**Chemical Carcinogenesis: Risk Factors, Early Detection and Biomedical Engineering**

John I. Anetor1, Gloria O. Anetor2, Segun Adeola1 and Ijeoma Esiaba1 *1Department of Chemical Pathology, College of Medicine, University of Ibadan, 2Department of Human Kinetics and Health Education, Faculty of Education, University of Ibadan, Nigeria* 

### **1. Introduction**

68 Biomedical Science, Engineering and Technology

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Cancer is now recognized in both humans and in other multicellular animals as arising from a number of different causes, including specialized viruses, radiation, chemicals, certain highly irritative parasites (inflammation) and a number of other factors, such as specific genetic defects present in individual humans and possibly in every member of a colony of specially bred animal models. Cancer from non genetic causes largely from environmental factors, of which chemicals have a disproportionate share, is believed to contribute nearly 70% of all cancer cases. Chemical carcinogenesis originally derives from experimental induction of malignant skin tumor in mice with chemicals. Early studies indicated some agents such as polycyclic aromatic hydrocarbons (PAH) could cause cancer of the skin if they were painted on to mice in high doses. These early studies also showed that the induction of cancer was dose dependent; in low dosage they would not cause cancer but would render the skin susceptible to developing cancer on exposure to another agent, which, on its own would not induce cancer.

Thus at the dawn of the 20th century, it was recognized that chemicals cause cancer; though individual cancer causing molecules had not yet been identified, nor their cellular targets clearly known. It was however clearly understood that carcinogenesis, at the cellular level, was predominantly an irreversible process. Knowledge of the mechanisms by which chemicals cause cancer and the molecular changes that characterize tumor progression was lacking. The origin of the understanding that cancer had a cause was first pointed out by the Italian investigator, Ramazini in 1700. Seven and a half decades later, the British Surgeon, Percival Pott made the connection between exposure to soot, rich in hydrocarbons and scrotal cancer (Pott, 1775). It is now known that at the most fundamental level, cancer is caused by abnormal gene expression. This abnormal gene expression occurs through a number of mechanisms, including direct damage to the DNA, and inappropriate transcription and translation of cellular genes. The contribution of chemicals to the carcinogenic process is well known to have increased given the parallel between industrialization with associated increased chemical production and utilization and the prevalence of cancer.

Increasing use of chemicals, particularly in the industrializing developing countries (Pakin et al., 1993; Pearce et al., 1994) places new demands on these countries, as they have limited resources to adequately regulate exposure to chemicals. Majority of the chemicals cause mutation in DNA among others. The consequences of increased exposure to chemicals, risk of cancer, early detection of chemical-induced neoplastic changes and the prominent role of biomedical engineering is poorly recognized generally and particularly in the developing countries where chemical carcinogenesis is believed to be currently more prevalent (Huff and Rall,1992). Cancer is classically viewed as the result of series of mutations, including dominantly acting oncogenes and recessively acting tumor- suppressor genes. Each mutation leads to the selective overgrowth of a monoclonal population of tumor cells, and each significant tumor property (invasiveness, metastasis and drug resistance) is accounted for by such mutation (figure 1). The seminal observation that carcinogenesis is a multistage process helps to explain why some chemical carcinogens lack apparently important properties exhibited by others. Such agents may act as promoters on tissues that have been previously initiated or have the ability to produce naturally occurring tumors without treatment.

Fig. 1. Stages of the carcinogenic process

Increasing use of chemicals, particularly in the industrializing developing countries (Pakin et al., 1993; Pearce et al., 1994) places new demands on these countries, as they have limited resources to adequately regulate exposure to chemicals. Majority of the chemicals cause mutation in DNA among others. The consequences of increased exposure to chemicals, risk of cancer, early detection of chemical-induced neoplastic changes and the prominent role of biomedical engineering is poorly recognized generally and particularly in the developing countries where chemical carcinogenesis is believed to be currently more prevalent (Huff and Rall,1992). Cancer is classically viewed as the result of series of mutations, including dominantly acting oncogenes and recessively acting tumor- suppressor genes. Each mutation leads to the selective overgrowth of a monoclonal population of tumor cells, and each significant tumor property (invasiveness, metastasis and drug resistance) is accounted for by such mutation (figure 1). The seminal observation that carcinogenesis is a multistage process helps to explain why some chemical carcinogens lack apparently important properties exhibited by others. Such agents may act as promoters on tissues that have been previously

initiated or have the ability to produce naturally occurring tumors without treatment.

Fig. 1. Stages of the carcinogenic process


Table 1. Classification of chemicals with carcinogenic activity

Foulds (1969) suggested that cancer development consisted of three, rather than two processes: (1) initiation, or the conversion of normal cells to a potentially precancerous form (2) promotion, or the expansion of the clones of initiated cells to form tumors; and (3) progression, or the development of tumors to increasing levels of malignancy. The original view was based on Foulds' wealth of experience with both clinical and experimental cancer. It has however, been expanded greatly since it was first propounded by Foulds (1982). Other investigators have also made significant contributions to the understanding of the process of carcinogenesis by suggesting that there are two major cell-based processes essential to the formation of tumors (Ames and Gold, 1981).The first, or initiating stage, is due to mutation; alteration of the DNA of the affected cell through permanent modification of the DNA. These mutations take place at specific locations on the DNA, referred to as oncogenes and tumor suppressor genes, if these individual cells are to serve as precursors of cancer (Willis, 1960; Klein and Klein, 1984). This area remains intensely investigated in the last couple of decades. What is perhaps worthy of note is that while the activation of an oncogene requires mutation at a specific single base (arrangement of the amines making up the DNA) pair on the DNA template, inhibition of a tumor suppressor gene may be achieved by a much wider range of damaging interactions.

In current research, emphasis is laid on the identification of the genes that are involved in the mutation and subsequent molecular events. The failure in the control mechanisms regulating the expression of and response to tissue growth factors is of considerable interest in chemical carcinogenesis. This contributes to the risk of chemical carcinogenesis and is in turn attributable to a number of factors that will be discussed subsequently. A critical process in carcinogenesis is promotion. This involves cellular proliferation, which involves the division of cells to form two unusually identical cells. This may increase the number of both "normal" and neoplastic mutated or preneoplastic cells, enhancing the chance of a tumor being expressed in a clinically observable form. Surprisingly, such increased levels of cellular proliferation may not be apparent in normal cells of a particular tissue but may occur only in pretumor cells thus making early detection difficult. Tumors are well known to increase in their degree of malignancy with time, a process named "progression" by Foulds. Cohen and Elwein (1991) have suggested that progression is the result of a cascade of further critical mutations in the neoplastic cell population followed by further cell proliferation to increase the number of genetically altered cells and the chance of their forming an increasingly malignant, clinically apparent cancer.
