Carcinogens: what are they and what are they?

The development of tumors is the result of the interaction of carcinogenic factors and the body. According to the World Health Organization (WHO), cancer is 80-90% related to environmental factors. Carcinogens constantly affect the human body throughout life.

The concepts of specific agents causing tumors initially arose in the field of professional pathology. They developed gradually and underwent significant evolution. Initially, during the period of dominance of R. Virchow's ideas on the role of irritation in the development of cancer, various factors of chronic damage, both mechanical and chemical, were attributed to them. However, since the beginning of the 20th century, as experimental oncology, chemistry, physics, virology developed, and thanks to systematic epidemiological studies, clear, specific concepts of carcinogenic agents have emerged.

The WHO Expert Committee gave the following definition of the concept of carcinogen: "Carcinogens are agents capable of causing or accelerating the development of a neoplasm, regardless of the mechanism of its action or the degree of specificity of the effect. Carcinogens are agents that, due to their physical or chemical properties, can cause irreversible changes or damage in those parts of the genetic apparatus that carry out homeostatic control over somatic cells" (WHO, 1979).

It is now firmly established that tumors can be caused by chemical, physical or biological carcinogens.

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Chemical carcinogens

Experimental studies on the experimental induction of tumors by various agents in animals, begun at the beginning of the 20th century by K. Yamagiwa and K. Ichikawa (1918), led to the discovery of a significant number of chemical compounds of various structures, which received the general name blastomogenic, or carcinogenic, substances.

One of the outstanding researchers of this problem was E. Kennaway, who in the 1930s isolated benzo(a)pyrene, the first of the currently known chemical carcinogens in the environment. In the same years, T. Yoshida and R. Kinosita discovered a group of carcinogenic aminoazo compounds, and W. Heuper was the first to demonstrate the carcinogenicity of aromatic amines. In the 1950s, P. Magee and J. Barnes, and then H. Druckrey et al. identified a group of carcinogenic N-nitroso compounds. At the same time, the carcinogenicity of some metals was demonstrated, and the carcinogenic properties of individual natural compounds (aflatoxins) and drugs were revealed. These experimental studies confirmed the results of epidemiological observations on the occurrence of tumors in humans.

Currently, all known chemical carcinogens are divided into classes according to their chemical structure.

1. Polycyclic aromatic hydrocarbons (PAHs).
2. Aromatic azo compounds.
3. Aromatic amino compounds.
4. Nitroso compounds and nitramines.
5. Metals, metalloids and inorganic salts.

Depending on the nature of their effect on the body, chemical carcinogens are divided into three groups:

1. carcinogens that cause tumors primarily at the site of application;
2. carcinogens of remote selective action, causing a tumor in one or another organ;
3. multiple-action carcinogens that provoke the development of tumors of different morphological structures and in various organs.

The International Agency for Research on Cancer (Lyon, France), which is a specialized body of the WHO, has summarized and analyzed information on carcinogenic factors. More than 70 volumes published by the agency contain data indicating that out of approximately 1,000 agents suspected of carcinogenicity, only 75 substances, industrial hazards, and other factors have been proven to cause cancer in humans. The most reliable evidence comes from long-term epidemiological observations of large groups of people in many countries, which have shown that contact with substances in industrial conditions caused the formation of malignant tumors. However, the evidence of the carcinogenicity of hundreds of other substances in causing cancer in humans is indirect rather than direct. For example, chemicals such as nitrosamines or benz(a)pyrene cause cancer in experiments on many animal species. Under their influence, normal human cells cultured in an artificial environment can turn into malignant cells. Although this evidence is not supported by a statistically significant number of human observations, the carcinogenic hazard of such compounds is beyond doubt.

The International Agency for Research on Cancer has compiled a detailed classification of factors studied for carcinogenicity. In accordance with this classification, all chemical substances are divided into three categories. The first category is substances that are carcinogenic to humans and animals (asbestos, benzene, benzidine, chromium, vinyl chloride, etc.). The second category is probable carcinogens. This category is in turn divided into subgroup A (high-probability carcinogens), represented by hundreds of substances that are carcinogenic to animals of two or more species (aflatoxin, benz(a)pyrene, beryllium, etc.), and subgroup B (low-probability carcinogens), characterized by carcinogenic properties for animals of one species (adriamycin, chlorophenols, cadmium, etc.). The third category is carcinogens, substances or groups of compounds that cannot be classified due to lack of data.

The named list of substances is currently the most convincing international document containing data on carcinogenic agents and the degree of evidence of their carcinogenic danger to humans.

Regardless of the structure and physical and chemical properties, all chemical carcinogens have a number of common features of action. First of all, all carcinogens are characterized by a long latent period of action. It is necessary to distinguish between the true, or biological, and clinical latent periods. Malignancy of cells does not begin from the moment of their contact with the carcinogen. Chemical carcinogens undergo biotransformation processes in the body, resulting in the formation of carcinogenic metabolites, which, penetrating the cell, cause profound disturbances that are fixed in its genetic apparatus, causing malignancy of the cell.

The true, or biological, latent period is the period of time from the formation of carcinogenic metabolites in the body to the onset of uncontrolled proliferation of malignant cells. The concept of clinical latent period is usually used, which is significantly longer than the biological one. It is calculated as the time from the onset of contact with a carcinogenic agent to the clinical detection of a tumor.

