Joint International Conference on Long-term Experiments ...

The appendix describes two tests for homogeneous scatter, one along the first principal
component of the data, the other along the second principal component. The principal
components are vectors that identify the directions of greatest spread among the points. The
linear sum of elements that defines the projection of a point along a principal component is
uncorrelated with the sum that defines the projection along another principal component.
Because of this, the nominal significance test associated with two such tests can be adjusted
to ensure a false-positive rate of 5%. In this situation, a nominal p value of 0,0253 or less for
either of the tests implies an overall significance level of 5 %.
For each of the six tested compounds, there are significant treatment-related clusters in
at least one sex or species.
The results of this analysis support the contention that all tested compounds will have
an effect, in the current design of these studies.
DISCUSSION
If the hypothesis that every compound tested will cause some sort of a shift in neoplastic
lesions is true, then it will be necessary to reconsider the interpretation of these studies. A
treatment-related increase in tumors of one type is no more indicative, by itself, of
“carcinogenesis” than a decrease in tumors of another type is indicative of an
“antineoplastic” effect. The cause of these shifts is a complex biological interaction of a
living animal seeking homeostasis in the face of a biochemical derangement of its milieu.
The several hundred chronic toxicity tests that have been run in the past 10-15 years
provide the science of toxicology with an unprecedented opportunity to investigate the
nature of biological homeostasis and the response of a living animal to toxic pressure.
Regardless, of the eventual use of these studies to identify “carcinogens”, there is a wealth
of useful information in them, waiting to be uncovered.
In the meantime, can these studies be used to identify “carcinogens” (or even
“antineoplastic” agents), if the hypothesis of universal effect is true?
The answer, clearly, is no. In fact, the hypothesis of universal effect brings the problem
of finding “carcinogens” back among the traditional problems of toxicology. In traditional
toxicology, we recognized that chemical compounds cannot be divided into two classes,
poisons, (or toxic chemicals) and nonpoisons (or nontoxic chemical). All chemical will
cause biological damage at sufficiently high doses, and the dual task of toxicology is to
identify the nature of that damage as a function of dose and determine dose levels that have
a good chance of being “safe”. So, if all chemicals will cause a derangement of senile
neoplastic lesions, then it mekes no sense to divide the universe of chemicals into
“carcinogens” and “noncarcinogens”. This derangement of neoplastic lesions is more
complicated than the usual type of biological damage seen in subchronic and acute studies.
There are problems due to latency of expression and irreversibility of some of the lesions.
But, the problems of “carcinogenic” effects still belong in the general class of toxicological
problems. We need to find parallels to the two tasks described in the previous paragraph.
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