benzo(a)pyrene

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon found in coal tar with the formula C₂₀H₁₂. The compound is one of the benzopyrenes, formed by a benzene ring fused to pyrene, and is the result of incomplete combustion at temperatures between {{convert|300|°C|°F}} and {{convert|600|°C|°F}}.

The main source of atmospheric BaP is residential wood burning.{{cite web |title=Assessment of Benzo-alpha-pyrene Emissions in the Great Lakes Region |pages=23–24 |url=http://www.epa.gov/ttnchie1/conference/ei20/session10/asoehl_pres.pdf}} It is also found in coal tar, in automobile exhaust fumes (especially from diesel engines), in all smoke resulting from the combustion of organic material (including cigarette smoke), and in charbroiled food.

A 2001 National Cancer Institute study found levels of BaP to be significantly higher in foods that were cooked well-done on the barbecue, particularly steaks, chicken with skin, and hamburgers: Cooked meat products have been shown to contain up to 4 ng/g of BaP,{{cite journal | last1 = Kazerouni | first1 = N | last2 = Sinha | first2 = R | last3 = Hsu | first3 = CH | last4 = Greenberg | first4 = A | last5 = Rothman | first5 = N |display-authors=3 | year = 2002 | title = Analysis of 200 food items for benzo[a]pyrene and estimation of its intake in an epidemiologic study | journal = Food and Chemical Toxicology | volume = 40 | issue = 1| pages = 423–36 | doi = 10.1016/S0278-6915(00)00158-7 | pmid = 11313108 }} and up to 5.5 ng/g in fried chicken{{cite journal | last1 = Lee | first1 = BM | last2 = Shim | first2 = GA | date = Aug 2007 | title = Dietary exposure estimation of benzo[a]pyrene and cancer risk assessment | journal = Journal of Toxicology and Environmental Health Part A | volume = 70 | issue = 15–16| pages = 1391–4 | pmid = 17654259 | doi=10.1080/15287390701434182| s2cid = 21302834 }} and 62.6 ng/g in overcooked charcoal barbecued beef.{{cite journal | pmid = 16638662 | doi=10.1080/09637480500465436 | volume=56 | issue=8 | title=Determination of benzo[a]pyrene in charcoal grilled meat samples by HPLC with fluorescence detection | date=December 2005 | journal=Int J Food Sci Nutr | pages=581–5 | last1 = Aygün | first1 = SF | last2 = Kabadayi | first2 = F| s2cid=35095622 }}

BaP is discharged in wastewater by industries such as smelters, particularly iron and steel millsU.S. Environmental Protection Agency (EPA), Washington, D.C. (2002). "Iron and Steel Manufacturing Point Source Category." Code of Federal Regulations, [https://www.ecfr.gov/cgi-bin/text-idx?SID=7e2e50f207072b35927561ef22e99dfa&mc=true&node=pt40.31.420&rgn=div5 40 CFR Part 420]. and aluminium smelters.EPA (1984). "Nonferrous Metals Manufacturing Point Source Category." Code of Federal Regulations, [https://www.ecfr.gov/cgi-bin/text-idx?SID=cbb3de2695690bb75aab6eb27d17ccc2&mc=true&node=pt40.31.421&rgn=div5 40 CFR Part 421].

In the 18th century, young British chimney sweeps who climbed into chimneys suffered from chimney sweeps' carcinoma, a scrotal cancer peculiar to their profession, and this was connected to the effects of soot in 1775,{{cite book |last1=Pott |first1=Percivall |title=Chirurgical Observations … |date=1775 |publisher=L. Hawes, W. Clarke, and R. Collins |location=London, England |pages=63–68 |url=https://books.google.com/books?id=15htmgEACAAJ&pg=PA63}} From p. 67: "The disease, in these people [i.e., chimney sweeps], seems to derive its origin from a lodgment of soot in the rugae of the scrotum, … " in the first work of occupational cancer epidemiology and also the first connection of any chemical mixture to cancer formation. Frequent skin cancers were noted among fuel industry workers in the 19th century. In 1933, BaP was determined to be the compound responsible for these cases, and its carcinogenicity was demonstrated when skin tumors occurred in laboratory animals repeatedly painted with coal tar.{{cite journal | last1 = Cook | first1 = J. W. | last2 = Hewett | first2 = C. L. | last3 = Hieger | first3 = I. | year = 1933 | title = The isolation of a cancer producing Hydrocarbon from coal tar | url = https://pubs.rsc.org/en/Content/ArticleLanding/1933/JR/jr9330000395 | journal = J. Chem. Soc. | volume = 1933 | pages = 395–405 | doi = 10.1039/jr9330000395 | url-access = subscription }} BaP has since been identified as a prime carcinogen in cigarette smoke.{{cite journal | last1 = Hecht | first1 = SS | year = 1999 | title = Tobacco smoke carcinogens and lung cancer | journal = J Natl Cancer Inst | volume = 91 | issue = 14| pages = 1194–210 | pmid = 10413421 | doi = 10.1093/jnci/91.14.1194 | doi-access = free }}

