Some chemicals are neither initiators nor growth promoters, and they are not carcinogenic in themselves, but they can enhance the effects of initiators and growth promoters, that is, they can accelerate the process of carcinogenesis. Such substances are called carcinogens. The common carcinogens are sulfur dioxide, ethanol, catechol, pyrene and dodecane. Crotonol diester, which can promote growth, is also a carcinogen. Carcinogens are different from growth promoters. Growth promoter can only promote the proliferation of cancerous cells, but has no effect on initiator; While that carcinogen can enhance and promote both the body initiator and the growth promoter which are contac with the carcinogen at the same time. Strictly speaking, carcinogens are not carcinogens, but carcinogens often induce tumors under the synergistic effect of carcinogens. When identifying the carcinogenicity of chemicals and evaluating their harm to the body, we should fully consider the role of various carcinogens.
Some chemical carcinogens have a direct carcinogenic effect, which can cause cancer without biotransformation in the body, and are called direct carcinogens. Some chemical carcinogens themselves are not directly carcinogenic, and the derivatives formed by biotransformation in the body have carcinogenic effects, which are called indirect carcinogens, and the transformation process is called metabolic activation of carcinogens. Known chemical carcinogens are mostly indirect carcinogens.
Derivatives with carcinogenic effects formed by direct carcinogens and indirect carcinogens are collectively referred to as terminal carcinogens. Indirect carcinogens that must undergo metabolic activation to have carcinogenic effects are called precancers. Among a series of intermediate metabolites formed by the metabolic activation of pre-carcinogens, some have certain carcinogenic effects, but they are not final carcinogens. Such substances are called near carcinogens or semi-carcinogens.
Carcinogens can be divided into confirmed carcinogens, suspected carcinogens and potential carcinogens according to their different carcinogenic effects on humans and mammals. Confirmed that carcinogens have been confirmed to have carcinogenic effects through animal experiments and population epidemiological investigations. It is suspected that carcinogens are carcinogenic in animals, but also in many animals, especially in primates closely related to human beings. However, there are only a few clinical reports of carcinogenesis in humans, which have not been confirmed in population epidemiological investigations. Potential carcinogens are carcinogenic to animals, but there is no data to show that they are carcinogenic to humans, but they are carcinogenic to humans.
Since 197 1, the International Agency for Research on Cancer (IARC) affiliated to the World Health Organization has compiled the information about chemical carcinogens in various countries into a book, and by 1980, 25 volumes have been published. It is reported in the book that 140 kinds of chemicals have been identified as carcinogenic to animals. According to epidemiological investigation, only 2 1 species [such as benzo (a) pyrene and some nitroso compounds] are carcinogenic to humans, and another 18 species are suspected to be carcinogenic to humans.
The chemicals that have been studied for carcinogenicity by IARC are classified into four categories: 1, which has sufficient evidence of carcinogenicity to human beings; Type 2, the evidence of carcinogenicity in group A is limited, but the evidence of carcinogenicity in animals is sufficient, and the evidence of carcinogenicity in group B is limited and the evidence of carcinogenicity in animals is not sufficient; Category 3, the existing evidence fails to grade and evaluate human carcinogenicity; Category 4, which may be non-carcinogenic to people.
Since 198 1 year, Weisburger and Williams put forward the classification table of carcinogens mainly according to their action characteristics, and revised it many times later. Carcinogens can now be divided into three categories.
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Genotoxic carcinogen
Most of the "classic" organic carcinogens basically belong to this category.
(1) The inherent characteristics of the chemical structure of direct carcinogens are that they have electrophilic activity without metabolic activation (with few exceptions), and can combine with nucleophilic molecules (including DNA) to form an adduct. Most of these substances are synthetic organic compounds, including lactones (such as β-propenolide, propane sultone and a,β- unsaturated hexacyclopropyl ester); Alkene epoxide (such as 1,2,3,4- butadiene epoxide); Sub-gum; Sulfates; Mustard gas and nitrogen mustard; Active halogenated hydrocarbons (such as dichloromethyl ether, benzyl chloride, methyl iodide and dimethylaminoformyl chloride), in which the higher halogenated hydrocarbon homologues of dichloromethanol decrease their carcinogenic activity with the increase of alkyl carbon atoms. In addition to the alkylating agents mentioned above, some platinum coordination complexes (such as platinum dichloride, platinum dichloride (pyrrolidine), and platinum dioxo-1, 2- diaminocyclohexane) also have direct carcinogenic activity, and the cis isomer is usually more active than the trans isomer.
