PRINCIPLES OF TOXICOLOGY - Biology East Borneo

13.6 INTERPRETATION ISSUES RAISED BY CONDITIONS OF THE TEST PROCEDURE 297induce nutritional changes in the animal secondary to organ toxicity, which, if ameliorated, maysignificantly 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 responsemight be when human data are unavailable, it should be remembered that when one makes ananimal-to-human extrapolation, the basic assumption of that extrapolation is that the animal responseis both qualitatively and quantitatively the same as the human response. However, because two differentspecies may respond differently, either qualitatively and quantitatively, to the same dosage of aparticular 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 ina sense requires prior knowledge of both outcomes. So, even though toxicologists frequently use animaldata to predict possible human outcomes, the potential for significant qualitative and quantitativedifferences to exist among species requires that the human response first be known before anappropriate animal model can be selected for testing and extrapolation purposes. But the selection ofthe appropriate animal model is complicated by the fact that innumerable and vast species differencesexist. These differences are related primarily to the anatomical, physiological, and biochemicalspecificity 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 differencesare then combined with species-related differences in the physiology or biochemistry of thetarget organ, it is not surprising that significantly different responses may be achieved when one movesto a different test species. The major point of interest here, however, is that because these differencesexist, the extrapolation of animal responses to humans should be viewed as being fraught withconsiderable difficulty and uncertainty. Important species differences encompass, but are not limitedto, the following:1. Basal metabolic rates2. Anatomy and organ structure3. Physiology and cellular biochemistry4. The distribution of chemicals in tissues (toxicodynamics); pharmacokinetics, absorption,elimination, excretion, and other factors5. The metabolism, bioactivation, and detoxification of chemicals and their metabolic intermediatesA few well-known examples that illustrate the magnitude of these differences are discussed below.Anatomic DifferencesLaboratory animals possess some anatomic structures that humans lack, and when cancer is observedin one of these structures, the particular relevance to humans is unknown and cannot be assumed withany scientific reliability. For example, the Zymbal gland, or auditory sebaceous gland, is a specializedsebaceous 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 squamouscell papillomas of the Zymbal gland in Fischer rats might be argued as providing no informationrelevant to discerning the carcinogenic potential of this chemical in humans.Another such problem exists with rodent species because they also possess an additional structurewith no known human correlate: the forestomach. The esophagus empties into this organ, and it is herethat ingested materials are stored before passing to the glandular stomach. The forestomach of rodentshas a high pH, as opposed to the low pH of the human stomach, and high digestive enzyme activity.