File:Benzo(a)pyrene numbered.png ring and numbering and ring fusion locations according to IUPAC nomenclature of organic chemistry.]]

Prenatal exposure of BaP in rats is known to affect learning and memory in rodent models. Pregnant rats eating BaP were shown to negatively affect the brain function in the late life of their offspring. At a time when synapses are first formed and adjusted in strength by activity, BaP diminished NMDA receptor-dependent nerve cell activity measured as mRNA expression of the NMDA NR2B receptor subunit.{{Cite journal|pmc=2752856|year=2008|last1=McCallister|first1=M. M.|title=Prenatal Exposure to Benzo[a]pyrene Impairs Later-Life Cortical Neuronal Function|journal=NeuroToxicology|volume=29|issue=5|pages=846–854|last2=Maguire|first2=M|last3=Ramesh|first3=A|last4=Aimin|first4=Q|last5=Liu|first5=S|last6=Khoshbouei|first6=H|last7=Aschner|first7=M|last8=Ebner|first8=F. F.|last9=Hood|first9=D. B.|display-authors=3|doi=10.1016/j.neuro.2008.07.008|pmid=18761371}}.

BaP has an effect on the number of white blood cells, inhibiting some of them from differentiating into macrophages, the body's first line of defense to fight infections. In 2016, the molecular mechanism was uncovered as damage to the macrophage membrane's lipid raft integrity by decreasing membrane cholesterol at 25%. This means less immunoreceptors CD32 (a member of the Fc family of immunoreceptors) could bind to IgG and turn the white blood cell into a macrophage. Therefore, macrophage membranes become susceptible to bacterial infections.{{cite journal | title=Validation of research trajectory 1 of an Exposome framework: Exposure to benzo[a]pyrene confers enhanced susceptibility to bacterial infection. | vauthors=Clark RS, Pellom ST, Booker B, Ramesh A, Zhang T, Shanker A, Maguire M, Juarez PD, Patricia MJ, Langston MA, Lichtveld MY, Hood DB |display-authors=3| journal=Environ Research | year=2016 | volume=146 | pages=173–84 | doi=10.1016/j.envres.2015.12.027 | pmid=26765097| pmc=5523512 | bibcode=2016ER....146..173C }}

In experiments with male rats, subchronic exposure to inhaled BaP has been shown to generally reduce the function of testicles and epididymis with lower sex steroid/testosterone production and sperm production.{{cite journal | last1 = Ramesh A1 | first1 = Inyang F | last2 = Lunstra | first2 = DD | last3 = Niaz | first3 = MS | last4 = Kopsombut | first4 = P | last5 = Jones | first5 = KM | last6 = Hood | first6 = DB | last7 = Hills | first7 = ER | last8 = Archibong | first8 = AE |display-authors=3| date = Aug 2008 | title = Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene | journal = Exp Toxicol Pathol | volume = 60 | issue = 4–5| pages = 269–80 | doi = 10.1016/j.etp.2008.02.010 | pmc = 3526104 | pmid = 18499416 }}

BaP's metabolites are mutagenic and highly carcinogenic, and it is listed as a Group 1 carcinogen by the IARC. Chemical agents and related occupations, Volume 10, A review of Human Carcinogens, IARC Monographs, Lyon France 2009 A review of human carcinogens—part F: chemical agents and related occupations

In June 2016, BaP was added as benzo[def]chrysene to the REACH Candidate List of Substances of very high concern for Authorisation.{{cite web|last1=European Chemicals Agency|title=ED/21/2016|url=http://echa.europa.eu/documents/10162/4b054c5b-8511-4a30-8ef8-35ab143b4fd0|website=ECHA|access-date=21 June 2016}}

