Fig. 1. Schematic representation of the multimutational process of carcinogenesis. Individual factors (in italics) modulate the rate of the process or affect the number of steps required for malignant transformation. (From Ref. 4, with permission of Elsevier Science.)

damage but also by damage associated with misrepair, DNA replication, and chromosome segregation. The most direct type of DNA damage is a chemical interaction of the chemical with the DNA molecule, for instance, by covalent binding to form carcinogen-DNA adducts.

C. Background DNA Damage

Mutations and DNA damage are not only the result of exposure to exogenous carcinogens. Endogenous DNA-damaging agents result in a background level of damage (6-8). Table 2 gives some examples. The endogenous part can be subdivided into chemical and biochemical processes, and it includes the consequences of oxygen stress. The exogenous sources have been subdivided according to the question of avoidability rather than type. Numerous exogenous sources can hardly be eliminated. Physical carcinogens, such as UV and ionizing radiation, have for a long time been accepted to result in a background DNA damage. Accordingly, exposure standards at the workplace have been set in relation to a background dose. For chemical carcinogens, this has not been done. The idea prevailed that chemically induced DNA damage could be avoided if it were possible to exclude exposure to exogenous carcinogens. On this basis, exposure standards for exogenous genotoxic carcinogens were often set to 0 (i.e., the "Delaney clause" for carcinogens in foods). Meanwhile, it has become increasingly clear that a zero tolerance is unrealistic. New guidelines for setting exposure limits are required. The knowledge of the background DNA damage observed under various conditions could help set a benchmark.

A total background damage on the order of 1 modification in 100,000 DNA nucleotides has been suggested recently (9). Depurinations, oxidative lesions, alkyl phosphotriesters, and cyclic adducts from unsaturated aldehydes predominated. On the basis of this background DNA damage, it can also be postulated that the process of carcinogenesis has a finite rate in the absence of exogenous DNA-damaging chemicals. A substantial fraction of the total cancer incidence could be explained on that basis (10, 11).

D. Modulation of the Process of Carcinogenesis

For a DNA-reactive chemical to induce a mutation, a number of conditions have to be met. Some are depicted in Figure 2. The first question is whether the phase I reaction of biotransformation results in the formation of a DNA-reactive intermediate. Secondly, does the reactive intermediate escape the various enzymatic and nonenzymatic detoxication processes? Thirdly, does it react with DNA or with another molecule? Although the reaction with water or other small molecules represents detoxification, the formation of protein adducts can be indirectly genotoxic, for instance by disturbing chromosome segregation or by cytotoxicity followed by regenerative hyperplasia.

Table 2. Sources of Background DNA Damage




Endogenous Chemical Biochemical


Pathophysiological Exogenous Hardly avoidable

Avoidable in part

Avoidable (in principle)

DNA instability Errors during DNA replication Errors during DNA repair DNA-reactive chemicals

Oxygen stress-derived (ROS)

Formation of carcinogens in vivo


Natural radioactive isotopes Carcinogens in ambient air Some therapeutic drugs Natural dietary carcinogens Carcinogens from food processing Food pyrolysis products Exposure at the workplace Carcinogens in ambient air Active smoking

"Unnecessary" dietary, environmental, and work-related exposures

Depurination Essential metal ions


Aldehyde forms of carbohydrates HO*, NO*, peroxides Lipid peroxidation products Nitroso-compounds (NOC)

UV, ionizing radiation 222Rn, 40K PAH,* benzene Tumor therapy Estragóle Urethane

Arylamines, PAH, NOC Vinyl chloride Passive smoking

•Polynuclear aromatic hydrocarbons

Fig. 2. Sequence of events that modulate the probability of cancer induction from exposure to endogenous or exogenous genotoxic carcinogens.

Once a carcinogen-DNA adduct is formed, the question is whether it is repaired before the DNA is replicated. Figure 3 shows how a DNA methylation at the Opposition of guanine can result in a permanent genetic change after two rounds of DNA replication. O6-Methylguanine is known to pair with thymine instead of cytosine. If this mismatch is not repaired before the second replication, one of the four daughter cells will have undergone a GC to AT base pair substitution mutation. If the associated change in the amino acid sequence results in the loss of function, for instance of a tumor suppressor protein, one step in the process of malignant transformation could have been taken. A final question in the sequence shown is: does the mutation lead to the death of the cell? If not, the

Fig. 3. Schematic representation of the fixation of a DNA damage as a permanent genetic change by two rounds of DNA replication. The example shows the methylation of guanine at the O6 position, followed by mispairing with thymine, resulting in a GC to AT transition mutation.

cycle can be repeated until the necessary number of permanent changes is reached and the cell gains a fully malignant phenotype.

The sequence of events depicted in Figure 2 is probably not the only way to induce a permanent genetic change. Regulation of gene expression in the course of cell differentiation appears to be irreversible to some extent. It cannot be excluded, therefore, that tumor suppressor genes can be turned off without a change in the respective base sequence. At this time, however, the understanding that a DNA lesion is "fixed" as a mutation in the course of DNA replication is more conspicuous and is also supported by the evidence that nondividing cells rarely transform to malignancy. Other, so-called "epigenetic" mechanisms are not yet as well understood.

E. Susceptibility Factors

At all crossroads shown in Figure 2, numerous factors modulate the rate of the process (12). Genetic polymorphisms in tumor suppressor genes and proto-oncogenes can result in large differences in the susceptibility of individuals to develop cancer. As indicated in Figure 1, this could be caused by a reduction of the number of steps necessary for malignant transformation. On the other hand, susceptibility factors can modulate the rate of the process. This is expected for polymorphisms of DNA repair enzymes or of enzymes catalyzing metabolic activation and detoxication (13).

Modulation by lifestyle-dependent factors can also be important. For instance, exposure to one carcinogen can result in an increased potency of another carcinogen. Examples are the supra-additive (synergistic) cancer risks from smoking plus alcohol for cancer of the oral cavity, the larynx, and the esophagus, or from smoking plus radon or asbestos for lung cancer.

In conclusion, the potency of a carcinogen is not equal for all individuals. The consequence of this idea for low dose risk assessment will be discussed in chapter III.

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