Carcinogen

The international pictogram for chemicals that are sensitising, mutagenic, carcinogenic or toxic to reproduction.

A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise in both natural and synthetic substances.[1] Carcinogens are not necessarily immediately toxic, thus their effect can be insidious.

Cancer is any disease in which normal cells are damaged and do not undergo programmed cell death as fast as they divide via mitosis. Carcinogens may increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors. Usually, severe DNA damage leads to apoptosis, but if the programmed cell death pathway is damaged, then the cell cannot prevent itself from becoming a cancer cell.

There are many natural carcinogens. Aflatoxin B1, which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally occurring microbial carcinogen. Certain viruses such as hepatitis B and human papilloma virus have been found to cause cancer in humans. The first one shown to cause cancer in animals is Rous sarcoma virus, discovered in 1910 by Peyton Rous. Other infectious organisms which cause cancer in humans include some bacteria (e.g. Helicobacter pylori [2][3]) and helminths (e.g. Opisthorchis viverrini [4] and Clonorchis sinensis [5]).

Dioxins and dioxin-like compounds, benzene, kepone, EDB, and asbestos have all been classified as carcinogenic.[6] As far back as the 1930s, industrial smoke and tobacco smoke were identified as sources of dozens of carcinogens, including benzo[a]pyrene, tobacco-specific nitrosamines such as nitrosonornicotine, and reactive aldehydes such as formaldehyde—which is also a hazard in embalming and making plastics. Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.

Co-carcinogens are chemicals that do not necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer.

After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation. The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. However, in some cases, these reactions can also convert a less toxic carcinogen into a more toxic carcinogen.

DNA is nucleophilic, therefore soluble carbon electrophiles are carcinogenic, because DNA attacks them. For example, some alkenes are toxicated by human enzymes to produce an electrophilic epoxide. DNA attacks the epoxide, and is bound permanently to it. This is the mechanism behind the carcinogenicity of benzo[a]pyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.

IUPAC definition

Carcinogenicity: Ability or tendency to produce cancer.

Note: In general, polymers are not known as carcinogens or mutagens,
however, residual monomers or additives can cause genetic mutations.[7]

Radiation

CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation (alpha, beta, gamma, or neutron and the radioactive strength), its consequent capacity to cause ionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. Carcinogenicity of radiation depends of the type of radiation, type of exposure, and penetration. For example, alpha radiation has low penetration and is not a hazard outside the body, but emitters are carcinogenic when inhaled or ingested. For example, Thorotrast, a (incidentally radioactive) suspension previously used as a contrast medium in x-ray diagnostics, is a potent human carcinogen known because of its retention within various organs and persistent emission of alpha particles. Low level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.[8][9][10]

Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum including radio waves, microwaves, infrared radiation and visible light are thought not to be, because they have insufficient energy to break chemical bonds. Evidence for carcinogenic effects of non-ionizing radiation is generally inconclusive, though there are some documented cases of radar technicians with prolonged high exposure experiencing significantly higher cancer incidence.[11]

Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses. For most people, ultraviolet radiations from sunlight is the commonest cause of skin cancer. In Australia, where people with pale skin are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.[12][13]

Substances or foods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic. In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can produce secondary radiation through nuclear transmutation.

In prepared food

Chemicals used in processed and cured meat such as bacon, sausages and ham may produce carcinogens.[14] For example, nitrites used as food preservatives in cured meat such as bacon have also been noted as being carcinogenic with links to colon cancer.[15] Cooking food at high temperatures, for example grilling or barbecuing meats, can also lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzo[a]pyrene).[16] Charring of food resembles coking and tobacco pyrolysis, and produces similar carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by human enzymes into epoxides, which attach permanently to DNA. Pre-cooking meats in a microwave oven for 2–3 minutes before grilling shortens the time on the hot pan, and removes heterocyclic amine (HCA) precursors, which can help minimize the formation of these carcinogens.[17]

Reports from the Food Standards Agency have found that the known animal carcinogen acrylamide is generated in fried or overheated carbohydrate foods (such as french fries and potato chips).[18] Studies are underway at the FDA and European regulatory agencies to assess its potential risk to humans.

In cigarettes

Main article: Tobacco and health

There is a strong association of smoking with lung cancer; the lifetime risk of developing lung cancer increases significantly in smokers.[19] A large number of known carcinogens are found in cigarette smoke, potent carcinogens found in cigarette smoke include polycyclic aromatic hydrocarbons (PAH, such as benzo[a]pyrene), Benzene, and Nitrosamine. [20] In addition, small amounts of polonium-210 (210Po), which is a radioactive carcinogen, is also found in cigarette smoke.[21]

Mechanisms of carcinogenicity

Carcinogens can be classified as genotoxic or nongenotoxic. Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-nitroso-N-methylurea (NMU) or non-chemical agents such as ultraviolet light and ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.

Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic compounds.[22]

Classification

Approximate equivalences
between classification schemes
IARC GHS NTP ACGIH EU
Group 1 Cat. 1A Known A1 Cat. 1
Group 2A Cat. 1B Reasonably
suspected		 A2 Cat. 2
Group 2B
Cat. 2   A3 Cat. 3
Group 3
  A4  
Group 4 A5

International Agency for Research on Cancer

The International Agency for Research on Cancer (IARC) is an intergovernmental agency established in 1965, which forms part of the World Health Organization of the United Nations. It is based in Lyon, France. Since 1971 it has published a series of Monographs on the Evaluation of Carcinogenic Risks to Humans[23] that have been highly influential in the classification of possible carcinogens.

Globally Harmonized System

The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) is a United Nations initiative to attempt to harmonize the different systems of assessing chemical risk which currently exist (as of March 2009) around the world. It classifies carcinogens into two categories, of which the first may be divided again into subcategories if so desired by the competent regulatory authority:

U.S. National Toxicology Program

The National Toxicology Program of the U.S. Department of Health and Human Services is mandated to produce a biennial Report on Carcinogens.[24] As of June 2011, the latest edition was the 12th report (2011).[6] It classifies carcinogens into two groups:

American Conference of Governmental Industrial Hygienists

The American Conference of Governmental Industrial Hygienists (ACGIH) is a private organization best known for its publication of threshold limit values (TLVs) for occupational exposure and monographs on workplace chemical hazards. It assesses carcinogenicity as part of wider assessment of the occupational hazards of chemicals.

European Union

The European Union classification of carcinogens is contained in the Dangerous Substances Directive and the Dangerous Preparations Directive. It consists of three categories:

This assessment scheme is being phased out in favor of the GHS scheme (see above), to which it is very close in category definitions.

Safe Work Australia

Under a previous name, the NOHSC, in 1999 Safe Work Australia published the Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(1999)].[25] Section 4.76 of this document outlines the criteria for classifying carcinogens as approved by the Australian government. This classification consists of three categories:

Procarcinogen

A procarcinogen is a precursor to a carcinogen. One example is nitrites when taken in by the diet. They are not carcinogenic themselves, but turn into nitrosamines in the body, which are carcinogenic.[26]

Common carcinogens

Occupational carcinogens

Occupational carcinogens are agents that pose a risk of cancer in several specific work-locations:

Carcinogen Associated cancer sites or types Occupational uses or sources
Arsenic and its compounds
  • Smelting byproduct
  • Component of:
    • Alloys
    • Electrical and semiconductor devices
    • Medications (e.g. melarsoprol)
    • Herbicides
    • Fungicides
    • Animal dips
    • Drinking water from contaminated aquifers.
Asbestos

Not in widespread use, but found in:

  • Constructions
    • Roofing papers
    • Floor tiles
  • Fire-resistant textiles
  • Friction linings (brake pads) (only outside Europe)
    • Replacement friction linings for automobiles still may contain asbestos
Benzene
Beryllium and its compounds
  • Lung
  • Missile fuel
  • Lightweight alloys
    • Aerospace applications
    • Nuclear reactors
Cadmium and its compounds[27]
Hexavalent chromium(VI) compounds
  • Lung
  • Paints
  • Pigments
  • Preservatives
IC engine exhaust gas
Ethylene oxide
  • Leukemia
  • Ripening agent for fruits and nuts
  • Rocket propellant
  • Fumigant for foodstuffs and textiles
  • Sterilant for hospital equipment
Nickel
  • Nose
  • Lung
  • Nickel plating
  • Ferrous alloys
  • Ceramics
  • Batteries
  • Stainless-steel welding byproduct
Radon and its decay products
  • Lung
  • Uranium decay
    • Quarries and mines
    • Cellars and poorly ventilated places
Vinyl chloride
Shift work that involves

circadian disruption[29]
Involuntary smoking (Passive smoking)[30]
  • Lung
    Radium-226, Radium-224,
    Plutonium-238, Plutonium-239[31]
    and other alpha particle
    emitters with high atomic weight
    Unless otherwise specified, ref is:[32]

    Others

    Major carcinogens implicated in the four most common cancers worldwide

    In this section, the carcinogens implicated as the main causative agents of the four most common cancers worldwide are briefly described. These four cancers are lung, breast, colon, and stomach cancers. Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths (for more detailed information on the carcinogens implicated in these and other cancers, see references[33][34]).

