Prediction of Rodent Carcinogenesis: An Evaluation of Prechronic Liver Lesions as Forecasters of Liver Tumors in NTP Carcinogenicity Studies

Abstract

The National Toxicology Program (NTP) developed the chronic 2-year bioassay as a mechanism for predicting the carcinogenic potential of chemicals in humans. The cost and duration of these studies has limited their use to small numbers of selected chemicals. Many different short-term methods aimed at increasing predictive accuracy and the number of chemicals evaluated have been developed in attempts to successfully correlate their results with evidence of carcinogenicity (or lack of carcinogenicity). Using NTP studies, the effectiveness of correlating prechronic liver lesions with liver cancer encompassing multiple studies using mice (83 compounds) and rats (87 compounds) was assessed. These lesions include hepatocellular necrosis, hepatocellular hypertrophy, hepatocellular cytomegaly, bile duct hyperplasia, and hepatocellular degeneration, along with increased liver weight. Our results indicate that pooling 3 of these prechronic data points (hepatocellular necrosis, hepatocellular hypertrophy, and hepatocellular cytomegaly) can be very predictive of carcinogenicity in the 2-year study (p < 0.05). The inclusion of increased liver weight as an endpoint in the pool of data points increases the number of rodent liver carcinogens that are successfully predicted (p < 0.05), but also results in the prediction of increased numbers of noncarcinogenic chemicals as carcinogens. The use of multiple prechronic study endpoints provides supplementary information that enhances the predictivity of identifying chemicals with carcinogenic potential.

Keywords

Rat mouse prechronic toxicity liver tumors carcinogenicity bioassay.

References

Aardema, M.J. , Isfort, R.J. , Thompson, E.D. , and LeBoeuf, R.A. (1996). The low pH Syrian hamster embryo (SHE) cell transformation assay: a revitalized role in carcinogen prediction. Mutat Res 356, 5—9.

Ashby, J. (1996). Alternatives to the 2-species bioassay for the identification of potential human carcinogens. Hum Exp Toxicol 15, 183—202.

Ashby, J. , and Tennant, R.W. (1994). Prediction of rodent carcinogenicity for 44 chemicals: results. Mutagenesis 9, 7—15.

Cunningham, A.R. , Klopman, G. , and Rosenkranz, H.S. (1998). Identification of structural features and associated mechanisms of action for carcinogens in rats. Mutat Res 405, 9—27.

Elcombe, C.R. , Odum, J. , Foster, J.R. , Stone, S. , Hasmall, S. , Soames, A.R. , Kimber, I. , and Ashby, J. (2002). Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens. Environ Health Perspect 110, 363—75.

Foster, J.R. (1997). The role of cell proliferation in chemically induced carcinogenesis. J Comp Pathol 116, 113—44.

Huff, J. (1999). Long-term chemical carcinogenesis bioassays predict human cancer hazards. Issues, controversies, and uncertainties. Ann NY Acad Sci 895, 56—79.

Richard, A.M. (1998). Structure-based methods for predicting mutagenicity and carcinogenicity: are we there yet? Mutat Res 400, 493—507.

Spalding, J.W. , French, J.E. , Stasiewicz, S. , Furedi-Machacek, M. , Conner, F. , Tice, R.R. , and Tennant, R.W. (2000). Responses of transgenic mouse lines p53() and Tg.AC to agents tested in conventional carcinogenicity bioassays. Toxicol Sci 53, 213—23.

10.

Tennant, R.W. , French, J.E. , and Spalding, J.W. (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect 103, 942—50.

11.

Ward, J.M. , and Ito, N. (1988). Development of new medium-term bioassays for carcinogens . Cancer Res 48, 5051—4.