Chemical Carcinogenesis and Classification of Agents
Thousands of potentially hazardous compounds exist, but only about twenty have a proven role in human carcinogenesis. Clear examples include occupational cancers: contact with aniline dyes causes bladder cancer, working with asbestos leads to lung cancer, and polyvinyl chloride production is associated with hepatic angiosarcoma.
Chemical carcinogens are divided into two large groups based on their mechanism of interaction with the cell:
- Genotoxic agents. Damage DNA directly or after metabolic activation. These include polycyclic aromatic hydrocarbons, aromatic amines, and nitroso compounds.
- Non-genotoxic (epigenetic) agents. Do not yield positive results in mutagenicity assays, yet their administration induces tumor development (e.g., organochlorine compounds and immunosuppressants).
Genotoxic agents can be direct-acting (interact directly with DNA without requiring modifications) or indirect-acting (procarcinogens). The latter require metabolic activation involving the monooxygenase system (cytochrome P450), epoxide hydrolases, and transferases. This process occurs most actively in the liver, as well as in the epithelium of the bronchi, kidneys, and gastrointestinal tract. Consequently, active metabolites are formed that cause alkylation of DNA bases (adenine, guanine, etc.) and point mutations.
Stages of Chemically Induced Tumor Development
The process does not occur instantaneously and involves sequential stages, each requiring specific factors:
- Initiation. The carcinogen interacts with the genome, causing an irreversible alteration. However, initiation alone is insufficient for malignant transformation.
- Promotion. An additional agent — a promoter (often an epigenetic carcinogen or a substance not carcinogenic on its own) — comes into play. It provokes further genetic damage, after which the cell undergoes malignant transformation and begins to divide uncontrollably.
It is important to remember that the effect of carcinogens depends on the dose and duration of exposure, with no safe threshold, and the effects of different substances can be cumulative.
Endogenous Chemical Carcinogens
Not all hazardous substances come from external (exogenous) sources. Some are formed within the body against the background of chronic hypoxia or prolonged diseases. Endogenous carcinogens include:
- Bile acids and cholesterol;
- Tryptophan;
- Lipid peroxides;
- Certain steroid hormones.
Physical Carcinogenesis (Radiation)
Physical factors also exert their effects primarily through DNA damage. Three main groups are distinguished:
- Ultraviolet (UV) radiation. The carcinogenic effect of solar radiation is well established and is a primary cause of melanoma. Individuals in near-equatorial regions, especially those with fair skin, are at maximum risk. The pigment melanin provides a protective function here by shielding cells from the mutagenic effects of UV rays.
- Ionizing radiation. This became a critical issue in the second half of the 20th century due to atomic bombings, nuclear testing, nuclear power plant accidents, and medical X-rays.
- Radioactive substances.
Classic examples of radiation carcinogenesis include occupational diseases: lung cancer in uranium miners (due to inhalation of radioactive radon gas) and bone sarcomas in workers who painted watch dials with luminous paint (accumulation of radioactive particles in bone tissue). Large-scale radiation disasters, such as the Chornobyl accident, lead to a sharp increase in cancer incidence, primarily leukemias and solid tumors.