    Lung cancer

    Lung cancer is the most common cancer in the world, both in terms of cases (1.6 million cases; 12.7% of total cancer cases) and deaths (1.4 million deaths; 18.2% of total cancer deaths).[35] Lung cancer is largely caused by tobacco smoke. Risk estimates for lung cancer in the United States indicate that tobacco smoke is responsible for 90% of lung cancers. Other factors are implicated in lung cancer, and these factors can interact synergistically with smoking, so that total attributable risk adds up to more than 100%. These factors include occupational exposure to carcinogens (about 9-15%), radon (10%) and outdoor air pollution (1-2%).[36] Tobacco smoke is a complex mixture of more than 5,300 identified chemicals. The most important carcinogens in tobacco smoke have been determined by a “Margin of Exposure” approach.[37] Using this approach, the most important tumorigenic compounds in tobacco smoke were, in order of importance, acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, cadmium, acetaldehyde, ethylene oxide and isoprene. Most of these compounds cause DNA damage by forming DNA adducts or by inducing other alterations in DNA.[34] DNA damages are subject to error-prone DNA repair or can cause replication errors. Such errors in repair or replication can result in mutations in tumor suppressor genes or oncogenes leading to cancer.

    Breast cancer

    Breast cancer is the second most common cancer [(1.4 million cases, 10.9%), but ranks 5th as cause of death (458,000, 6.1%)].[35] Increased risk of breast cancer is associated with persistently elevated blood levels of estrogen.[38] Estrogen appears to contribute to breast carcinogenesis by three processes; (1) the metabolism of estrogen to genotoxic, mutagenic carcinogens, (2) the stimulation of tissue growth, and (3) the repression of phase II detoxification enzymes that metabolize ROS leading to increased oxidative DNA damage.[39][40][41] The major estrogen in humans, estradiol, can be metabolized to quinone derivatives that form adducts with DNA.[42] These derivatives can cause dupurination, the removal of bases from the phosphodiester backbone of DNA, followed by inaccurate repair or replication of the apurinic site leading to mutation and eventually cancer. This genotoxic mechanism may interact in synergy with estrogen receptor-mediated, persistent cell proliferation to ultimately cause breast cancer.[42] Genetic background, dietary practices and environmental factors also likely contribute to the incidence of DNA damage and breast cancer risk.

    Colon cancer

    Colorectal cancer is the third most common cancer [1.2 million cases (9.4%), 608,000 deaths (8.0%)].[35] Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States.[43] In addition, substantial evidence implicates bile acids as an important factor in colon cancer. Twelve studies (summarized in Bernstein et al.[44]) indicate that the bile acids deoxycholic acid (DCA) and/or lithocholic acid (LCA) induce production of DNA damaging reactive oxygen species and/or reactive nitrogen species in human or animal colon cells. Furthermore, 14 studies showed that DCA and LCA induce DNA damage in colon cells. Also 27 studies reported that bile acids cause programmed cell death (apoptosis). Increased apoptosis can result in selective survival of cells that are resistant to induction of apoptosis.[44] Colon cells with reduced ability to undergo apoptosis in response to DNA damage would tend to accumulate mutations, and such cells may give rise to colon cancer.[44] Epidemiologic studies have found that fecal bile acid concentrations are increased in populations with a high incidence of colon cancer. Dietary increases in total fat or saturated fat result in elevated DCA and LCA in feces and elevated exposure of the colon epithelium to these bile acids. When the bile acid DCA was added to the standard diet of wild-type mice invasive colon cancer was induced in 56% of the mice after 8 to 10 months.[45] Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging carcinogens in colon cancer.

    Stomach cancer

    Stomach cancer is the fourth most common cancer [990,000 cases (7.8%), 738,000 deaths (9.7%)].[35] Helicobacter pylori infection is the main causative factor in stomach cancer. Chronic gastritis (inflammation) caused by H. pylori is often long-standing if not treated. Infection of gastric epithelial cells with H. pylori results in increased production of reactive oxygen species (ROS).[46][47] ROS cause oxidative DNA damage including the major base alteration 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG resulting from ROS is increased in chronic gastritis. The altered DNA base can cause errors during DNA replication that have mutagenic and carcinogenic potential. Thus H. pylori-induced ROS appear to be the major carcinogens in stomach cancer because they cause oxidative DNA damage leading to carcinogenic mutations. Diet is thought to be a contributing factor in stomach cancer - in Japan where very salty pickled foods are popular, incidence of stomach cancer is high. Preserved meat such as bacon, sausages and ham increases the risk, while a diet high in fresh fruit and vegetables may reduce the risk. The risk also increases with age.[48]

