The Problem of Extrapolation

29 May

Since bacterial mutagenicity  (Figure 13.1) is the most widely and extensively utilized test for estimating  the qualitative  carcinogenic  potential of an agent, a number of investigations  have been directed toward determining the relationship of bacterial mutagenesis and carcinogenesis of the same chemical, usually in rodents. An early graphical relationship of such a series of tests is seen in Figure 13.11. Obviously, considerably  more efforts have been carried out since the publication of this in 1976 (Sugimura et al., 1976). However, the figure does place in rather de- finitive terms compounds that exhibit either carcinogenic and/or mutagenic activities. The indi- cated description of complete carcinogen, promoting agent, initiating agent, etc., is an exercise allowing the further classification of such agents in multistage carcinogenesis. In a far more ex- tensive study, Tennant et al. (1987) related the results of bacterial mutagenicity to carcinogenic potential as determined in the chronic 2-year bioassay and found that the short-term assay de- tected only about half of the carcinogens as mutagens. These studies and a slightly later one by Ashby (1989) pointed again to the importance of using more than a single short-term assay in attempting to relate DNA structural alterations to potential carcinogenicity. Although the predic- tion of carcinogenic potential by the bacterial mutagenicity tests together with other short-term tests is in the neighborhood of 60% to 70%, it is somewhat surprising that interspecies extrapo- lation of carcinogenesis in rats and mice is not much greater than this. In an analysis by Gold et al. (1989), chronic bioassays for carcinogenic  potential in either mice or rats were only about

Figure 13.11 Graphical representation  of mutagens and nonmutagens  in relation to their known carci- nogenic potential in animal tests. The labeling of the quadrants using the classification  of Table 9.10 is a further potential extrapolation  of these data. (After Sugimura et al., 1976, with permission  of the authors and publisher.)

70% to 75% predictive of carcinogenicity in the other species. In a more recent study (Fung et al., 1993) of 379 chemicals tested by the National Cancer Institute/National Toxicology Program for carcinogenic potential, only slightly more than 50% of the chemicals tested exhibited carci- nogenicity in at least one organ of one sex of one species. Less than half of these exhibited carci- nogenic potential in both species tested, a situation most likely to be indicative of a carcinogenic hazard to humans.

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