Numerous studies since the 1970s have documented links between BaP and cancers.{{cite book|chapter-url = https://books.google.com/books?id=Fw_G7Sk382IC&q=Benzo%28a%29pyrene-7%2C8-dihydrodiol-9%2C10-epoxide+cas&pg=PA102|first = W.|last = Kleiböhmer|publisher = Elsevier|year = 2001|chapter = Polycyclic Aromatic Hydrocarbon (PAH) Metabolites|pages = 99–122|title = Environmental Analysis (Volume 3 of Handbook of Analytical Separations)|isbn = 978-0-08-050576-3}} It has been more difficult to link cancers to specific BaP sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion).{{cite journal | title=Lung Cancer Risk After Exposure to Polycyclic Aromatic Hydrocarbons: A Review and Meta-Analysis | journal=Environmental Health Perspectives | volume=112 | issue=9 | pages=970–978 | pmc=1247189 | year=2004 | last1=Armstrong | first1=B. | last2=Hutchinson | first2=E. | last3=Unwin | first3=J. | last4=Fletcher | first4=T. | pmid=15198916 | doi=10.1289/ehp.6895 }} A link between vitamin A deficiency and emphysema in smokers was described in 2005 to be due to BaP, which induces vitamin A deficiency in rats.{{Cite web| title=Benzopyrene and Vitamin A deficiency | work=Researcher links cigarettes, vitamin A and emphysema | url=http://www.tobacco.org/news/171229.html| access-date=March 5, 2005 }}

A 1996 study provided molecular evidence linking components in tobacco smoke to lung cancer. BaP was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung tumours.{{Cite journal |last1=Denissenko |first1=M. F. |last2=Pao |first2=A. |last3=Tang |first3=M. |last4=Pfeifer |first4=G. P. |date=1996-10-18 |title=Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53 |journal=Science |volume=274 |issue=5286 |pages=430–432 |doi=10.1126/science.274.5286.430 |pmid=8832894|bibcode=1996Sci...274..430D |s2cid=3589066 }}

Regular consumption of cooked meats has been epidemiologically associated with increased levels of colon cancer{{cite journal | pmid = 12351160 | volume=506–507 | title=Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii | date=September 2002 | journal=Mutat. Res. | pages=205–14 | last1 = Le Marchand | first1 = L | last2 = Hankin | first2 = JH | last3 = Pierce | first3 = LM | display-authors = etal | doi=10.1016/s0027-5107(02)00167-7}} (although this in itself does not prove carcinogenicity),{{cite journal | last1 = Truswell | first1 = AS | date = Mar 2002 | title = Meat consumption and cancer of the large bowel | journal = European Journal of Clinical Nutrition | volume = 56 | issue = Suppl 1| pages = S19–24 | pmid = 11965518 | doi=10.1038/sj.ejcn.1601349| s2cid = 23886438 | doi-access = }}

A 2005 NCI study found an increased risk of colorectal adenomas was associated with BaP intake, and more strongly with BaP intake from all foods.{{Cite journal |last1=Sinha |first1=Rashmi |last2=Kulldorff |first2=Martin |last3=Gunter |first3=Marc J. |last4=Strickland |first4=Paul |last5=Rothman |first5=Nathaniel |display-authors=3|date=August 2005 |title=Dietary benzo[a]pyrene intake and risk of colorectal adenoma |url=https://aacrjournals.org/cebp/article/14/8/2030/258146/Dietary-Benzo-a-Pyrene-Intake-and-Risk-of |journal=Cancer Epidemiology, Biomarkers & Prevention |volume=14 |issue=8 |pages=2030–2034 |doi=10.1158/1055-9965.EPI-04-0854 |pmid=16103456|s2cid=33819830 |doi-access=free }}

The detoxification enzymes cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) are both protective and necessary for benzo[a]pyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1 and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of BaP, and that removing this protection accumulates large concentrations of BaP. Unless CYP1B1 is also knocked out, toxicity results from the bioactivation of BaP to benzo[a]pyrene -7,8-dihydrodiol-9,10-epoxide, the ultimate toxic compound.Data presented by Daniel W. Nebert in research seminars 2007{{better source|date=July 2016}}

File:Benzo(a)pyrene metabolism.svg benzo[a]pyren-7,8-dihydrodiol-9,10-epoxide.]]

