Carcinogen

The hazard symbol for carcinogenic chemicals in the Globally Harmonized System.

A carcinogen is any substance, radionuclide or radiation, that is an agent directly involved in the exacerbation of cancer or in the increase of its propagation. 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 carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke.

Cancer is a disease in which damaged cells do not undergo programmed cell death. 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 DNA damage, if too severe to repair, leads to programmed cell death, 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 viruses 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.

Benzene, kepone, EDB, asbestos, and the waste rock of oil shale mining have all been classified as carcinogenic.^[1] 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. But these reactions can also convert a less toxic carcinogen into a more toxic one.

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 carcinogenity of benzo[a]pyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.

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. Carcinogenity 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 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. Marie Curie, one of the pioneers of radioactivity, died of cancer caused by radiation exposure during her experiments.

Not all types of electromagnetic radiation are in fact carcinogenic. Low-energy waves on the electromagnetic spectrum are generally not, including radio waves, microwave radiation, infrared radiation and visible light. Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses.

Several published studies suggest a link between exposure to light at night and risk of breast cancer, due to suppression of the normal nocturnal production of melatonin.^[2][3] In 1978 Cohen et al. proposed that reduced production of the hormone melatonin might increase the risk of breast cancer and citing "environmental lighting" as a possible causal factor.^[4] Researchers at the National Cancer Institute (NCI) and National Institute of Environmental Health Sciences have concluded a study that suggests that artificial light during the night can be a factor for breast cancer.^[5] A good review of current knowledge of the health consequences of exposure to artificial light at night and an explanation of the causal mechanisms has been published in the Journal of Pineal Research in 2007.^[6]

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 by making bombarded substances radioactive.)

Carcinogens in prepared food

Cooking food at high temperatures, for example grilling or barbecuing meats, can 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).^[7] 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.^[8]

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).^[9] Studies are underway at the FDA and European regulatory agencies to assess its potential risk to humans.

Dr. T. Colin Campbell argues in The China Study that the milk protein casein, found in milk and many prepared foods, is also a carcinogen.^[10] However, independent studies report that casein and other milk proteins protect against cancer.^[11]

Carcinogens in cigarettes

Tobacco smoke contains over 4000 chemical compounds, many of which are carcinogenic or otherwise toxic. One of these is a compound marketed as a rat poison.^[12]

Circadian disruption

"Shiftwork that involves circadian disruption" was listed, in 2007, as a probable carcinogen by the World Health Organization's International Agency for Research on Cancer. (IARC Press release No. 180).^[13] Multiple studies have documented a link between night shift work and the increased incidence of breast cancer.^{[14][15][16][17]} Circadian disruption by exposure to light at night suppresses the production of the hormone melatonin which leads to reduction in cellular immune defense and surveillance necessary for protection from development of cancers. Melatonin also seems to have a direct protective effect against cancer possibly in part because of its strong anti oxidant properties.^[6]

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.^[18]

Classification of carcinogens

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^[19] that have been highly influential in the classification of possible carcinogens.

• Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
• Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
• Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
• Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
• Group 4: the agent (mixture) is probably not carcinogenic to humans.

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:

• Category 1: known or presumed to have carcinogenic potential for humans
  • Category 1A: the assessment is based primarily on human evidence
  • Category 1B: the assessment is based primarily on animal evidence
• Category 2: suspected human carcinogens

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.^[20] As of March 2009, the latest edition was the 11th report (2005).^[1] It classifies carcinogens into two groups:

• Known to be a human carcinogen
• Reasonably anticipated to be a human carcinogen

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.

• Group A1: Confirmed human carcinogen
• Group A2: Suspected human carcinogen
• Group A3: Confirmed animal carcinogen with unknown relevance to humans
• Group A4: Not classifiable as a human carcinogen
• Group A5: Not suspected as a human carcinogen

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:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances which should be regarded as if they are carcinogenic to humans.
• Category 3: Substances which cause concern for humans, owing to possible carcinogenic effects but in respect of which the available information is not adequate for making a satisfactory assessment.

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

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.^[21]

Common carcinogens

Occupational carcinogens

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

Others

• Gasoline (contains aromatics)
• Lead and its compounds
• Alkylating antineoplastic agents (chemotherapy)
• Other alkylating agents (e.g. dimethyl sulfate)
• Ultraviolet radiation from the sun and UV lamps
• Other ionizing radiation (X-rays, gamma rays, etc.)

See also

• Industrial Union Department v. American Petroleum Institute
• International Agency for Research on Cancer
• Mutagen
• Possible carcinogen
• Teratogen
• Warburg hypothesis

Notes

External links

• U.S. National Toxicology Program's Report on Carcinogens
• Recognized Carcinogens
• American Cancer Society
• Database of Rodent Carcinogens
• Comparing Possible Cancer Hazards from Human Exposures to Rodent Carcinogens