Joint International Conference on Long-term Experiments ...

DETERMINATION OF “CARCINOGENESIS” BY ALTERNATIVE BIOASSAYS
Camelia Bara, Lucian Bara
University of Oradea, Faculty of Environmental Protection
26, General Magheru Street, Oradea
ABSTRACT
Chhabra et al. (1988) describe a “carcinogenesis” bioassay that appeared to show the
inhibition of spontaneous tumors by 4-hexylresorcinol in rats and mice. This is not an
unusual finding. It is even possible to find consistent patterns among these
“antitumorigens”. All four of the antidiabetic drugs tested in the program and all but one of
the antioxidants belong to the group with statistically significant dose-related reductions in
spontaneous tumors only; however, the group also includes a dioxin.
Chhabra et al. suggest that their test compound might be investigated as an
antineoplastic agent. Since there are more than 40 other compounds with the same property,
should they also be investigated as antineoplastic agents? If we think of the
“carcinogenesis” bioassay in a symmetric fashion (as capable of showing both tumorigenic
and antitumorigenic activity), a finding that a compound is a potential “carcinogen” have the
same validity as the finding that a compound is a potential “antineoplastic” agent.
In the following sections, an argument is made that, with the current design (maximum
tolerated dose and 18-24 months exposure), it can be expected that every compound tested
will produce an effect on the incidence of tumors, regardless of whether the compound is a
potential “carcinogen”, “antineoplastic” agent, or neither. Next, a statistical procedure is
outlined that can be used to test this hypothesis, and the procedure is applied to six
bioassays that were run on similar compounds in the same laboratory during the same
period. Finally, the implications of this hypothesis for interpretation of these bioassays are
discussed.
INTRODUCTION
The philosophical foundation of toxicology as a science rests on a thought experiment
attributed to the Renaissance alchemist Paracelsus (1493-1541). In this thought experiment,
a potential victim is given ever smaller doses of a “poison” until a dose is found that has no
apparent effect. Then, the potential victim is given ever-larger doses of some “nonpoison”
until serious biological damage results. The conclusion is the aphorism, “Solely the dose
determines that a thing is not a poison”.
There is a modern version of this thought experiment. Let as consider giving a rat or a
mouse a dose of a biologically active drug, such as a B-adrenergic receptor-blocking agent.
Let the dose be large enough to produce almost 100 % blockade. The catecholamines that
the body produces in the normal course of life will fail to have the effects expected, and
homeostasis will be affected, perhaps calling forth greater output of catecholamines. These
agents will then bind to secondary receptor sites, producing responses, which, in turn, will
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