larger number of metabolites are formed in the lungs, which might explain why benzo[c]fluorene is such a potent lung tumorigen. It is possible that benzo[c]fluorene may have a unique (and still unknown) mechanism of activation or transportation, which explains why the lungs are targeted. [9] The initial steps of the metabolism, the phase I biotransformation, are described above.

For many PAHs it has been proven that they are conjugated, in phase II, with either glucuronide, sulfate or glutathione. More research on this topic is necessary for benzo[c]fluorene. Glucuronide and sulfate conjugates of PAH metabolites are generally excreted in the bile and urine. Glutathione conjugates are further metabolized to mercapturic acids in the kidney and are excreted in the urine. The hydroxylated metabolites of the PAHs are excreted in human urine both as free hydroxylated metabolites and as hydroxylated metabolites conjugated to glucuronic acid and sulfate. [8]

Mechanism of action

The carcinogenic metabolites of benzo[c]fluorene bind to DNA which involves the opening of the epoxide ring in benzo[c]fluorene anti- and syn-diolepoxide. The benzo[c]fluorene metabolites bind in a yet unknown fashion to the DNA.

When a DNA adduct forms at a site critical to the regulation of cell differentiation or growth it can cause cancer. If an aberration in the DNA is not well repaired by the NER, a mutation will occur during cell replication. In addition, it is known that the cells affected most appear to be those with rapid replication, such as bone marrow, skin, and lung tissue, whereas tissues with slower turnover rate like the liver are less susceptible. [1] [2]

Exposure to benzo[c]fluorene in vivo leads to the induction of mainly lung tumors where it acts as a DNA adductor. Lung tumors arise after topical application in mice with coal tar, but also when it is ingested. Next to its involvement in lung tumors, benzo[c]fluorene and its metabolites are expected to be involved in the formation of different tumors. The formation of DNA adducts in human breast tumors, hepatoma and colon adenocarcinoma by these metabolites has been shown in vitro. These adducts and the ones that were observed in lung tumors of mice were similar, which strengthens the hypothesis that human cells are capable of forming the mutagenic metabolites. [9] [12]

Environmental exposure

Benzo[c]fluorene belongs to a group of compounds called polycyclic aromatic hydrocarbons (PAHs). PAHs and their derivatives are ubiquitous in the environment and they are produced in several industrial and combustion processes. [13]

Workers in industries or trades using or producing coal, crude oil or coal products are at highest risk for PAH exposure. In general, the PAHs are formed during these industrial processes by incomplete combustion or pyrolysis of organic matter. The higher the temperature the more PAHs are formed. [14]

Some of these PAHs, such as benzo[c]fluorene, are carcinogens and mutagens and act as possible endocrine disruptors. To estimate the health effects that arise from exposure to PAHs and benzo[c]fluorene it is necessary to determine the concentration of these compounds in the atmosphere. This was done in a study by Morisaki et al. 2016. They compared the concentrations of different PAHs including benzo[c]fluorene in Beijing and Kanazawa in winter and summer.

Concentrations of benzo[c]fluorene and some other PAHs in air in Beijing and Kanazawa and the relative potency of these PAHs. [13]
RPF
Beijing
Kanazawa
winter
summer
winter
summer
pg/m3
BaPeq
pg/m3
BaPeq
pg/m3
BaPeq
pg/m3
BaPeq
Fluorene
0.08
46000±28000
3.7
550±140
0.04
160±72
0.013
57±22
0.005
B[a]P
1
27000±20000
26.9
960±320
0.96
93±49
0.093
99±18
0.099
B[c]F
20
11000±6100
215.5
40±12
0.79
13±5
0.254
2.7±0.52
0.053
...
Total
360000±23000
292.8
8500±2100
3.05
1600±710
0.58
890±170
0.29

