Module 3: Toxicology - Section 13: Occupational Carcinogenesis

TOX 13.2: Stages of Carcinogenicity - Initiation

MECHANISMS AND THEORIES OF CARCINOGENESIS

STAGES OF CARCINOGENICITY

Evidence from animal studies has shown that carcinogenesis has distinct biological stages. These have been mathematically modelled by Armitage and Doll in a multistage model.  The ILO encyclopaedia discusses various  models and views the most explanatory and simple theory to be that proposed by Moolgavkar in 1989 which involves  a mutation of a healthy stem cell whose growth and development into intermediate cells is encouraged by promoters, one or more of which will undergo further mutations producing a malignant cancer. The three stages are referred to as initiation, promotion and progression.  There appear to be no "complete"  occupational carcinogens with most being either intiators or promotors.  This is why most occupational cancers have such a long induction period.

INITIATION:

This results from an irreversible genetic alteration in a single cell or small number of cells. It is triggered by mutation of DNA following its interaction with carcinogenic agents. Initiation may remain dormant for many cell cycles, passing initiating mutations to successive generations of daughter cells. This step is generally insufficient for the development of cancer. Another theory of initiation is the presence of specific genes such as oncogenes or defective tumour supressor genes resulting from DNA mutation.

Carcinogen Metabolism:

The primary steps in chemical carcinogenesis actually occur before the interaction of the chemical with the DNA. Most carcinogens are not very reactive and the complex detoxification (cytochrome P₄₁₃₀) enzyme systems convert them into water soluble electrophilic form, thereby assisting in the removal of the toxic agents by the body (liver, kidneys). In some cases however, the intermediates produced during the reactions involving the P4130 system form complexes with the DNA. These DNA-chemical adducts, if not quickly repaired can lead to DNA mutations and the initiation of neoplasia. If this metabolic activity is required for carcinogenesis, then the parent compound is referred to as the proximate carcinogen and the metabolite that reacts with the DNA is called the ultimate carcinogen. This process is often species or tissue specific.

Not all chemical carcinogens need interact in this indirect way. Direct acting carcinogens can also produce adducts with DNA. Direct acting agents often produce effects in diverse organs as opposed to the indirect agents which affect specific organs (eg liver). Each agent may produce a myriad DNA adducts of which only one need be responsible for the carcinogenic effect (from a DNA mutation).

Oncogene Theory of Cancer:

This theory holds  that tumour viruses contain genes which following infection, transform the host cell.  These genes, which are termed oncogenes,  are integrated into the chromosome of the target cell, where they remain silent until either by accident or through some damaging event caused by chemicals or radiation, the cancer genes are expressed. 

Postgraduate Diploma in Occupational Health (DOH) - Modules 3: Occupational Medicine & Toxicology (Basic) by Profs Mohamed Jeebhay and Rodney Ehrlich, Health Sciences UCT is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2.5 South Africa License. Major contributors: Mohamed Jeebhay, Rodney Ehrlich, Jonny Myers, Leslie London, Sophie Kisting, Rajen Naidoo, Saloshni Naidoo. Source available from here. For any updates to the material, or more permissions beyond the scope of this license, please email healthoer@uct.ac.za or visit www.healthedu.uct.ac.za. Last updated Jan 2007.
Disclaimer note: Some resources and descriptions may be out-dated. For suggested updates and feedback, please contact healthoer@uct.ac.za.