Acarcinogen (/kɑːrˈsɪnədʒən/) is any agent that promotes the development ofcancer.[1] Carcinogens can includesynthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizingradiation, andbiologic agents such as viruses andbacteria.[2] Most carcinogens act by creating mutations inDNA that disrupt a cell's normal processes for regulating growth, leading to uncontrolled cellular proliferation.[1] This occurs when the cell'sDNA repair processes fail to identify DNA damage allowing the defect to be passed down todaughter cells. The damage accumulates over time. This is typically a multi-step process during which the regulatory mechanisms within the cell are gradually dismantled allowing for uncheckedcellular division.[2]
The specific mechanisms for carcinogenic activity is unique to each agent and cell type. Carcinogens can be broadly categorized, however, as activation-dependent and activation-independent which relate to the agent's ability to engage directly with DNA.[3] Activation-dependent agents are relatively inert in their original form, but are bioactivated in the body intometabolites or intermediaries capable of damaging human DNA.[4] These are also known as "indirect-acting" carcinogens. Examples of activation-dependent carcinogens includepolycyclic aromatic hydrocarbons (PAHs),heterocyclic aromatic amines, andmycotoxins. Activation-independent carcinogens, or "direct-acting" carcinogens, are those that are capable of directly damaging DNA without any modification to their molecular structure. These agents typically includeelectrophilic groups that react readily with the net negative charge of DNA molecules.[3] Examples of activation-independent carcinogens includeultraviolet light,ionizing radiation andalkylating agents.[4]
The time from exposure to a carcinogen to the development of cancer is known as thelatency period. For most solid tumors in humans the latency period is between 10 and 40 years depending on cancer type.[5] For blood cancers, the latency period may be as short as two.[5] Due to prolonged latency periods identification of carcinogens can be challenging.
A number of organizations review and evaluate the cumulative scientific evidence regarding the potential carcinogenicity of specific substances. Foremost among these is theInternational Agency for Research on Cancer (IARC). IARC routinely publishes monographs in which specific substances are evaluated for their potential carcinogenicity to humans and subsequently categorized into one of four groupings: Group 1: Carcinogenic to humans, Group 2A: Probably carcinogenic to humans, Group 2B: Possibly carcinogenic to humans and Group 3: Not classifiable as to its carcinogenicity to humans.[6] Other organizations that evaluate the carcinogenicity of substances include theNational Toxicology Program of theUS Public Health Service,NIOSH, theAmerican Conference of Governmental Industrial Hygienists and others.[7]
CERCLA identifies allradionuclides as carcinogens, although the nature of the emittedradiation (alpha,beta,gamma, orneutron and the radioactive strength), its consequent capacity to causeionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. Carcinogenicity of radiation depends on 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 acontrast medium inx-ray diagnostics, is a potent human carcinogen known because of its retention within variousorgans 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 andcancer.[11][12][13]
Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on theelectromagnetic spectrum includingradio waves,microwaves,infrared radiation andvisible light are thought not to be, because they have insufficient energy to break chemical bonds. Evidence for carcinogenic effects of non-ionizing radiation is generallyinconclusive, though there are some documented cases of radar technicians with prolonged high exposure experiencing significantly higher cancer incidence.[14]
Higher-energy radiation, includingultraviolet radiation (present insunlight) generallyis carcinogenic, if received in sufficient doses. For most people, ultraviolet radiations from sunlight is the most common 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.[15][16]
Substances orfoods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic.[17] In contrast, non-electromagneticneutron radiation produced inside nuclear reactors can produce secondary radiation throughnuclear transmutation.