    See also

    References

    1. ↑ Ames, Bruce N; Gold, Lois Swirsky (2000). "Paracelsus to parascience: The environmental cancer distraction". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 447: 3. doi:10.1016/S0027-5107(99)00194-3.
    2. ↑ Hatakeyama M, Higashi H (2005). "Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis". Cancer Science 96 (12): 835–843. doi:10.1111/j.1349-7006.2005.00130.x. PMID 16367902.
    3. ↑ González CA, Sala N, Rokkas T (2013). "Gastric cancer: epidemiologic aspects". Helicobacter 18 (Supplement 1): 34–38. doi:10.1111/hel.12082. PMID 24011243.
    4. ↑ Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T, Smout M, Pairojkul C, Bhudhisawasdi V, Tesana S, Thinkamrop B, Bethony JM, Loukas A, Brindley PJ (2007). "Liver fluke induces cholangiocarcinoma". PLoS Medicine 4 (7): 1148–1155. doi:10.1371/journal.pmed.0040201. PMC 1913093. PMID 17622191.
    5. ↑ Rustagi T, Dasanu CA (2012). "Risk Factors for Gallbladder Cancer and Cholangiocarcinoma: Similarities, Differences and Updates". Journal of Gastrointestinal Cancer 43 (2): 137–147. doi:10.1007/s12029-011-9284-y. PMID 21597894.
    6. 1 2 Report on Carcinogens, Eleventh Edition; U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program (2011).
    7. ↑ "Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)" (PDF). Pure and Applied Chemistry 84 (2): 377–410. 2012. doi:10.1351/PAC-REC-10-12-04.
    8. ↑ Acharya, PVN; The Effect of Ionizing Radiation on the Formation of Age-Correlated Oligo Deoxyribo Nucleo Phospheryl Peptides in Mammalian Cells; 10th International Congress of Gerontology, Jerusalem. Abstract No. 1; January 1975. Work done while employed by Dept. of Pathology, University of Wisconsin, Madison.
    9. ↑ Acharya, PVN; Implicatons of The Action of Low Level Ionizing Radiation on the Inducement of Irreparable DNA Damage Leading to Mammalian Aging and Chemical Carcinogenesis.; 10th International Congress of Biochemistry, Hamburg, Germany. Abstract No. 01-1-079; July 1976. Work done while employed by Dept. of Pathology, University of Wisconsin, Madison.
    10. ↑ Acharya, PV Narasimh; Irreparable DNA-Damage by Industrial Pollutants in Pre-mature Aging, Chemical Carcinogenesis and Cardiac Hypertrophy: Experiments and Theory; 1st International Meeting of Heads of Clinical Biochemistry Laboratories, Jerusalem, Israel. April 1977. Work conducted at Industrial Safety Institute and Behavioral Cybernetics Laboratory, University of Wisconsin, Madison.
    11. ↑ Richter E, Berman T, Ben-Michael E, Laster R, Westin JB (2000). "Cancer in radar technicians exposed to radiofrequency/microwave radiation: Sentinel episodes". International journal of occupational and environmental health 6 (3): 187–193. doi:10.1179/oeh.2000.6.3.187. PMID 10926722.
    12. ↑ "Skin Cancer Facts and Figures". Retrieved 2010-07-02.
    13. ↑ Skin-tone gene could predict cancer risk
    14. ↑ "Processed meats do cause cancer - WHO". BBC. 26 October 2015.
    15. ↑ Scanlan RA. (1983). "Formation and occurrence of nitrosamines in food". Cancer Res. 43 (5 Suppl): 2435s–2440s. PMID 6831466.
    16. ↑ Wei Zheng, Deborah R Gustafson, Rashmi Sinha, James R Cerhan, et al. "Well-done meat intake and the risk of breast cancer." Journal of the National Cancer Institute. Oxford: Nov 18, 1998.Vol. 90, Iss. 22; pg. 1724, 6 pgs.
    17. ↑ "National Cancer Institute, 2004 analysis and recommendations". Cancer.gov. 2004-09-15. Retrieved 2010-09-22.
    18. ↑ "Acrylamide".
    19. ↑ Villeneuve PJ, Mao Y (1994). "Lifetime probability of developing lung cancer, by smoking status, Canada". Canadian Journal of Public Health = Revue Canadienne De Santé Publique 85 (6): 385–8. PMID 7895211.
    20. ↑ "Harms of Cigarette Smoking and Health Benefits of Quitting". National Cancer Institute.
    21. ↑ "Radioactive polonium in cigarette smoke". Cancer Research UK.
    22. ↑ "The Gale Encyclopedia of Cancer: A guide to Cancer and its Treatments, Second Edition. Page no. 137".
    23. ↑ "IARC Monographs". Monographs.iarc.fr. Retrieved 2010-09-22.
    24. ↑ Section 301(b)(4) of the Public Health Service Act, as amended by Section 262, Pub. L. 95–622.
