**5. Mechanisms of chemical carcinogenesis**

As part of daily existence, DNA frequently sustains damage. If unrepaired, this can lead to mutations that replicate resulting in abnormal and cancerous development. Some biological mechanisms usually inhibit this process. An enzyme 8-oxoguanine DNA glycosylase (OGG1) among others repairs DNA by excising damaged nitrogen bases constituting the DNA. DNA damage may occur through exposure to chemicals present in cigarette smoke, ionizing radiation and oxidative stress, which can be induced by a number of chemicals such as cadmium and the polycyclic aromatic hydrocarbons. The levels of OGG1 can thus be used to predict an individual's risk of developing cancer.

At least four fundamentally different mechanisms of cancer induction by chemicals have been identified. These may lead to cancer as individual processes or on occasion, the same agent may exert its effects through two or more processes to lead to tumor formation. The importance of the mutation/proliferation approach to the development of cancer lies in its ability to encompass each of these mechanisms within a single frame work. This as has been demonstrated (Clayson, 2001), means that if we can measure changes in mutation and proliferation frequencies, due to a specific carcinogen, there may be no need to elucidate the detailed mechanism of carcinogenesis for every chemical carcinogen before attempting to calculate accurately the risk it may carry for exposed human subjects. This requires exquisite

DNA and a carcinogen or its metabolite) by benzo (*a*) pyrene (Carrel et al., 1997) and aflatoxin B1 (Croy et al., 1978). The concepts developed in investigating mechanisms of chemical carcinogenesis also led to discoveries that are relevant to other human conditions in addition to cancer, including atherosclerosis, cirrhosis, and aging. The fact that genetic changes in individual cancer cells are essentially irreversible and that malignant changes are transmitted from one generation of cells to another strongly points to DNA as the critical cellular target modified by environmental chemicals. DNA damage by chemicals occurs randomly; the phenotypes of associated carcinogenic changes are determined by selection. Epidemiologic studies from all over the world have identified environmental and occupational chemicals as potential carcinogens. The most definitive epidemiologic studies have been those in which a small group is exposed to a tremendously large amount of a specific chemical, such as aniline dyes. The table below (table 3) lists some of the fairly well

> Skin, lungs Lungs

Skin, Lungs Liver

Lungs Renal pelvis

Bladder

As part of daily existence, DNA frequently sustains damage. If unrepaired, this can lead to mutations that replicate resulting in abnormal and cancerous development. Some biological mechanisms usually inhibit this process. An enzyme 8-oxoguanine DNA glycosylase (OGG1) among others repairs DNA by excising damaged nitrogen bases constituting the DNA. DNA damage may occur through exposure to chemicals present in cigarette smoke, ionizing radiation and oxidative stress, which can be induced by a number of chemicals such as cadmium and the polycyclic aromatic hydrocarbons. The levels of OGG1 can thus be

At least four fundamentally different mechanisms of cancer induction by chemicals have been identified. These may lead to cancer as individual processes or on occasion, the same agent may exert its effects through two or more processes to lead to tumor formation. The importance of the mutation/proliferation approach to the development of cancer lies in its ability to encompass each of these mechanisms within a single frame work. This as has been demonstrated (Clayson, 2001), means that if we can measure changes in mutation and proliferation frequencies, due to a specific carcinogen, there may be no need to elucidate the detailed mechanism of carcinogenesis for every chemical carcinogen before attempting to calculate accurately the risk it may carry for exposed human subjects. This requires exquisite

Urinary bladder Lungs, nasal sinuses

Oesophagus, Liver, Kidney, stomach

characterized chemicals sites where they have induced cancer.

**Chemical mixtures** Soots, tars, oils

**Industrial chemicals** Benzidine

**Drugs** Mustard gas

Table 3. List of Chemical Carcinogens.

**Naturally occuring compounds** 

**Carcinogens Site of cancer** 

Cigarette smoke

Nickel compound

Arsenic Vinyl choride

Phenacetin

Cyclomates

**5. Mechanisms of chemical carcinogenesis** 

used to predict an individual's risk of developing cancer.

Nitroso compounds

and very sensitive instruments, and appears to be one challenge to specialists in biomedical engineering. Fortunately by the wide range of flow cytometry and mass spectrometry based techniques, the field of biomedical engineering appears to be rising to the challenge. It needs not be emphasized that a great deal of thought and effort will be required if mutation rates and proliferation in specific cell types are to be measured in humans by non-invasiveness.

A number of chemical carcinogens now appear to exert their primary effect on the mutational part of the carcinogenic process, while some others seem to be relatively devoid of the ability to interact with DNA and appear to work mainly through a mechanism of induction of cellular proliferation. Mutation on the other hand appears to be induced by chemical carcinogens by at least two major modes. The modes involve direct interaction with the DNA through the formation of highly reactive, positively charged entities known as "electrophiles" This entity is capable of reacting chemically with many different cellular constituents, including the genetic material, DNA (Miller et al, 1961). The adducts formed with DNA the interaction products of such carcinogen-derived electrophiles with DNA, are not regarded as genetic lesions in their own right. They only represent the first stage in the formation of a mutational event. The adducts may be effectively repaired by the DNA repair enzyme system found in the cell nucleus as earlier indicated. In the alternative, if they are not repaired they may affect important sites on the DNA and consequently die, or if the DNA replicates while they are still present, may lead to mutations through base-mispairing or other errors, that is culminating in true genetic lesions. This has been broadly illustrated by the figure below (figure 3).

Fig. 3. Overview of genotoxic and non-genotoxic effects of carcinogens.

If the induced mutations occur at one or a relatively few critical sites on the DNA, then the cells may be converted from a "normal" to a preneoplastic state. Chemically-induced mutations are not limited to critical genes, different pretumor cells may demonstrate a variety of different growth potentials due to the range of altered " non-critical" genes, thus enabling those cells with most favourable properties to transform most rapidly to clinically apparent tumours. Alternatively, the carcinogens may act indirectly through the formation of reactive oxygen species or nitrogen radicals, some types of which are also highly reactive with macromolecules such as DNA. The process of raised cellular proliferation is also multifactorial in its genesis. It may arise from, for instance, direct hormone-like stimulation of specific cell types, from perturbation of tissue processes that lead to a balance between cell proliferation and cell death (apoptosis), it may alternatively arise from massive cell-killing or cytotoxicity followed by proliferative regeneration to maintain the physiological functioning of the affected tissues. A yet further way by which excess, tumor-inducing cellular division may be induced is that exhibited by the urinary bladder. Oyasu and his colleagues (1981) and in his subsequent studies (1995) showed by using heterotopical transplant rat bladder technique that urine by itself, but not water can induce proliferation. The mechanism by which this happens is not quite clear.

It was however conceived that urine contained epithelial growth factors that stimulate cell division and that such factors would penetrate the epithelium should it be injured by the presence of a foreign agent in the bladder. A fourth type of mechanism of carcinogenesis may arise from the ability of the agent to form a complex with a specific protein. This complex (ligand-protein) may have the property of altering the expression of specific and important region in the DNA. There is the emerging but incompletely understood involvement of epigenetics; alteration in the genetic processes not involving DNA base sequence. Many epimutagens have already been identified and a number of existing chemicals such as cadmium are also known to act through this pathway.