(2) Indirect carcinogens, such carcinogens, often do not cause cancer in the local contact area, but in the tissues where metabolic activation occurs. Precursors can be divided into two categories: natural and synthetic. Synthetic ones include polycyclic or heterocyclic aromatic hydrocarbons [such as benzo (a) pyrene, benzo (a) anthracene, 3-methylcholanthrene, 7, 12-H toluene (a) anthracene, dibenzo (a,h) anthracene, etc.]; Monocyclic aromatic amines (such as o-toluidine, o-anisidine); Bicyclic or polycyclic aromatic amines (such as 2- naphthylamine, benzidine, etc.); Quinoline (such as benzo (g) quinoline, etc.); Nitrofuran; Azo compounds (such as dimethylaminoazobenzene, etc.); Chain or cyclic nitrosamines are almost carcinogenic. However, with the different alkyl groups, the target organs are also different; Dimethyl hydrazine in alkyl hydrazine can cause cancer, and hydrazine itself has weak carcinogenicity; Formaldehyde and acetaldehyde; Acetic acid, propyl ester and butyl ester in carbamate are all carcinogenic, among which urethane (urethane, also known as urethane) has the strongest carcinogenic ability, and the carcinogenic effect of vinyl chloride in halogenated hydrocarbons has been widely concerned in recent years. It is characterized by inducing hepatic angiosarcoma.
Natural substances and their processed products account for 5 of the 34 human carcinogens published in union for international cancer control (IARC) 1978, including aflatoxin, cyclosporine A, tobacco and smoke, betel nut and alcoholic beverages.
Aflatoxin B 1 is already one of the strongest carcinogens, while aflatoxin G 1 has much lower carcinogenicity. Aflatoxin B2 and G2 are not carcinogenic by themselves, but it is considered that B2 can be biotransformed into a small part of B 1 in vivo, so it also has a certain carcinogenicity. Aflatoxin B 1 can induce liver cancer in humans and various experimental animals except mice, and can also induce kidney cancer and colon cancer under special conditions. It may be that the activity level of GSH transferase is high in mice, which can effectively detoxify.
The products of some poisonous bacteria, such as cyclosporine A, doxorubicin, daunomycin and gentamicin, are also pre-carcinogens. These substances are often used as medicines. Tobacco will contain carcinogens such as nitroso-nornicotine even if it has not been burned and pyrolyzed. Tobacco smoke contains many carcinogens, such as polycyclic aromatic hydrocarbons, heterocyclic compounds, phenolic derivatives and other carcinogens. Tobacco smoke also contains a lot of cancer-promoting substances, which is one of the reasons for advocating quitting smoking. Nitrosamines contained in chewing tobacco leaves and using snuff can induce oral cancer and upper respiratory cancer. Arecoline in betel nut can form nitrosamines, and chewing betel nut can increase the incidence and mortality of oral cancer and upper digestive tract cancer.
(3) Inorganic carcinogens such as cobalt, radium and radon may cause cancer due to their radioactivity. Nickel, chromium, lead, beryllium and some of their salts can cause cancer under certain conditions, among which nickel and titanium are the most carcinogenic.
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Non-genotoxic carcinogen
Refers to carcinogens that cannot react with DNA according to current tests.
(1) Although the cancer promoter alone does not cause cancer, it can promote the carcinogen with a sub-carcinogenic dose to cause cancer after contact with the body, so it is considered that the cancer promoter is a necessary condition for carcinogenesis.
TPA is a typical cancer promoter in the two-stage mouse skin cancer induction test, which has cancer promoting effect in various cell systems in vitro. Phenobarbital can promote the occurrence of liver cancer in rats or mice. Tryptophan and its metabolites and saccharin can also promote bladder cancer. Butylated hydroxy-toluene, BHT) has been widely used in recent years as a cancer promoter to induce lung tumors in mice, and it also has a cancer promoting effect on hepatocellular adenoma and bladder cancer. DDT, polychlorinated biphenyls, chlordane and TCDD are promoters of liver cancer.
It is worth noting that the detoxification process, especially the binding reaction, may be enhanced due to the induction of metabolic enzymes. Some cancer promoters, such as phenobarbital, DDT and BHT, may reduce the occurrence of tumors when ingested at the same time as the initiator. But they were found to act as cancer AIDS.
