**9. Early studies in chemical carcinogenesis and risk factors**

Early in the field of chemical carcinogenesis, investigators recognized that perturbation of the normal microenvironment by physical means, such as wounding of mouse skin or partial hepatectomy in rodents (Hennings and Boutwell, 1970; Fausto etal, 2006) or chemical agents, such as exposure of the mouse skin to certain phorbol esters (Berenblum, 1941), can drive clonal expansion of the initiated cells toward cancer. In the second stage, tumor promotion results in proliferation of the initiated cells to a greater extent than normal cells and enhances the probability of additional genetic damage, including endogenous mutations that accumulate in the expanding population. This classic view of two-stage carcinogenesis (Berenblum, 1941) has been conceptually important but also an oversimplification of the increasing understanding of the multiplicity of biological processes that are deregulated in cancer. In addition, an active debate continues on the relative contribution of procarcinogenic endogenous mechanisms—for example, free-radical– induced DNA damage (Halliwell and Aruoma, 1991), DNA depurination (Lindahl and Nyberg, 1972), DNA polymerase infidelity (Loeb et al, 1974), and deamination of 5 methylycytosine (Lindahl and Nyberg, 1974)—compared with exposure to exogenous environmental carcinogens (Ames et al, 1973).

The enhancement of carcinogens by epigenetic mechanisms such as halogenated organic chemicals and phytoestrogens (Martin et al, 2007), as well as the extrapolation of results from animal bioassays for identifying carcinogens to human cancer risk assessment, are also difficult to quantify (Swenberg et al., 1998). As discussed below, this debate is not merely an academic event, in that societal and regulatory decisions critical to public health are at issue. The identification of chemical carcinogens in the environment and occupational settings

recently experimentally verified. The list below shows some commonly employed analytical

Some analytical areas that may be particularly relevant in chemical carcinogenesis will


The latter is particularly promising as it enables the simultaneous measurement of transcription of thousands of genes using microchips containing thousands of probes of complementary DNA (cDNA) immobilized in predetermined array. But suffers the caveat of being very expensive especially for the developing countries that appear to be mostly in

Early in the field of chemical carcinogenesis, investigators recognized that perturbation of the normal microenvironment by physical means, such as wounding of mouse skin or partial hepatectomy in rodents (Hennings and Boutwell, 1970; Fausto etal, 2006) or chemical agents, such as exposure of the mouse skin to certain phorbol esters (Berenblum, 1941), can drive clonal expansion of the initiated cells toward cancer. In the second stage, tumor promotion results in proliferation of the initiated cells to a greater extent than normal cells and enhances the probability of additional genetic damage, including endogenous mutations that accumulate in the expanding population. This classic view of two-stage carcinogenesis (Berenblum, 1941) has been conceptually important but also an oversimplification of the increasing understanding of the multiplicity of biological processes that are deregulated in cancer. In addition, an active debate continues on the relative contribution of procarcinogenic endogenous mechanisms—for example, free-radical– induced DNA damage (Halliwell and Aruoma, 1991), DNA depurination (Lindahl and Nyberg, 1972), DNA polymerase infidelity (Loeb et al, 1974), and deamination of 5 methylycytosine (Lindahl and Nyberg, 1974)—compared with exposure to exogenous

The enhancement of carcinogens by epigenetic mechanisms such as halogenated organic chemicals and phytoestrogens (Martin et al, 2007), as well as the extrapolation of results from animal bioassays for identifying carcinogens to human cancer risk assessment, are also difficult to quantify (Swenberg et al., 1998). As discussed below, this debate is not merely an academic event, in that societal and regulatory decisions critical to public health are at issue. The identification of chemical carcinogens in the environment and occupational settings

techniques requiring the attention of biomedical engineering and technology.



**9. Early studies in chemical carcinogenesis and risk factors** 


environmental carcinogens (Ames et al, 1973).

include:


chromatography


need of it currently.



[benzo (*a*) pyrene and tobacco-specific nitrosamines in cigarette smoke, aflatoxin B1 (AFB1), residues from fossil fuel, vinyl chloride, pesticides and benzene] has led to regulations that have reduced the incidence of cancer. Further reduction or near total elimination may be achieved by sensitive instruments that enable early detection of up- stream changes that may culminate in cancer. This needless to say has heavy reliance on biomedical engineering.

### **9.1 Risk factors and early detection: role for micronutrient deficiency and oxidative stress**

The risk of contracting cancer generally increases as the population grows older; this has been reported to be directly proportional to the number of years raised to the fourth power (Tolonen, 1990). This may be modified in the case of chemical carcinogenesis to include dose of chemicals or environmental agent to which the population is exposed and the stoichiometric bioavailability of protective factors such as the micronutrients. In animal models, such as the mice, the life-span of the models has been increased and cancer prevented by calorie restriction (reducing oxygen intermediates) and feeding them antioxidants. This suggests that excess calorie and antioxidant deficit (oxidative stress) are risk factors that may enhance the carcinogenic process. The natural dietary antioxidants, selenium, zinc, vitamins A, C, and E plus β-carotene protect against free radicals, lipid peroxidation (Tolonen, 1990) and thus the risk of chemical carcinogenesis. Ames (1983) has greatly emphasised the role of antioxidants largely derived from micronutrients as anticarcinogenesis. Vitamin C for instance is well known to counteract carcinogenic nitrous amine in the stomach. Urban population are more exposed to the risk of cancer than rural dwellers. This perhaps can be explained by the probability that the rural population is exposed to fewer carcinogens present in the environment.

Additionally, there is the often neglected element of greater host resistance in that rural populations are more likely to consume diet replete with antioxidant micronutrients some of which will also enhance the immune system. This is important in that its contact with carcinogens either in the diet or environment is inevitable. Thus it may be possible for us to avoid the most prominent risk factors the most pragmatic option appears to be reinforcing host resistance .This may be enhanced by the use of biomarkers. Biomarkers are playing an increasing role in the assessment of human exposure to hazardous environmental pollutants or chemicals and in risk assessment to these compounds. Biomarkers may be applied at any stage in the toxicological process, ranging from measurement of the external dose as an indicator of exposure to determine altered structure and function of cells as a marker of effect- carcinogenesis. Genetic carcinogens interact with nucleic acids to produce adducts, measurement of which is an indicator of the dose of active material which has reached the cells in question, termed biologically active dose (BAD), in the individual. This consequently incorporates the inter-individual variation in absorption, metabolism, and excretion of the compound which may affect risk assessment.