The researchers corrected for the relative mutagenicity of compounds compared to benzo[a]pyrene. [15] The results of this are presented as BaPeq, which equals the concentration of the compound, times the potency of the compound compared to benzo[a]pyrene (RPF). Although the concentrations measured of benzo[c]fluorene are quite low, when corrected for mutagenicity, benzo[c]fluorene is the most important PAH of those that were measured in terms of possible health risks. [13]

Safety

Carcinogenity

In one study, the Ames test was performed on benzo[c]fluorene. Two different strains were used, TA100 and TA98. One group of each strain had a rat liver fraction and one group did not. The difference between the TA100 and the TA98 strain is that the TA98 strain has a frameshift mutation, and the TA100 has a base substitution mutation. When the amount of benzo[c]fluorene is increased in TA 100 yeast strain, the amount of revertants per plate does not increase. Only in the TA98 strain plate, which contained a fraction of a rat liver, a higher dose of benzo[c]fluorene seems to correspond with a larger amount of revertants. This indicates that benzo[c]fluorene is metabolized by enzymes in the rat liver into more potent mutagenic compounds. These compounds only affected the TA98 strain. This indicates that the adducts formed by benzo[c]fluorene metabolites cause frameshift mutations, and not point mutations. [16]

Dose response benzo c fluorene.png Ames test benzo c fluorene.png
Dose response curve of benzo[c]fluorene was applied to the skin of mice. Data derived from [17] Ames test of benzo[c]fluorene. Data derived from [16]

Effects on animals

In one animal study, mice that were fed coal tar developed lung tumors. DNA adducts in these mice were analyzed and could be traced back to benzo[c]fluorene. This and another similar study suggest a contribution of benzo[c]fluorene to the carcinogenic potency of coal tar when administered orally. [1] [18]

Another study found that benzo[c]fluorene is also carcinogenic in mice when applied topically, inducing lung and skin cancer. Of the results of this study a dose-response curve has been made, see the image above.

This figure shows the DNA adduct level after a certain dose of benzo[c]fluorene was applied to the skin of mice. This level is similar in the lungs and in the skin implying that benzo[c]fluorene is a systemic mutagen. [17]

The effects of exposure to benzo[c]fluorene were also researched on rats. In one of these studies the liver was established to be the main place of disposition of benzo[c]fluorene after a single oral dose regardless of the size of the dose. It was found that 55-69% of the labelled benzo[c]fluorene was excreted via the feces while 8–10% was found to be eliminated via urine. While the benzo[c]fluorene found in the feces was not biotransformed, the urine samples mainly showed polar metabolites of benzo[c]fluorene. [19]

See also

Related Research Articles

Coal tar is a thick dark liquid which is a by-product of the production of coke and coal gas from coal. It is a type of creosote. It has both medical and industrial uses. Medicinally it is a topical medication applied to skin to treat psoriasis and seborrheic dermatitis (dandruff). It may be used in combination with ultraviolet light therapy. Industrially it is a railroad tie preservative and used in the surfacing of roads. Coal tar was listed as a known human carcinogen in the first Report on Carcinogens from the U.S. Federal Government, issued in 1980.

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

<span class="mw-page-title-main">Mutagen</span> Physical or chemical agent that increases the rate of genetic mutation

In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.

<span class="mw-page-title-main">Polycyclic aromatic hydrocarbon</span> Hydrocarbon composed of multiple aromatic rings

A polycyclic aromatic hydrocarbon (PAH) is a class of organic compounds that is composed of multiple aromatic rings. The simplest representative is naphthalene, having two aromatic rings, and the three-ring compounds anthracene and phenanthrene. PAHs are uncharged, non-polar and planar. Many are colorless. Many of them are found in coal and in oil deposits, and are also produced by the incomplete combustion of organic matter—for example, in engines and incinerators or when biomass burns in forest fires.

Benzo(<i>a</i>)pyrene Carcinogenic compound found in smoke and soot

Benzo[a]pyrene (BaP or B[a]P) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites (more commonly known as BPDE) react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.

