PRINCIPLES OF TOXICOLOGY

13.6 INTERPRETATION ISSUES RAISED BY CONDITIONS OF THE TEST PROCEDURE 297
induce nutritional changes in the animal secondary to organ toxicity, which, if ameliorated, may
significantly alter the outcome of the bioassay.
What Animal Species Represents the Most Relevant Animal Model?
While it may be prudent for regulatory purposes to use animal data to predict what the human response
might be when human data are unavailable, it should be remembered that when one makes an
animal-to-human extrapolation, the basic assumption of that extrapolation is that the animal response
is both qualitatively and quantitatively the same as the human response. However, because two different
species may respond differently, either qualitatively and quantitatively, to the same dosage of a
particular chemical, any animal-to-human extrapolation should be considered a catch-22 situation.
That is, to know whether it is valid to extrapolate between a particular animal species and humans in
a sense requires prior knowledge of both outcomes. So, even though toxicologists frequently use animal
data to predict possible human outcomes, the potential for significant qualitative and quantitative
differences to exist among species requires that the human response first be known before an
appropriate animal model can be selected for testing and extrapolation purposes. But the selection of
the appropriate animal model is complicated by the fact that innumerable and vast species differences
exist. These differences are related primarily to the anatomical, physiological, and biochemical
specificity of each species; these differences may produce significant wide variation in the metabolism,
pharmacokinetics, or target organ concentrations of a chemical between species. When these differences
are then combined with species-related differences in the physiology or biochemistry of the
target organ, it is not surprising that significantly different responses may be achieved when one moves
to a different test species. The major point of interest here, however, is that because these differences
exist, the extrapolation of animal responses to humans should be viewed as being fraught with
considerable difficulty and uncertainty. Important species differences encompass, but are not limited
to, the following:
1. Basal metabolic rates
2. Anatomy and organ structure
3. Physiology and cellular biochemistry
4. The distribution of chemicals in tissues (toxicodynamics); pharmacokinetics, absorption,
elimination, excretion, and other factors
5. The metabolism, bioactivation, and detoxification of chemicals and their metabolic intermediates
A few well-known examples that illustrate the magnitude of these differences are discussed below.
Anatomic Differences
Laboratory animals possess some anatomic structures that humans lack, and when cancer is observed
in one of these structures, the particular relevance to humans is unknown and cannot be assumed with
any scientific reliability. For example, the Zymbal gland, or auditory sebaceous gland, is a specialized
sebaceous gland associated with the ears in Fischer rats. This gland secretes a product known as sebum.
Although there is little information about the specific function of the secretion of the Zymbal gland,
there is no known human structural correlate. Thus, the fact that dibromopropanol can cause squamous
cell papillomas of the Zymbal gland in Fischer rats might be argued as providing no information
relevant to discerning the carcinogenic potential of this chemical in humans.
Another such problem exists with rodent species because they also possess an additional structure
with no known human correlate: the forestomach. The esophagus empties into this organ, and it is here
that ingested materials are stored before passing to the glandular stomach. The forestomach of rodents
has a high pH, as opposed to the low pH of the human stomach, and high digestive enzyme activity.