The second significant pattern of action of carcinogens is the “dose-time-effect” relationship: the higher the single dose of the substance, the shorter the latent period and the higher the incidence of tumors.

Another pattern characteristic of the action of carcinogens is the staging of morphological changes preceding the development of cancer. These stages include diffuse uneven hyperplasia, focal proliferates, benign and malignant tumors.

Chemical carcinogens are divided into two groups depending on their nature. The overwhelming majority of carcinogenic chemical compounds are of anthropogenic origin, their appearance in the environment is associated with human activity. Currently, many technological operations are known in which, for example, the most common carcinogens - polycyclic aromatic hydrocarbons - can be formed. These are primarily processes associated with the combustion and thermal processing of fuel and other organic materials.

The second group is natural carcinogens not associated with industrial or other human activities. These include waste products of some plants (alkaloids) or mold fungi (mycotoxins). Thus, aflatoxins are metabolites of the corresponding microscopic mold fungi that parasitize on various food products and feed.

Previously, it was assumed that aflatoxin-producing fungi were found only in tropical and subtropical countries. According to modern concepts, the potential danger of these fungi, and therefore of food contamination with aflatoxins, is almost universal, with the exception of cold climate countries such as Northern Europe and Canada.

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Physical carcinogens

These include the following carcinogens:

• various types of ionizing radiation (X-rays, gamma rays, elementary particles of the atom - protons, neutrons, alpha, beta particles, etc.);
• ultraviolet radiation;
• mechanical tissue trauma.

It should be noted that even before the discovery of chemical carcinogens, in 1902 E. Frieben described skin cancer in humans caused by X-rays, and in 1910 J. Clunet was the first to obtain tumors in animals using X-ray irradiation. In subsequent years, through the efforts of many radiobiologists and oncologists, including domestic ones, it was established that tumorigenic effects are caused not only by various types of artificially induced ionizing radiation, but also by natural sources, including ultraviolet radiation from the sun.

In modern literature, only radiation factors are considered physical carcinogenic agents of the environment - ionizing radiation of all types and kinds and ultraviolet radiation from the sun.

Considering carcinogenesis as a multistage process consisting of initiation, promotion and progression, it has been established that ionizing radiation is a weak mutagen in the activation of proto-oncogenes, which may be important in the early stages of carcinogenesis. At the same time, ionizing radiation is highly effective in deactivating tumor suppressor genes, which is important for tumor progression.

Biological carcinogens

The question of the role of viruses in the etiology of tumors arose at the beginning of the 20th century. In 1910, P. Rous was the first to transplant a tumor in birds with a cell-free filtrate and explained this by the presence of a tumor virus, thereby confirming the position of A. Borrel and even earlier authors on viruses as the cause of cancer.

It is currently known that 30% of all cancers are caused by viruses, including human papillomaviruses. Human papillomavirus is detected in 75-95% of cases of squamous cell carcinoma of the cervix. Several types of human papillomavirus have been found in tumors of invasive cancer of the oral cavity, oropharynx, larynx, and nasal cavity. Human papillomaviruses of types 16 and 18 play an important role in the carcinogenesis of head and neck cancer, especially in oropharynx cancer (54%) and larynx cancer (38%). Scientists are studying the relationship between the herpes virus and lymphomas, Kaposi's sarcoma, and the hepatitis B and C viruses and liver cancer.

However, the incidence of cancer is an order of magnitude lower than the frequency of viral infections. This suggests that the presence of viruses alone is not enough for the development of a tumor process. Some cellular changes or changes in the host's immune system are also necessary. Therefore, at the current stage of oncology and oncovirology development, it should be assumed that oncogenic viruses are not infectious from a clinical point of view. Viruses, like chemical and physical carcinogens, serve only as exogenous signals that affect endogenous oncogenes - genes that control cell division and differentiation. Molecular analysis of viruses associated with cancer development has shown that their function is, at least in part, associated with changes in the coding of suppressor proteins that regulate cell growth and apoptosis.

From the point of view of oncogenicity, viruses can be divided into "truly oncogenic" and "potentially oncogenic". The former, regardless of the conditions of interaction with the cell, cause the transformation of normal cells into tumor cells, i.e. they are natural, natural pathogens of malignant neoplasms. These include RNA-containing oncogenic viruses. The second group, including DNA-containing viruses, is capable of causing cell transformation and the formation of malignant tumors only in laboratory conditions and in animals that are not natural, natural carriers ("hosts") of these viruses.

By the beginning of the 1960s, L. A. Zilber had formulated the virogenetic hypothesis in its final form, the main postulate of which is the idea of the physical integration of the genomes of the virus and the normal cell, i.e. when an oncogenic virus enters an infected cell, the former introduces its genetic material into the chromosome of the host cell, becoming its integral part - the “genome” or “gene battery”, thereby inducing the transformation of a normal cell into a tumor cell.

The modern scheme of viral carcinogenesis is as follows:

1. the virus enters the cell; its genetic material becomes fixed in the cell by physically integrating with the cell's DNA;
2. the viral genome contains specific genes - oncogenes, the products of which are directly responsible for the transformation of a normal cell into a tumor cell; such genes as part of the integrated viral genome must begin to function with the formation of specific RNA and oncoproteins;
3. Oncoproteins - products of oncogenes - affect the cell in such a way that it loses sensitivity to the influences regulating its division, and becomes tumorous and according to other phenotypic characteristics (morphological, biochemical, etc.).

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