File:Benzopyrene DNA adduct 1JDG.png (at center) of benzo[a]pyrene, the major mutagen in tobacco smoke.Created from [http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1JDG PDB 1JDG] {{Webarchive|url=https://web.archive.org/web/20080922150848/http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1JDG |date=2008-09-22 }}]]

Properly speaking, BaP is a procarcinogen, meaning that its mechanism of carcinogenesis depends on its enzymatic metabolism to BaP diol epoxide{{cite thesis |last=Bogdan |first=Dennis Paul|title=Interactions Of Benzopyrene And Nucleic Acids In The Presence Of A Mixed-Function Oxidase System - Ph.D. Dissertation (requires login). |url=https://www.proquest.com/docview/302781013 |id={{ProQuest|302781013}} |isbn=979-8661021359 |date=February 1, 1973 |publisher=State University of New York at Buffalo |access-date=May 9, 2021 }} It intercalates in DNA, and the electrophilic epoxide is attacked by nucleophilic guanine bases, forming a bulky guanine adduct.

DG rxn with BPDE

X-ray crystallographic and nuclear magnetic resonance structure studies have shown how this binding distorts the DNA{{Cite journal |last1=Volk |first1=David E. |last2=Thiviyanathan |first2=Varatharasa |last3=Rice |first3=Jeffrey S. |last4=Luxon |first4=Bruce A. |last5=Shah |first5=Jamshed H. |last6=Yagi |first6=Haruhiko |last7=Sayer |first7=Jane M. |last8=Yeh |first8=Herman J. C. |last9=Jerina |first9=Donald M. |last10=Gorenstein |first10=David G. |display-authors=3|date=2003-02-18 |title=Solution structure of a cis-opened (10R)-N6-deoxyadenosine adduct of (9S,10R)-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in a DNA duplex |journal=Biochemistry |volume=42 |issue=6 |pages=1410–1420 |doi=10.1021/bi026745u |pmid=12578353}} by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence of cancer after exposure. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine.{{Cite journal |last1=Eaton |first1=D. L. |last2=Gallagher |first2=E. P. |date=1994 |title=Mechanisms of aflatoxin carcinogenesis |journal=Annual Review of Pharmacology and Toxicology |volume=34 |pages=135–172 |doi=10.1146/annurev.pa.34.040194.001031 |pmid=8042848}}

There are indications that benzo[a]pyrene diol epoxide specifically targets the protective p53 gene.{{Cite journal |last1=Pfeifer |first1=Gerd P. |last2=Denissenko |first2=Mikhail F. |last3=Olivier |first3=Magali |last4=Tretyakova |first4=Natalia |last5=Hecht |first5=Stephen S. |last6=Hainaut |first6=Pierre |display-authors=3|date=2002-10-21 |title=Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers |journal=Oncogene |volume=21 |issue=48 |pages=7435–7451 |doi=10.1038/sj.onc.1205803 |pmid=12379884|s2cid=6134471 }} This gene is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. By inducing G (guanine) to T (thymidine) transversions in transversion hotspots within p53, there is a probability that benzo[a]pyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer.

Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is the carcinogenic product of three enzymatic reactions:{{cite journal | last1 = Jiang | first1 = Hao | last2 = Gelhaus | first2 = Stacy L. | last3 = Mangal | first3 = Dipti | last4 = Harvey | first4 = Ronald G. | last5 = Blair | first5 = Ian A. | last6 = Penning | first6 = Trevor M. |display-authors=3| year = 2007 | title = Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography-Mass Spectrometry | journal = Chem. Res. Toxicol. | volume = 20 | issue = 9| pages = 1331–1341 | pmc=2423818 | pmid=17702526 | doi=10.1021/tx700107z}}

1. Benzo[a]pyrene is first oxidized by cytochrome P450 1A1 to form a variety of products, including (+)benzo[a]pyrene-7,8-epoxide.{{cite journal | last1 = Shou | first1 = M | last2 = Gonzalez | first2 = FJ | last3 = Gelboin | first3 = HV |author3-link=Harry Gelboin | date = December 1996 | title = Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase | journal = Biochemistry | volume = 35 | issue = 49| pages = 15807–13 | doi=10.1021/bi962042z | pmid=8961944}}
2. This product is metabolized by epoxide hydrolase, opening up the epoxide ring to yield (−)benzo[a]pyrene-7,8-dihydrodiol.
3. The ultimate carcinogen is formed after another reaction with cytochrome P450 1A1 to yield the (+)benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA.