<span class="mw-page-title-main">Methylcholanthrene</span> Chemical compound

Methylcholanthrene is a highly carcinogenic polycyclic aromatic hydrocarbon produced by burning organic compounds at very high temperatures. Methylcholanthrene is also known as 3-methylcholanthrene, 20-methylcholanthrene or the IUPAC name 3-methyl-1,2-dyhydrobenzo[j]aceanthrylene. The short notation often used is 3-MC or MCA. This compound forms pale yellow solid crystals when crystallized from benzene and ether. It has a melting point around 180 °C and its boiling point is around 280 °C at a pressure of 80 mmHg. Methylcholanthrene is used in laboratory studies of chemical carcinogenesis. It is an alkylated derivative of benz[a]anthracene and has a similar UV spectrum. The most common isomer is 3-methylcholanthrene, although the methyl group can occur in other places.

<span class="mw-page-title-main">Sudan I</span> Chemical compound

Sudan I is an organic compound, typically classified as an azo dye. It is an intensely orange-red solid that is added to colourise waxes, oils, petrol, solvents, and polishes. Sudan I has also been adopted for colouring various foodstuffs, especially curry powder and chili powder, although the use of Sudan I in foods is now banned in many countries, because Sudan I, Sudan III, and Sudan IV have been classified as category 3 carcinogens by the International Agency for Research on Cancer. Sudan I is still used in some orange-coloured smoke formulations and as a colouring for cotton refuse used in chemistry experiments.

<span class="mw-page-title-main">Fluoranthene</span> Chemical compound

Fluoranthene is a polycyclic aromatic hydrocarbon (PAH). The molecule can be viewed as the fusion of naphthalene and benzene unit connected by a five-membered ring. Although samples are often pale yellow, the compound is colorless. It is soluble in nonpolar organic solvents. It is a member of the class of PAHs known as non-alternant PAHs because it has rings other than those with six carbon atoms. It is a structural isomer of the alternant PAH pyrene. It is not as thermodynamically stable as pyrene. Its name is derived from its fluorescence under UV light.

<span class="mw-page-title-main">CYP1A1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.

<span class="mw-page-title-main">Chrysene</span> Chemical compound

Chrysene is a polycyclic aromatic hydrocarbon (PAH) with the molecular formula C
18H
12 that consists of four fused benzene rings. It is a natural constituent of coal tar, from which it was first isolated and characterized. It is also found in creosote at levels of 0.5–6 mg/kg.

Tobacco-specific nitrosamines (TSNAs) comprise one of the most important groups of carcinogens in tobacco products, particularly cigarettes and fermented dipping snuff.

<span class="mw-page-title-main">Benzopyrene</span>

A benzopyrene is an organic compound with the formula C20H12. Structurally speaking, the colorless isomers of benzopyrene are pentacyclic hydrocarbons and are fusion products of pyrene and a phenylene group. Two isomeric species of benzopyrene are benzo[a]pyrene and the less common benzo[e]pyrene. They belong to the chemical class of polycyclic aromatic hydrocarbons.

Benzo(<i>ghi</i>)perylene Chemical compound

Benzo[ghi]perylene is a polycyclic aromatic hydrocarbon with the chemical formula C22H12.

Benzo(<i>j</i>)fluoranthene Chemical compound

Benzo[j]fluoranthene (BjF) is an organic compound with the chemical formula C20H12. Classified as a polycyclic aromatic hydrocarbon (PAH), it is a colourless solid that is poorly soluble in most solvents. Impure samples can appear off white. Closely related isomeric compounds include benzo[a]fluoranthene (BaF), bendo[b]fluoranthene (BbF), benzo[e]fluoranthene (BeF), and benzo[k]fluoranthene (BkF). BjF is present in fossil fuels and is released during incomplete combustion of organic matter. It has been traced in the smoke of cigarettes, exhaust from gasoline engines, emissions from the combustion of various types of coal and emissions from oil heating, as well as an impurity in some oils such as soybean oil.