    25. ↑ Safe Work Australia, NOHSC. (1999). Approved criteria for classifying hazardous substances [NOHSC:1008(1999)] § 4.76. Accessed 21/05/2011
    26. ↑ "Web definitions for Procarcinogen". Lactospore.com. Retrieved 2010-09-22.
    27. ↑ Hartwig, Andrea (2013). "Chapter 15. Cadmium and cancer". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Cadmium: From Toxicology to Essentiality. Metal Ions in Life Sciences 11. Springer. pp. 491–507. doi:10.1007/978-94-007-5179-8_15.
    28. 1 2 "IARC: DIESEL ENGINE EXHAUST CARCINOGENIC" (Press release). International Agency for Research on Cancer (IARC). Retrieved June 12, 2012. June 12, 2012 ‐‐ After a week-long meeting of international experts, the International Agency for Research on Cancer (IARC), which is part of the World Health Organization (WHO), today classified diesel engine exhaust as carcinogenic to humans (Group 1), based on sufficient evidence that exposure is associated with an increased risk for lung cancer
    29. ↑ "IARC Monographs Programme finds cancer hazards associated with shiftwork, painting and firefighting, International Agency for Research on Cancer". Retrieved 2011-07-01
    30. ↑ Tobacco Smoke and Involuntary Smoking, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 83 (2004).
    31. ↑ Survival, causes of death, and estimated tissue doses in a group of human beings injected with plutonium, 751053, R. E. Rowland and Patricia W. Durbin, 1975.
    32. ↑ Table 6-2 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.
    33. ↑ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 ISBN 978-1604565812
    34. 1 2 Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
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    36. ↑ Alberg AJ, Ford JG, Samet JM (2007). Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). American College of Chest Physicians. Chest 132(3 Suppl):29S-55S. doi:10.1378/chest.07-1347 PMID 17873159
    37. ↑ Cunningham FH, Fiebelkorn S, Johnson M, Meredith C (2011). "A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants". Food Chem Toxicol 49 (11): 2921–33. doi:10.1016/j.fct.2011.07.019. PMID 21802474.
    38. ↑ Yager JD, Davidson NE (2006). "Estrogen carcinogenesis in breast cancer". N Engl J Med 354 (3): 270–82. doi:10.1056/NEJMra050776. PMID 16421368.
    39. ↑ Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB (2004). "In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens". Endocrinology 145 (1): 311–317. doi:10.1210/en.2003-0817. PMID 14551226.
    40. ↑ Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF (2007). "Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation". Cancer Res 67 (2): 812–817. doi:10.1158/0008-5472.CAN-06-2133. PMID 17234793.
    41. ↑ Bolton JL, Thatcher GR. (2008). Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol 21(1):93-101. Review. doi:10.1021/tx700191p PMID 18052105
    42. 1 2 Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL (2003). "Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis". J Steroid Biochem Mol Biol 86 (3-5): 477–486. doi:10.1016/s0960-0760(03)00377-7. PMID 14623547.
    43. ↑ Giovannucci E, Martínez ME (1996). "Tobacco, colorectal cancer, and adenomas: A review of the evidence". Journal of the National Cancer Institute 88 (23): 1717–1730. doi:10.1093/jnci/88.23.1717. PMID 8944002.
    44. 1 2 3 Bernstein H, Bernstein C, Payne CM, Dvorak K. (2009). Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol 15(27):3329-3340. doi:10.3748/wjg.15.3329 PMID 19610133
    45. ↑ Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H (2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Archives of Toxicology 85 (8): 863–871. doi:10.1007/s00204-011-0648-7. PMC 3149672. PMID 21267546.
    46. ↑ Ding SZ, Minohara Y, Fan XJ, Wang J, Reyes VE, Patel J, Dirden-Kramer B, Boldogh I, Ernst PB, Crowe SE (2007). "Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells". Infect Immun 75 (8): 4030–4039. doi:10.1128/IAI.00172-07. PMID 17562777.
    47. ↑ Handa O, Naito Y, Yoshikawa T. (2011). Redox biology and gastric carcinogenesis: the role of Helicobacter pylori. Redox Rep 16(1):1-7. doi:10.1179/174329211X12968219310756. Review. PMID 21605492
    48. ↑ "Stomach cancer risks and causes". Cancer Research UK.

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