Carcinogenic chemicals and irradiation (ionizing and ultraviolet) are known to affect DNA
and to be mutagenic under certain conditions. Thus, one of the long-standing theories of carcinogenesis
is that cancer is caused by a genetic mutation; however, it is now known that epigenetic
mechanisms are also involved. Evidence that chemicals can induce cancer in
humans has been accumulating since the sixteenth century (reviewed in Reference 7). In
1567, Paracelsus described a ‘‘wasting disease of miners’’ and proposed that exposure to something
in the mined ores caused the condition. A similar condition was described in 1926 in Saxony
and was later identified as the ‘‘lung cancer of the Schneeberg mines.’’ It was realized much
later that the cause of this was probably exposure to radon. Nevertheless, Paraclesus could
probably be called ‘‘the father of occupational carcinogenesis.’’ It is Bernadini Ramazzini, however,
who published a systematic account of work-related diseases in 1700, who is more
logically considered the founder of occupational medicine.7
Later in the eighteenth century, the first direct observation associating chemicals was made by
John Hill, who in 1761 noted that nasal cancer occurred in people who used snuff excessively.
In 1775, Percival Pott reported a high incidence of scrotal skin cancer among men who had spent
their childhood as chimney sweeps. One hundred years later, von Volkman, in Germany, and
Bell, in Scotland, observed skin cancer in workers whose skin was in continuous contact with
tar and paraffin oils, which we now know contain polycyclic aromatic hydrocarbons. In 1895, Rehn reported the development of urinary bladder cancer in aniline dye workers in Germany. Similar
observations were later made in a number of countries and established a relationship between
heavy exposure to 2-naphthylamine, benzidine, or 4-aminobiphenyl and bladder cancer. Thus,
the first observations of chemically induced cancer were made in humans. These observations
led to attempts to induce cancer in animals with chemicals.
One of the first successful attempts was made in 1915, when Yamagiwa and Ichikawa induced skin carcinomas by the repeated application of coal tar to the ears of rabbits. This and similar observations by other investigators led to a search for the active carcinogen in coal tar and to the conclusion that the carcinogenic agents in tars are the polycyclic aromatic hydrocarbons. Direct evidence for that came in the 1930s from the work of Kennaway and Heiger, who demonstrated that synthetic 1,2,5,6-dibenzanthracene is a carcinogen, and from the identification of the carcinogen 3,4-benzpyrene in coal tar by Cook, Hewitt, and Hieger. Induction of tumors by other chemical and hormonal carcinogens
was described in the 1930s, including the induction of liver tumors in rats and mice with 20,
3-dimethyl-4-aminoazobenzene by Yoshida, of urinary bladder cancer in dogs with 2-naphthylamine
by Hueper, Wiley, and Wolfe, and of mammary cancer in male mice with estrone by
Lacassagne. The list of known carcinogenic chemicals expanded in the 1940s with the discovery
of the carcinogenicity of 2-acetylaminofluorene, halogenated hydrocarbons, urethane,
beryllium salts, and certain anticancer alkylating agents. Since the 1940s, various nitrosamines,
intercalating agents, nickel and chromium compounds, asbestos, vinyl chloride, diethylstilbestrol,
and certain naturally occurring substances, such as aflatoxins, have been added to the list of known carcinogens. A list of some known human carcinogens is found in Table 2–1, and the structures
of some known carcinogens.
