Medium-Term Bioassays

29 May

While tissue-specific  bioassays  were directed in part at decreasing  the time required for the analysis of carcinogenic potential in vivo, at least two assays have been specifically designated as having reduced the time for the development of an end point. The one most intensively used today, primarily in Japan, is the model developed by Dr. Nobuyuki Ito and colleagues (Ogiso et al., 1990; Shirai, 1997). A diagram of the format for this assay is seen in Figure 13.8. The entire assay takes only 8 weeks, and the end point is nodules and focal lesions in the liver of rats that stain for glutathione  S-transferase  pi (GST-P). The initial “programming”  of the liver by

Figure 13.8 The medium-term  liver bioassay  protocol  for identification  of potentially  carcinogenic agents. DEN, diethylnitrosamine; GST-P, glutathione S-transferase pi. (Reproduced from Shirai, 1997, with permission of the author and publisher.)

administration of a necrogenic dose of diethylnitrosamine poses some problems in that this dose by itself is carcinogenic, but only after a year or more. Furthermore, this high dose is also clasto- genic to rat hepatocytes  in vivo (Sargent et al., 1989). However,  these authors and their col- leagues have demonstrated a significant degree of correlation between long- and medium-term results, indicating the usefulness of this assay as a potential surrogate for the chronic bioassay (Ogiso et al., 1990). More recently these authors have used a slightly modified protocol in which five potent carcinogenic agents are administered for a 4-week period, followed by administration of the test chemical for a subsequent 24- to 32-week period (Ito et al., 1996). Unlike the assay depicted in Figure 13.7, this more complicated procedure may allow the detection of promoting and progressor agents as well as complete carcinogens in a variety of different tissues. However, outside of Japan these assay procedures have not been generally utilized.

The newborn mouse model of chemical carcinogenesis was initially described by Shubik and colleagues (Pietra et al., 1959) and later used extensively in studies of mouse hepatocarcino- genesis by Vesselinovitch  and colleagues (1978). More recently, Fujii (1991) has utilized this procedure in the determination of the carcinogenic potential of 45 different chemicals with quite reasonable results. The end point of neoplasms in a variety of different tissues, including lung, liver, lymphoid and hematopoietic  tissues, is determined  within a 1-year period. The assay is relatively inexpensive, utilizing small amounts of the test materials. As yet, however, this assay has not found general usefulness in the determination  of carcinogenic  potential by regulatory agencies.

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