(2) The oldest theory of cytotoxicants is that chronic stimulation can cause cancer. At present, it is believed that substances that cause cell death can cause compensatory proliferation, resulting in tumors. The exact mechanism is not clear, but it may involve the increased susceptibility of the body to carcinogenesis caused by environmental harmful factors. The mechanism of some chlorinated hydrocarbon carcinogens may be related to cytotoxicity.
Nitrilotriacetic acid, NTA) can cause renal cancer and bladder cancer in rats and mice. It was found that its mechanism of action was to bring zinc from blood into renal tubular ultrafiltrate and be reabsorbed by renal tubular epithelium. Because zinc is toxic to these cells, it can cause damage and cell death, resulting in proliferation and renal tumor formation. In urine, NTA also complexes with calcium, which causes calcium to seep out from the transitional epithelium of renal pelvis and bladder, thus stimulating cell proliferation and forming tumors.
(3) It was discovered 40 years ago that estrogen can cause animal tumors. It was later found that most substances that interfere with the function of endocrine organs can increase the number of tumors in these organs. The carcinogenic mechanism of estrogen is not clear, but it is likely to be related to cancer promotion; It is generally believed that it takes a long time to maintain a high level of hormones in the body to induce tumors in endocrine sensitive organs.
When pregnant women use synthetic estrogen (DES) to protect their fetus, it may cause vaginal clear cell cancer in adolescent women. Its mechanism is quite complicated.
(4) The immunosuppression process of immunosuppressants affects tumor formation in many ways. Immunosuppressants such as azathioprine and 6- mercaptopurine or immune serum can cause leukemia or lymphoma in animals and people, but few solid tumors occur. Cyclosporine A is an immunosuppressant used in organ transplantation in recent years, which was once thought not to cause cancer. However, it has been found that the incidence of lymphoma in patients who have used this drug has increased.
(5) After embedding plastic under the skin of rodents, after a long incubation period, sarcoma can be formed. Its chemical composition is not important, as long as it is thin, even metal can cause tumor formation as well as various plastics. The key is size and shape, and the smooth one is more effective than the rough one, and the porous one is worse than the non-porous one. Its mechanism may be that solid substances can provide a base for the proliferation of epithelial fibroblasts. Asbestos and other mineral dust, such as uranium ore or hematite dust, can enhance the role of smoking in lung cancer.
(6) Peroxisome proliferators have various substances that can proliferate peroxisome in rodent liver, which can induce liver tumors. Peroxisome proliferators have been found, such as ethyl isobutyrate Clofribate, fenofibrate, gemfibrate, tibric acid, plasticizer di -(2- ethylhexyl) phthalate and organic solvent 1,l,2- trichloroethylene. Antoine and bis (2- ethylhexyl) phthalate can promote liver tumors, but the carcinogenic mechanism of these substances cannot be summarized by promoting cancer. At present, it is believed that the increase of liver peroxisome and H202 can lead to the increase of reactive oxygen species, signal transduction, DNA damage and carcinogenesis.
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Undetermined genotoxic carcinogen
As mentioned earlier, some halogenated hydrocarbons are genotoxic carcinogens, while others are cancer promoters. Others, such as carbon tetrachloride, chloroform, some polychlorinated alkanes and olefins, have not been fully clarified. These substances are negative or suspicious in mutagenicity test, and in vivo and in vitro studies have not shown that they can be converted into active electrophilic metabolites. Thiourea, thioacetamide, thiourea pyrimidine and similar thioamides are carcinogenic. The target organ is the thyroid gland and sometimes the liver. Methapyrine, an antihistamine, was widely used as a hypnotic in the United States, and was later found to induce liver cancer in rats.
In addition, some scholars and research institutions also classify carcinogens into proved carcinogen, suspected carcinogen and potential carcinogen. In addition, they are classified by chemical structure, such as alkylation, polycyclic aromatic hydrocarbons, nitrosamines, phytotoxins and metals.
Primary carcinogen
There are four primary carcinogens: aflatoxin, nitrosamines, dioxins and nicotine.
Note: Sometimes nitrite such as sodium nitrite (-－NO2, organic matter containing "azo group (n = n)" can also be considered as primary carcinogens.
Sources of primary carcinogens
Aflatoxin: It is the most common from rotten peanuts, peanut oil, corn, rice and cottonseed.
Nitrosamines: from rotten grain, vegetables, fish and egg milk.
Dioxins: from tar, asphalt (so don't go to the newly paved road) and plastic burning (which is very harmful).
Nicotine: from tobacco
Sodium nitrite: Pickled vegetables from industrial salt.
Azo group: such as fake pork, etc.