BaP induces cytochrome P450 1A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol.{{Cite journal| last = Whitlock | first = JP Jr. | title = Induction of cytochrome P4501A1 | journal = Annual Review of Pharmacology and Toxicology | volume = 39 | pages = 103–125 |date = April 1999| doi = 10.1146/annurev.pharmtox.39.1.103 | pmid = 10331078}} Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator) and then binds xenobiotic response elements (XREs) in DNA located upstream of certain genes. This process increases transcription of certain genes, notably CYP1A1, followed by increased CYP1A1 protein production. This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo[a]pyrene to enter portal blood and systemic circulation.{{cite journal |last1=Uno |first1=S. |year=2008 |title=Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract.|journal=Free Radic Biol Med |volume=44 |issue=4 |pages=570–83|pmid=17997381 |doi= 10.1016/j.freeradbiomed.2007.10.044|last2=Dragin|first2=N |last3=Miller |first3=ML |pmc=2754765|display-authors=etal}} Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (TLR2),{{Cite journal| last1 = Do| first1 = KN |last2=Fink|first2=LN |last3=Jensen |first3=TE |last4=Gautier |first4=L | last5=Parlesak |first5=A |display-authors=3|year=2012 |title = TLR2 controls intestinal carcinogen detoxication by CYP1A1. | journal = PLOS ONE| volume = 7 | issue = 3 | pages = e32309 | doi = 10.1371/journal.pone.0032309 | pmid = 22442665 | pmc=3307708| bibcode = 2012PLoSO...732309D | doi-access = free }} which is a eukaryotic receptor for bacterial surface structures such as lipoteichoic acid.

Moreover, BaP has been found to activate a transposon, LINE1, in humans.{{cite journal | last1 = Stribinskis | first1 = Vilius | last2 = Ramos | first2 = Kenneth S. | year = 2006 | title = Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, a Ubiquitous Environmental Carcinogen | journal = Cancer Res | volume = 66 | issue = 5| pages = 2616–20 | doi = 10.1158/0008-5472.CAN-05-3478 | pmid = 16510580 | doi-access = free }}

As illustrated above, (+)benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) forms bulky covalent DNA adducts with guanines. Most of these adducts can be efficiently eliminated from DNA by the process of nucleotide excision repair.{{Cite journal |last1=Li |first1=Wentao |last2=Hu |first2=Jinchuan |last3=Adebali |first3=Ogun |last4=Adar |first4=Sheera |last5=Yang |first5=Yanyan |last6=Chiou |first6=Yi-Ying |last7=Sancar |first7=Aziz |display-authors=3|date=2017-06-27 |title=Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo[a]pyrene |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=114 |issue=26 |pages=6752–6757 |doi=10.1073/pnas.1706021114 |pmc=5495276 |pmid=28607059|bibcode=2017PNAS..114.6752L |doi-access=free }} Those adducts that are not removed can cause errors during DNA replication leading to carcinogenic mutations.

• Benzopyrene
• Benzo[e]pyrene
• Pyrene, a four-ring analogue
• Toxification

{{Reflist|30em}}

• {{ICSC|0104|01}}
• [http://www.npi.gov.au/resource/polycyclic-aromatic-hydrocarbons National Pollutant Inventory – Polycyclic Aromatic Hydrocarbon Fact Sheet]
• {{Cite web | title=Lung cancer as consequence by Benzopyrene in smokers | work=Lung Cancer | url=http://www.sarnia.com/groups/antidrug/mjmeds/mjcancr.html | access-date=March 5, 2005 | url-status=dead | archive-url=https://web.archive.org/web/20050414175548/http://www.sarnia.com/groups/antidrug/mjmeds/mjcancr.html | archive-date=April 14, 2005 }}
• {{Cite web| title=Levels of Benzopyrene in Burnt toasts| work=Guardian Unlimited, Special reports: Close encounters| url=https://www.theguardian.com/chemicalworld/story/0,14534,1219603,00.html | access-date=March 5, 2005 }}
• {{Cite journal| title=Crystal and molecular structure of a benzo[a]pyrene-7,8-diol-9,10-epoxide N2-deoxyguanosine adduct: Absolute configuration and conformation | journal=Proceedings of the National Academy of Sciences| volume=101 | doi=10.1073/pnas.0307305101 | year=2004 | last1 = Karle | first1 = I. L. | issue=6| pages=1433–8| pmid=14757823 | pmc=341736| bibcode=2004PNAS..101.1433K| doi-access=free}}

{{PAHs}}

{{Aryl hydrocarbon receptor modulators}}

Category:IARC Group 1 carcinogens

Category:Polycyclic aromatic hydrocarbons

Category:PBT substances