Combined Actions and Interactions of Chemicals in Mixtures

7.3 Carcinogenicity
Prepared by Lars Ove Dragsted
7.3.1 Introduction
Cancer has been known for more than 50 years to be the result of combinational
toxicology. In the nineteen forties Berenblum and co-workers published their
famous papers showing that chemical carcinogenesis can be divided into two
distinct processes, initiation and what was later called promotion (Berenblum,
1941a; Berenblum and Shubik, 1947). Moreover, very different compounds were
shown to affect either process. But even some years earlier, Twort and Twort
(Twort and Twort, 1939) had shown that the carcinogenic effect of polycyclic
aromatic hydrocarbons (PAHs) was dependent upon the vehicle by which they
were applied, thereby indicating the possible existence of co-carcinogenesis. In
fact, the first combination effect in carcinogenesis was noted as early as 1924 by
Deelman, who found that scarification of the skin enhanced mineral oil
carcinogenesis in the mouse skin model (Deelman, 1924). Early observations on
anticarcinogenesis date back to 1925, when Nakahara found that oleic acid
injections decreased spontaneous and grafted mammary tumours in mice
(Nakahara, 1925).
Several reviews, reports and international consensus documents have been
authored through the years on the issue of carcinogen mechanisms and interactions.
Some recent publications from international bodies are (Joint WCRF and AICR
study group, 1997; Greenwald and Kelloff, 1996; Kelloff et al., 1996; Wattenberg,
1996).
7.3.2 Combination effects in initiation
7.3.2.1 Initiation
Initiation is believed to be caused by changes in the cellular genetic material
causing changes in the response of a cell to the regulation of cell turnover,
including division and apoptosis. Clearly, compounds causing mutations or gene
rearrangements in a target cell will also be potential tumour initiators. Initiation
causes an altered response to external stimuli resulting in cell growth or apoptosis.
This makes the initiated cell vulnerable to abnormal division or to escape of signals
for programmed cell death, and these abnormal responses can be affected by a
range of internal or external stimuli including the influence of chemical, physical
and biological agents (see tumour promotion).
No formal test systems exist to test for cancer initiation. The most widely reported
systems are the initiation-promotion protocols for mouse skin and rat liver tumour
formation. In the mouse skin test, the test compound is applied to the shaved back
of a suitable mouse strain such as the Swiss or NMRI mouse or even the hypersensitive
Sencar mouse, and a tumour promoter is subsequently applied twice a
week thereafter until tumours are scored at around 10 weeks or later. Such a system
has successfully been applied to show the initiating effects of the weak carcinogen
urethane (Salaman and Roe, 1953). The rat liver system can be performed in
several variants (Autrup and Dragsted, 1987), which will not be detailed here.
Briefly the test compound is given orally or intraperitoneally, and liver growth is
induced by partial hepatectomy and/or by treatment with one of several chemicals
increasing liver cell turnover.
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