Page 362 - Industrial Ventilation Design Guidebook

3 I 8 CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGICAL CONSIDERATIONS

of such a carcinogenicity trial is irrelevant. It has also been argued that
high doses of chemicals used in animal carcinogenicity bioassays induce
mitogenesis (increased rate of cell division), and thus carcinogenesis, and
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are therefore not specific to the compound itself. 182 183
Mechanisms of Chemical Carcinogenesis
Carcinogens can be divided into two broad classes based on their mecha-
nism of chemical carcinogenicity: genotoxic and epigenetic carcinogens. Geno-
toxic carcinogens initiate the process of chemical carcinogenesis by acting as
mutagens. All other carcinogens belong to the group epigenetic carcinogens,
which includes foreign compound carcinogens, carcinogens acting through a
hormonal mechanism, carcinogens that amplify the carcinogenic effects of true
carcinogens when they are given after the true carcinogen, and cocarcinogens
that stimulate chemical carcinogenesis when delivered in conjunction with a
true carcinogen. Chemical carcinogenesis is a very complex cascade of events,
this being typical of all forms of carcinogenesis, such that the alterations lead-
ing to cancer take place in a stepwise and usually subtle fashion. In fact, it is
difficult if not impossible to find the point at which one step is over and the
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next one begins. 178 180
Experimental animal studies have played a key role in the understanding
of the mechanisms of chemical carcinogenesis. The duration of development of
a cancer in humans may be several decades, and the development probably in-
cludes several steps. Furthermore, individual susceptibility is also important
for the disease. Therefore, it has been extremely difficult to make the required
observations in exposed individuals.
Most genotoxic carcinogens require metabolic activation. The most im-
portant group of enzymes that participates in these processes are the P-450 en-
zymes, of which CYP1 Al is involved in the activation of polycyclic aromatic
hydrocarbons, CYP2 in the activation of aromatic amines, and CYP3A in the
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activation of aflatoxins. An activated compound binds to several macro-
molecules within cells, and an important event in chemical carcinogenesis is
binding to the genetic material, i.e., the formation of carcinogen-DNA adduces
which lead to alterations in the genes. Typically, activated compounds favor
guanine as the base to which they bind. In addition to the balance between the
activity of enzymes that activate chemicals and the activity of enzymes that re-
pair the chemical-induced damage to DNA, the stability of the adducts and
the amount of the adducts in the cells are important factors in the initial stages
of chemical carcinogenesis induced by genotoxic carcinogens. 184 186
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If enzymes responsible for DNA repair are unable to remove the DNA ad-
duct, or if an error takes place in the repair, then the error in the genetic code
remains when the cell divides. Thus, cellular proliferation is also required, in
addition to a mutation, for there to be a permanent effect of a chemical com-
pound. Accumulation of genetic errors, i.e., mutations, has been suspected to
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be an important factor in chemical carcinogenesis. 185 185
Recently a number of genes that are important in chemical carcinogenesis
have been identified. These include oncogenes (genes that promote carcinogen-
esis} and tumor suppressor genes (genes that prevent carcinogenesis). A
mutation of a proto-oncogene may be required for the transformation of a