Benzo(<i>a</i>)fluorene Chemical compound

Benzo[a]fluorene is a polycyclic aromatic hydrocarbon (PAH). It is currently listed as a Group 3 carcinogen by the IARC.

<span class="mw-page-title-main">Dibenzopyrenes</span> Chemical compound

Dibenzopyrenes are a group of high molecular weight polycyclic aromatic hydrocarbons with the molecular formula C24H14. There are five isomers of dibenzopyrene which differ by the arrangement of aromatic rings: dibenzo[a,e]pyrene, dibenzo[a,h]pyrene, dibenzo[a,i]pyrene, dibenzo[a,l]pyrene, and dibenzo[e,l]pyrene.

<span class="mw-page-title-main">Glycidamide</span> Chemical compound

Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless, oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide. It is a chiral molecule.

Benzofluorene or the molecular formula C17H12 may refer to:

(+)-Benzo(<i>a</i>)pyrene-7,8-dihydrodiol-9,10-epoxide Cancer-causing agent derived from tobacco smoke

(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is an organic compound with molecular formula C20H14O3. It is a metabolite and derivative of benzo[a]pyrene (found in tobacco smoke) as a result of oxidation to include hydroxyl and epoxide functionalities. (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a guanine nucleobase in DNA, distorting the double helix structure by intercalation of the pyrene moiety between base pairs through π-stacking. The carcinogenic properties of tobacco smoking are attributed in part to this compound binding and inactivating the tumor suppression ability of certain genes, leading to genetic mutations and potentially to cancer.

Indeno(1,2,3-<i>cd</i>)pyrene Polycyclic aromatic hydrocarbon

Indeno[1,2,3-cd]pyrene is a polycyclic aromatic hydrocarbon (PAH), one of 16 PAHs generally measured in studies of environmental exposure and air pollution. Many compounds of this class are formed when burning coal, oil, gas, wood, household waste and tobacco, and can bind to or form small particles in the air. The compounds are known to have toxic, mutagenic and/or carcinogenic properties. Over 100 different PAHs have been identified in environmental samples. One of these 16 is Indeno[1,2,3-cd]pyrene (IP). IP is the combination of an indeno molecule and a pyrene molecule with a fluoranthene network. In 1962, the National Cancer Institute reported that indeno[1,2,3-cd]pyrene has a slight tumor activity. This was confirmed in 1973 by the IARC in mice testing.

