Tissue-Specific Bioassays

29 May

During the performance of long-term bioassays, it became obvious that certain tissues in specific species exhibited neoplasms more frequently than others when a test agent was administered. From these observations, several tissue-specific bioassays were developed with the objective of a reasonably sensitive assay carried out in a shorter time than the usual chronic 2-year bioassay. The best-known  tissue-specific  assay is that utilizing the mouse liver. In a recent analysis of chronic bioassays carried out by the National Toxicology Program, Crump et al. reported that 108 of 390 studies indicated a positive carcinogenic response to the test chemical. In 81 of these studies, female mice exhibited significant increases in the incidence of hepatic neoplasms. As noted in Table 13.5, there is a high incidence of spontaneous  hepatoma development  in mice, more so in the male (Chapter 8). This has led to controversy in the interpretation of the signifi- cance of the development of mouse hepatomas, especially if they are the only statistically sig- nificant increased neoplastic  response in the test animals. As a result of this controversy,  the interpretation of the significance of the induction of mouse hepatic lesions has been called into question (cf. Dragan et al., 1998; Moch et al., 1996). A further complication of this assay is the fact that in at least one study, the majority of the chemicals testing positive exhibited no evidence of an ability to induce DNA damage or mutation (Carmichael et al., 1997).

Another  tissue-specific  bioassay  that was developed  by Shimkin  and associates  more than two decades ago (Shimkin and Stoner, 1975) is the development of pulmonary adenomas and carcinomas,  primarily  in strain A mice. The assay was shown to effectively  identify  a number of relatively potent carcinogenic agents, including a few inorganic carcinogens (Stoner et al., 1976). However, although the assay has not been generally accepted as a major com- ponent for the determination  of carcinogenicity  of chemicals,  it has found usefulness  in the determination  of the molecular  mechanisms  of pulmonary  carcinogenesis  in this strain of animals (You et al., 1989; Nuzum et al., 1990). In addition, as noted from Table 13.4, induction of gliomas  in the rat brain and of mammary  neoplasms  in both the rat and the mouse may exhibit potential for tissue-specific  bioassays. There have also been attempts to utilize lower vertebrates in the development of tissue-specific  bioassays, such as the rainbow trout embryo (Hendricks et al., 1980).

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