Alcohol is a carcinogen of the head and neck, esophagus, liver, colon and rectum, and breast. It has a synergistic effect with tobacco smoke in the development of head and neck cancers. In the United States approximately 6% of cancers and 4% of cancer deaths are attributable to alcohol use.[18]
Chemicals used in processed and cured meat such as some brands of bacon, sausages and ham may produce carcinogens.[19] For example, nitrites used as food preservatives in cured meat such as bacon have also been noted as being carcinogenic with demographic links, but not causation, to colon cancer.[20]
Cooking food at high temperatures, for examplegrilling orbarbecuing meats, may 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).[21]Charring of food looks likecoking and tobaccopyrolysis, and produces carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by humanenzymes intoepoxides, which attach permanently to DNA. Pre-cooking meats in amicrowave 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.[22]
Frying, grilling or broiling food at high temperatures, especially starchy foods, until a toasted crust is formed generatesacrylamides. This discovery in 2002 led to international health concerns. Subsequent research has however found that it is not likely that the acrylamides in burnt or well-cooked food cause cancer in humans;Cancer Research UK categorizes the idea that burnt food causes cancer as a "myth".[23]
Tobacco smoke contains at least 70 known carcinogens and is implicated in the development of numerous types of cancers including cancers of the lung, larynx, esophagus, stomach, kidney, pancreas, liver, bladder, cervix, colon, rectum and blood.[25] Potent carcinogens found in cigarette smoke includepolycyclic aromatic hydrocarbons (PAH, such as benzo(a)pyrene),benzene, andnitrosamine.[26][27]
Given that populations of workers are more likely to have consistent, often high level exposures to chemicals rarely encountered in normal life, much of the evidence for the carcinogenicity of specific agents is derived from studies of workers.[10]
Carcinogens can be classified as genotoxic or nongenotoxic.Genotoxins cause irreversible genetic damage or mutations by binding toDNA. Genotoxins include chemical agents likeN-nitroso-N-methylurea (NMU) or non-chemical agents such asultraviolet light andionizing 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.[35]
TheInternational Agency for Research on Cancer (IARC) is an intergovernmental agency established in 1965, which forms part of theWorld Health Organization of theUnited Nations. It is based inLyon,France. Since 1971 it has published a series ofMonographs on the Evaluation of Carcinogenic Risks to Humans[36] that have been highly influential in the classification of possible carcinogens.
Group 1: the agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
Group 2A: the agent (mixture) is most likely (product more likely to be) carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
Group 2B: the agent (mixture) is possibly (chance of product being) 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 most likely not carcinogenic to humans.
TheGlobally Harmonized System of Classification and Labelling of Chemicals (GHS) is aUnited 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
TheAmerican Conference of Governmental Industrial Hygienists (ACGIH) is a private organization best known for its publication ofthreshold limit values (TLVs) for occupational exposure and monographs on workplace chemical hazards. It assesses carcinogenicity as part of a 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
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.
Under a previous name, the NOHSC, in 1999Safe Work Australia published the Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(1999)].[40]Section 4.76 of this document outlines the criteria for classifying carcinogens as approved by the Australian government. This classification consists of three categories:
Category 1: Substances known to be carcinogenic to humans.
Category 2: Substances that should be regarded as if they were carcinogenic to humans.
Category 3: Substances that have possible carcinogenic effects in humans but about which there is insufficient information to make an assessment.
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[41]).
Lung cancer (pulmonary carcinoma) 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).[42] 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 withsmoking 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%).[43]
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.[44] 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.[citation needed] 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 is the second most common cancer [(1.4 million cases, 10.9%), but ranks 5th as cause of death (458,000, 6.1%)].[42] Increased risk of breast cancer is associated with persistently elevated blood levels ofestrogen.[45] 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 IIdetoxification enzymes that metabolizeROS leading to increased oxidative DNA damage.[46][47][48]
The major estrogen in humans,estradiol, can be metabolized to quinone derivatives that formadducts with DNA.[49] These derivatives can cause depurination, 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.[49] Genetic background, dietary practices and environmental factors also likely contribute to the incidence of DNA damage and breast cancer risk.
Consumption ofalcohol has also been linked to an increased risk for breast cancer.[50]
Colorectal cancer is the third most common cancer [1.2 million cases (9.4%), 608,000 deaths (8.0%)].[42] Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States.[51] In addition, substantial evidence implicatesbile acids as an important factor in colon cancer. Twelve studies (summarized in Bernstein et al.[52]) indicate that the bile acids deoxycholic acid (DCA) or lithocholic acid (LCA) induce production of DNA-damaging reactive oxygen species 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.[52] 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.[52] 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.[53] Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging carcinogens in colon cancer.
Stomach cancer is the fourth most common cancer [990,000 cases (7.8%), 738,000 deaths (9.7%)].[42]Helicobacter pylori infection is the main causative factor in stomach cancer. Chronicgastritis (inflammation) caused byH. pylori is often long-standing if not treated. Infection of gastric epithelial cells withH. pylori results in increased production of reactive oxygen species (ROS).[54][55] 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. ThusH. pylori-induced ROS appear to be the major carcinogens in stomach cancer because they cause oxidative DNA damage leading to carcinogenic mutations.
Diet is also thought to be a contributing factor in stomach cancer: in Japan, where very salty pickled foods are popular, the incidence of stomach cancer is high. Preserved meat such as bacon, sausages, and ham increases the risk, while a diet rich in fresh fruit, vegetables, peas, beans, grains, nuts, seeds, herbs, and spices will reduce the risk. The risk also increases with age.[56]
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