PRINCIPLES OF TOXICOLOGY - Biology East Borneo

292 CHEMICAL CARCINOGENESISmay be more relevant to the humans because they possess alterations in genes known to be involvedin many human tumors.13.6 INTERPRETATION ISSUES RAISED BY CONDITIONS OF THE TESTPROCEDUREHuman health hazards and, to allow for some quantitative assessment of the risk, the reliability of theanimal-to-human extrapolation of animal cancer data is understandably an important issue. And as istrue for any animal test procedure, questions concerning the reliability with which the results of thechronic bioassay can be extrapolated to human exposure conditions are frequently raised. However,in addition to the obvious potential for frank differences to arise in the human response because ofspecies differences, an issue that can be raised with the animal test data for any other toxic endpoint(e.g., liver injury or developmental deficits), a number of interpretation issues have been raised thatstem from the experimental conditions of the cancer bioassay test procedure itself. For example, it haslong been noted that a number of interpretation problems will simply arise out of the data collectedfrom this procedure because significant species differences may reasonably be anticipated and becauseof the test’s relatively crude and observational approach. That is, after approximately 3 years of testprocedure, tissue collection and histopathological examination, we are largely left with a single, simpleobservation, specifically, the number of tumors in a tissue following lifetime high-dose exposure.Because the test procedure is arguably a screening test for carcinogenic activity, regardless of dose,when a positive result is observed, little else is provided. For example, typically little or no informationis provided on dose–response or the mechanism by which the cancer was induced. Thus, it shouldperhaps not be surprising that the utility of this procedure continues to foster debate in the scientificcommunity, or that much additional research is routinely required to be able to reliably interpret andextrapolate the results obtained by this procedure.In a seminal article dealing with the problems associated with chronic cancer bioassay tests andtheir interpretation, Squire listed five experimental design issues that remain relevant today:1. Use of the MTD as currently defined2. The number of doses tested3. The relevance of findings in certain test species4. Route of exposure and vehicle5. Extent of the pathological examinationThese and related issues raised by this test procedure are discussed in the following paragraphs becausethey have a considerable impact on the hazard evaluation of the chemical in question, and because theyare frequently raised when debates occur over the significance of the observation or the regulation ofa particular chemical.The Doses Used to Test Chemicals Are Too HighThis has become perhaps the most frequently raised criticism of chronic animal cancer tests. Becausethe MTD is often selected as the highest dose the test animal can maintain for a lifetime withoutshortening the length of the test, it is often a dose where chronic toxicity and biological changes occur.The biological arguments against the applicability of positive results that are seen only at high doses,doses that produce chronic toxicity and substantially exceed the expected human exposure level, areas follows:1. High doses may alter the metabolism and disposition of the chemical such that the types ofreactive, toxic metabolites that are responsible for the critical biochemical changes producing cancer