Rodent carcinogenesis bioassay

This paper explores the theoretical and experimental basis for both the practical application of mechanistic data to the interpretation of rodent bioassay results as well as the development of a biologically-based, more wholistic, model of chemical carcinogenesis. 

The vivo NTP efforts include the NCI lifetime rodent bioassay for carcinogenesis. Approximately 75-100 new chemicals are started on test each year at a total bioassay cost of about 500,000 per chemical. Chemical support for the bioassay testing, as shown in Figure 2, is also provided by contract laboratories and includes ... 

CTAs are possible in vitro alternatives to the standard approach for the assessment of carcinogenicity (the 2-year bioassay in rodents), which have been shown to be a multistage process able to model the most important stages of in vivo carcinogenesis [50]. CTAs are faster and more economic than in vivo assay and they could be a valid and useful screening tool for chemicals. 

Gold LS, Ward JM, Bernstein L, et al. 1986. Association between carcinogenic potency and tumor pathology in rodent carcinogenesis bioassays. Fund AppI Toxicol 6 677-690. 

No evidence linking oral exposure to uranium to human cancer has been found. Although natural, depleted, or enriched uranium and uranium compounds have not been evaluated in rodent cancer bioassays by any route by the NTP (BEIR 1980, 1988, 1990 Hahn 1989 Sanders 1986 UNSCEAR 1982,1986,1988), there is potential for the carcinogenicity of uranium, since it emits primarily alpha radiation. Nevertheless, no evidence has been found to associate human exposure to uranium compounds and carcinogenesis. The National Academy of Sciences has determined that bone sarcoma is the most likely cancer from oral exposure to uranium however, their report noted that this cancer has not been observed in exposed humans and concluded that exposure to natural uranium may have no measurable effect (BEIR IV). 

Sontag, J.M. Page, N.P. Saffiotti, U. Guidelines for Carcinogen Bioassay in Small Rodents, National Cancer Institute Carcinogenesis Technical Report Series No. 1, DHEW Publication No. (NIH) 76-801, 1976. 

Finally, a third approach has been proposed with five stages that focus on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays, and finally, the application of accelerated bioassays. These accelerated bio assays require 40 weeks and apply to the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenesis process directed toward developing mechanistic information. This system would have the potential to replace the chronic bioassay in rodents in some circumstances and could serve a analternative to a chronic bioassay in a second species. ... 

Trout have thus become adopted and established as a model of carcinogenesis for a number of reasons. In summary, they (i) have low rearing costs compared to rodents, (ii) provide a highly sensitive early life-stage bioassay, (iii) are sensitive to a wide variety of carcinogens, (iv) are responsive to promoters and inhibitors, (v) have a well-defined tumor pathology, (vi) are mechanistically comparable to mammalian models and (vii) provide more tissues for analysis compared with smaller aquarium fish. 

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