More than 200 years after the first reports of chemically induced cancer in humans, many carcinogenic chemicals have been identified in the environment and the workplace.
Chemical carcinogenesis typically requires chronic exposure, followed by a period of years during which a complex series of events, involving DNA damage and alterations in gene expression, take place.
The earliest carcinogen-induced events typically include DNA structural damage, which often occurs as the result of covalent binding of carcinogens to DNA (DNA-adduct formation). This results in DNA mutations, leading to alterations in protein structure and function that can result in tumorigenesis.
In experimental models of chemical carcinogenesis, DNA adducts have been shown to be necessary, but not sufficient, for tumorigenesis. Proving such a relation in humans is difficult because it requires a correlation between DNA damage, which might have occurred 10–30 years earlier, and cancer incidence.
In recent years, progress has been made in our ability to detect carcinogen-induced DNA damage in humans. Two studies have shown that increases in DNA-adduct levels are associated with cancer risk in humans.
By analogy to experiments in animal models, administration of chemopreventive agents that reduce DNA-adduct formation might also reduce human cancer risk.
In regions of the world such as Linxian, China, where dietary exposure to polycyclic aromatic hydrocarbons is suspected in the aetiology of high oesophageal cancer rates and where reducing the level of this exposure is considered economically unfeasible, chemoprevention might be appropriate.
Chemical carcinogenesis involves a complex series of events, the earliest of which typically include DNA damage and the fixation of DNA mutations. Sophisticated new techniques have been developed to quantify DNA damage and to correlate the amount of damage with cancer risk. Approaches such as these are underway in Linxian, China, where food contains high levels of DNA-damaging, carcinogenic polycyclic aromatic hydrocarbons (PAHs), and where there is high mortality from oesophageal cancer. Gaining better insight into the mechanisms by which PAH exposure might increase oesophageal cancer risk could lead to new strategies for cancer prevention.
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The BP exposure calculations for diet and smoking in Linxian and the United States were generated by H. E. Van Gijssel. Box 1a was a gift from A. Weston, and Box 1c was from D. H. Phillips. Critical comments by F. A. Beland, S. M. Dawsey, P. R. Taylor, V. E. Walker, A. Weston and S. H. Yuspa, and editorial assistance by B. Sugar are much appreciated.
The author declares no competing financial interests.
- POLYCYCLIC AROMATIC HYDROCARBONS
(PAHs). Typically products of partial combustion of organic matter that consist of multiple fused benzene rings. These must be metabolized to react with cellular macromolecules, and many PAHs, such as benzo[a]pyrene, are known to be carcinogenic in humans.
- CHEMICAL CARCINOGENESIS
A long-term multistep process by which chemical carcinogens induce tumour formation. This process typically includes DNA damage and mutagenesis (initiation), followed by selective clonal expansion (promotion), a second mutagenic mechanism responsible for the transition to malignancy (conversion), and the ability of some malignant cells to acquire more aggressive characteristics (progression).
- AROMATIC AMINES
Hydrophobic compounds that consist of two or more benzene rings with one or more amino groups placed at varying positions on the ring structures. Aromatic amines are components of dye and rubber manufacturing processes, diesel-fuel combustion, ambient pollution, cigarette smoke and some heavily cooked meats. Several aromatic amines are implicated in the aetiology of human bladder and lung cancer.
Carcinogenic by-products of mould growth that are frequently found in high concentrations in corn, peanuts and grains produced and stored in very humid areas. Aflatoxins are implicated in the aetiology of human liver cancer.
An agent or process that interacts with cellular DNA, either directly or after metabolic biotransformation, resulting in alteration of DNA structure. DNA-adduct formation comprises one type of genotoxicity.
- DNA ADDUCT
A covalent addition product formed by binding of a chemical to a DNA base.
- MOLECULAR CANCER EPIDEMIOLOGY
The application of biochemical and molecular markers in research designed to understand the continuum of events between exposure and disease, to design rational intervention strategies, and to identify groups of individuals who are most likely to be at risk of developing neoplastic disease.
Inhibition of carcinogenesis through the application of agents capable of blocking DNA-damage formation, enhancing DNA repair or accelerating cell death.
- NESTED CASE–CONTROL STUDY
In this study approach, samples are collected from an apparently healthy group of individuals who might be at high risk for a particular type of disease. At a later time, archived samples from the group are examined for an association between specific biomarkers and disease incidence. A 'nested' case–control approach is used to determine the cancer risk of individuals who were positive for this biomarker.
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