References

  1. 1 2 3 Koganti A, Singh R, Rozett K, Modi N, Goldstein LS, Roy TA, Zhang FJ, Harvey RG, Weyand EH (2000). "7H-benzo[c]fluorene: a major DNA adduct-forming component of coal tar". Carcinogenesis. 21 (8): 1601–1609. doi: 10.1093/carcin/21.8.1601 . PMID   10910965.
  2. 1 2 3 Wang JQ, Weyand EH, Harvey RG (2002). "Synthesis of suspected carcinogenic metabolites of 7H-benzo[c]fluorene, a coal tar component implicated in causation of lung tumors". J Org Chem. 67 (17): 6216–6219. doi:10.1021/jo011149b. PMID   12182663.
  3. ↑ "7H-Benzo[c]fluorene". Pubchem. Retrieved 7 March 2016.
  4. ↑ "Benzo[c]fluorene on Chemspider". Chemspider. Retrieved 7 March 2016.
  5. ↑ "7H-Benzo[c]fluorene". trc-canada.com. Toronto Research Chemicals Toronto Research Chemicals. Retrieved 7 March 2016.
  6. ↑ Created from PDB 1JDG Archived 2008-09-22 at the Wayback Machine
  7. ↑ Kazlauskas K, Kreiza G, Radiunas E, Adomenas P, Adomeniene O, Karpavicius K, Bucevicius J, Jankauskas V, Jursenas S (2015). "Concentration effects on spontaneous and amplified emission in benzo[c]fluorenes". Physical Chemistry Chemical Physics. 17 (19): 12935–12948. Bibcode:2015PCCP...1712935K. doi:10.1039/C5CP01325A. PMID   25912324.
  8. 1 2 Agency for Toxic Substances and Disease Registry (ATSDR) (2009). "Toxicity of Polycyclic Aromatic Hydrocarbons (PAH)" . Retrieved 10 March 2016.{{cite journal}}: Cite journal requires |journal= (help)
  9. 1 2 3 Weyand EH, Parimoo B, Reuhl KR, Goldstein LS, Wang JQ, Harvey RG (2004). "7H-Benzo[C]Fluorene: A Potent Systemic Lung Carcinogen". Polycyclic Aromatic Compounds. 24 (1): 1–20. doi:10.1080/10406630490426942. S2CID   85148344.
  10. ↑ Seto H, Ohkubo T, Kanoh T, Koike M, Nakamura K, Kawahara Y (1993). "Determination of polycyclic aromatic hydrocarbons in the lung". Arch Environ Contam Toxicol. 24 (4): 498–503. doi:10.1007/bf01146169. PMID   8507106. S2CID   21678586.
  11. ↑ Librando V, Sarpietro MG, Castelli F (2003). "Role of lipophilic medium in the absorption of polycyclic aromatic compounds by biomembranes". Environmental Toxicology and Pharmacology. 14 (1–2): 25–32. doi:10.1016/s1382-6689(03)00007-3. PMID   21782659.
  12. ↑ Goth-Goldstein, Regine; Marion L. Russell; Bhama Parimoo & Eric H. Weyand (2002). "7H-Benzo[c]fluorene DNA adduct formation in different human cells in culture" . Retrieved 10 March 2016.{{cite journal}}: Cite journal requires |journal= (help)
  13. 1 2 3 Morisaki H, Nakamura S, Tang N, Toriba A, Hayakawa K (2016). "Benzo[c]fluorene in Urban Air: HPLC Determination and Mutagenic Contribution Relative to Benzo[a]pyrene". Anal Sci. 32 (2): 233–23. doi: 10.2116/analsci.32.233 . PMID   26860571.
  14. ↑ "BaP and PAH from coal-derived sources" (PDF). gezondheidsraad.nl. Health Council of the Netherlands. Retrieved 7 March 2016.[ permanent dead link ]
  15. ↑ "U.S. EPA. Development of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) Mixtures (External Review Draft)". epa.gov. U.S. Environmental Protection Agency. Retrieved 7 March 2016.
  16. 1 2 Lavoie EJ, Tulley L, Bedenko V, Hoffmann D (1981). "Mutagenicity of methylated fluorenes and benzofluorenes". Mutat Res. 91 (3): 167–176. doi:10.1016/0165-7992(81)90027-0. PMID   7017394.
  17. 1 2 Cizmas L; Zhou G-d; Safe SH; McDonald TJ; Zhu L; Donnelly KC (2004). "Comparative in vitro and in vivo genotoxicities of 7H-benzo[c]fluorene, manufactured gas plant residue (MGP), and MGP fractions". Environmental and Molecular Mutagenesis. 43 (3): 159–168. doi:10.1002/em.20011. PMID   15065203. S2CID   7039355.
  18. ↑ Koganti A, Singh R, Ma BL, Weyand EH (2001). "Comparative analysis of PAH:DNA adducts formed in lung of mice exposed to neat coal tar and soils contaminated with coal tar". Environ Sci Technol. 35 (13): 2704–2709. Bibcode:2001EnST...35.2704K. doi:10.1021/es001532i. PMID   11452595.
  19. ↑ Chopard-Lallier M, Perdu E, Jamin E, Brochot C, Craved J (2014). "Disposition of benzo[c]fluorene in rats". Toxicology Letters. 229 (supplement): 4141. doi:10.1016/j.toxlet.2014.06.838 . Retrieved 7 March 2016.
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