An evaluation of chronic 6- and 12-month rat toxicology studies as predictors of 2-year tumor outcome.

Chronic 6- and 12-month rat toxicology studies were evaluated for their ability to predict tumor outcome in 2-year rat carcinogenicity studies for 80 pharmaceuticals from commercial and Merck databases. The data consisted of 62 (6-month) and 54 (12-month) studies, which included 30 rat carcinogens and 50 noncarcinogens in 2-year studies. The histopathology findings considered as evidence of potential preneoplasia in the chronic studies were hyperplasia, cellular hypertrophy, and atypical cellular foci. The authors hypothesized that a whole animal-based approach should be taken, wherein (1) evidence of potential preneoplasia in any tissue may serve as a sensitive predictor of tumor outcome in any tissue in the whole animal and not necessarily the same tissue and (2) the absence of evidence for potential preneoplasia in all tissues may serve as a strong negative predictor of tumor outcome in any tissue. Based on this whole animal approach, 25 of 30 rat carcinogens showed histopathologic signals in chronic toxicology studies, yielding a test sensitivity of 83%. The negative predictivity of the absence of histopathology findings in chronic toxicology studies of 50 nontumorigenic compounds was 88%. The value of the extra 6-month treatment was not apparent. The 5 false negatives (negative chronic studies but positive 2-year studies) are for marketed drugs approved for non-life-threatening conditions and associated with rat-specific mechanisms. The absence of preneoplasia in the whole animal is a reliable predictor of negative tumor outcome in 2-year rat studies, and approximately 50% rat carcinogenicity studies could be eliminated for the 80 pharmaceuticals examined, with no risk to humans and with a substantial reduction in animal usage and drug development time.