PRINCIPLES OF TOXICOLOGY

272 CHEMICAL CARCINOGENESIS
Figure 13.2 Generalized scheme of initiation-promotion experiments. Initiation is caused by a single dose of an
initiating agent such as a carcinogenic polycyclic aromatic hydrocarbon; promotion is carried out by repeated
application or chronic dosing with a tumor promotor such as TPA. (I, initiator; P, promoter; solid line indicates
continual application of agent; dotted lines indicate the duration of time without exposure to an agent.)
• Initiation must occur prior to promotion.
• Repeated exposure to a promoter alone will result in few, if any tumors.
Experiments with initiation–promotion models have demonstrated that there are chemicals that
possess both initiator and promoter activity. These chemicals are known as complete carcinogens. By
the same token, chemicals that cannot by themselves induce cancer in experimental animal models are
called incomplete carcinogens. In reality, dosage is a critical factor in determining whether a chemical
is a complete carcinogen. At sufficiently low doses, most initiators require subsequent promotion for
the development of a tumor, while at very high doses, most carcinogens possess initiating and
promoting ability. As you will learn later, this has important implications for the identification and the
assessment of risk associated with potential carcinogens.
Electrophilic Theory
The nature of the initiation step in chemical carcinogenesis was the subject of much scientific inquiry
and debate for decades. Until 1940, the only known chemical carcinogens were aromatic hydrocarbons
and amines. Soon afterward, other aliphatic chemicals were also shown to be carcinogenic and by the
1960s the various chemical carcinogens belonged to over a dozen chemical classes (Figure 13.3).
Attempting to explain this structural diversity, in 1969 James and Elizabeth Miller hypothesized that
“most, if not all, chemical carcinogens either are, or are converted to, reactive electrophilic derivatives
which combine with nucleophilic growth crucial tissue components, such as nucleic acids or proteins.”
In what became known as the electrophilic theory of chemical carcinogenesis, the Millers described
the metabolic activation of inactive procarcinogens to intermediates they called proximate carcinogens
and on to ultimate carcinogens that covalently bind DNA and cause mutations. Examples of chemical
carcinogens that require metabolic activation include benzo[a]pyrene and other polycyclic aromatic
hydrocarbons, 1,3-butadiene, and 2-acetylaminofluorene. The bioactivation of several chemical carcinogens
is illustrated in Figure 13.4.